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Regulation of signal transduction by HDL1

Open AccessPublished:May 18, 2013DOI:https://doi.org/10.1194/jlr.R039479
      High density lipoprotein (HDL) cholesterol has direct effects on numerous cell types that influence cardiovascular and metabolic health. These include endothelial cells, vascular smooth-muscle cells, leukocytes, platelets, adipocytes, skeletal muscle myocytes, and pancreatic β cells. The effects of HDL or apoA-I, its major apolipoprotein, occur through the modulation of intracellular calcium, oxygen-derived free-radical production, numerous kinases, and enzymes, including endothelial nitric-oxide synthase (eNOS). ApoA-I and HDL also influence gene expression, particularly genes encoding mediators of inflammation in vascular cells. In many paradigms, the change in intracellular signaling occurs as a result of cholesterol efflux, with the cholesterol acceptor methyl-β-cyclodextrin often invoking responses identical to HDL or apoA-I. The ABC transporters ABCA1 and ABCG1 and scavenger receptor class B, type I (SR-BI) frequently participate in the cellular responses. Structure-function relationships are emerging for signal initiation by ABCA1 and SR-BI, with plasma membrane cholesterol binding by the C-terminal transmembrane domain of SR-BI uniquely enabling it to serve as a sensor of changes in membrane cholesterol. Further investigation of the processes underlying HDL and apoA-I modulation of intracellular signaling will potentially reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.
      Our understanding of how high density lipoprotein (HDL) cholesterol potentially modifies cardiovascular and metabolic disease risk or outcome has expanded beyond its participation in reverse cholesterol transport (RCT), in which HDL serves to shuttle cholesterol from peripheral tissues or cells to the liver. This review highlights recent advances in our knowledge of HDL-initiated processes mediated by changes in intracellular signaling in numerous cell types of relevance to both cardiovascular and metabolic conditions, which represent actions of the lipoprotein beyond its classical role in global cholesterol homeostasis. The evidence that HDL influences cardiovascular and metabolic health and disease will first be briefly summarized. Responses to HDL or to apoA-I, its major apolipoprotein, in cellular targets directly involved in vascular biology will then be reviewed, followed by a summary of the mechanisms that HDL influences in cell types participating in energy and glucose homeostasis. The processes underlying apoA-I- or HDL-induced changes in intracellular signaling will then be discussed, and finally presently unanswered questions in this realm of HDL biology will be considered. Although HDL cargo molecules can contribute to cellular responses to the lipoprotein (
      • Hammad S.M.
      Blood sphingolipids in homeostasis and pathobiology.
      ,
      • Heinecke J.W.
      The protein cargo of HDL: implications for vascular wall biology and therapeutics.
      ), herein emphasis will be placed primarily on signaling events directly induced by apoA-I or HDL, which are likely occurring in response to cholesterol efflux. To help leverage our present understanding of apoA-I- or HDL-initiated signaling in future studies, the signaling events and the proteins or mediators whose abundance or activity is altered by apoA-I or HDL in various cell types are summarized in Tables 1 and 2.
      TABLE 1Signaling modulated by apoA-I or HDL
      Process or Signaling MoleculeCell TypeReference
      Intracellular calciumEndothelium, platelet, macrophage(
      • Suc I.
      • Escargueil-Blanc I.
      • Troly M.
      • Salvayre R.
      • Negre-Salvayre A.
      HDL and ApoA prevent cell death of endothelial cells induced by oxidized LDL.
      ), (
      • Honda H.M.
      • Wakamatsu B.K.
      • Goldhaber J.I.
      • Berliner J.A.
      • Navab M.
      • Weiss J.N.
      High-density lipoprotein increases intracellular calcium levels by releasing calcium from internal stores in human endothelial cells.
      ), (
      • Nofer J.R.
      • van der Giet M.
      • Tolle M.
      • Wolinska I.
      • von Wnuck L.K.
      • Baba H.A.
      • Tietge U.J.
      • Godecke A.
      • Ishii I.
      • Kleuser B.
      • et al.
      HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3.
      ), (
      • Li X.A.
      • Titlow W.B.
      • Jackson B.A.
      • Giltiay N.
      • Nikolova-Karakashian M.
      • Uittenbogaard A.
      • Smart E.J.
      High density lipoprotein binding to scavenger receptor, class B, type I activates endothelial nitric-oxide synthase in a ceramide-dependent manner.
      ), (
      • Knorr M.
      • Locher R.
      • Vogt E.
      • Vetter W.
      • Block L.H.
      • Ferracin F.
      • Lefkovits H.
      • Pletscher A.
      Rapid activation of human platelets by low concentrations of low-density lipoprotein via phosphatidylinositol cycle.
      ), (
      • Takahashi Y.
      • Smith J.D.
      Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.
      )
      Oxygen-derived free radicalsEndothelium, VSM, adipocyte(
      • Tolle M.
      • Pawlak A.
      • Schuchardt M.
      • Kawamura A.
      • Tietge U.J.
      • Lorkowski S.
      • Keul P.
      • Assmann G.
      • Chun J.
      • Levkau B.
      • et al.
      HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
      ), (
      • Nofer J.R.
      • Levkau B.
      • Wolinska I.
      • Junker R.
      • Fobker M.
      • von Eckardstein A.
      • Seedorf U.
      • Assmann G.
      Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids.
      ), (
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      )
      eNOSEndothelium, EPC(
      • Feng Y.
      • Van Eck M.
      • Van Craeyveld E.
      • Jacobs F.
      • Carlier V.
      • Van Linthout S.
      • Erdel M.
      • Tjwa M.
      • De Geest B.
      Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer.
      ), (
      • Yuhanna I.S.
      • Zhu Y.
      • Cox B.E.
      • Hahner L.D.
      • Osborne-Lawrence S.
      • Lu P.
      • Marcel Y.L.
      • Anderson R.G.
      • Mendelsohn M.E.
      • Hobbs H.H.
      • et al.
      High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
      )
      Akt kinaseEndothelium, EPC, adipocyte, β cell(
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ), (
      • Nofer J.R.
      • Levkau B.
      • Wolinska I.
      • Junker R.
      • Fobker M.
      • von Eckardstein A.
      • Seedorf U.
      • Assmann G.
      Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids.
      ), (
      • Zhang Q.
      • Yin H.
      • Liu P.
      • Zhang H.
      • She M.
      Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway.
      ), (
      • Mineo C.
      • Yuhanna I.S.
      • Quon M.J.
      • Shaul P.W.
      High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases.
      ), (
      • Roehrich M.E.
      • Mooser V.
      • Lenain V.
      • Herz J.
      • Nimpf J.
      • Azhar S.
      • Bideau M.
      • Capponi A.
      • Nicod P.
      • Haefliger J.A.
      • et al.
      Insulin-secreting beta-cell dysfunction induced by human lipoproteins.
      )
      PI3 kinaseEndothelium, EPC, adipocyte(
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ), (
      • Seetharam D.
      • Mineo C.
      • Gormley A.K.
      • Gibson L.L.
      • Vongpatanasin W.
      • Chambliss K.L.
      • Hahner L.D.
      • Cummings M.L.
      • Kitchens R.L.
      • Marcel Y.L.
      • et al.
      High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
      ), (
      • Zhang Q.
      • Yin H.
      • Liu P.
      • Zhang H.
      • She M.
      Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway.
      ), (
      • Mineo C.
      • Yuhanna I.S.
      • Quon M.J.
      • Shaul P.W.
      High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases.
      ), (
      • Van Linthout S.
      • Foryst-Ludwig A.
      • Spillmann F.
      • Peng J.
      • Feng Y.
      • Meloni M.
      • Van Craeyveld E.
      • Kintscher U.
      • Schultheiss H.P.
      • De Geest B.
      • et al.
      Impact of HDL on adipose tissue metabolism and adiponectin expression.
      )
      G proteinsEndothelium(
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ), (
      • Miura S.
      • Fujino M.
      • Matsuo Y.
      • Kawamura A.
      • Tanigawa H.
      • Nishikawa H.
      • Saku K.
      High density lipoprotein-induced angiogenesis requires the activation of Ras/MAP kinase in human coronary artery endothelial cells.
      )
      p38 MAP kinaseEndothelium, platelet(
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ), (
      • Relou A.M.
      • Gorter G.
      • van Rijn H.J.
      • Akkerman J.W.
      Platelet activation by the apoB/E receptor-binding domain of LDL.
      )
      Rho kinaseEndothelium, fibroblast(
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ), (
      • Viswambharan H.
      • Ming X.F.
      • Zhu S.
      • Hubsch A.
      • Lerch P.
      • Vergeres G.
      • Rusconi S.
      • Yang Z.
      Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase.
      ), (
      • Okuhira K.
      • Fitzgerald M.L.
      • Tamehiro N.
      • Ohoka N.
      • Suzuki K.
      • Sawada J.
      • Naito M.
      • Nishimaki-Mogami T.
      Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation.
      )
      RasEndothelium(
      • Miura S.
      • Fujino M.
      • Matsuo Y.
      • Kawamura A.
      • Tanigawa H.
      • Nishikawa H.
      • Saku K.
      High density lipoprotein-induced angiogenesis requires the activation of Ras/MAP kinase in human coronary artery endothelial cells.
      )
      p42/44 MAP kinaseEndothelium, EPC(
      • Feng Y.
      • Van Eck M.
      • Van Craeyveld E.
      • Jacobs F.
      • Carlier V.
      • Van Linthout S.
      • Erdel M.
      • Tjwa M.
      • De Geest B.
      Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer.
      ), (
      • Mineo C.
      • Yuhanna I.S.
      • Quon M.J.
      • Shaul P.W.
      High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases.
      )
      Rac GTPaseEndothelium, VSM(
      • Tolle M.
      • Pawlak A.
      • Schuchardt M.
      • Kawamura A.
      • Tietge U.J.
      • Lorkowski S.
      • Keul P.
      • Assmann G.
      • Chun J.
      • Levkau B.
      • et al.
      HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
      ), (
      • Seetharam D.
      • Mineo C.
      • Gormley A.K.
      • Gibson L.L.
      • Vongpatanasin W.
      • Chambliss K.L.
      • Hahner L.D.
      • Cummings M.L.
      • Kitchens R.L.
      • Marcel Y.L.
      • et al.
      High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
      )
      Src kinaseEndothelium(
      • Seetharam D.
      • Mineo C.
      • Gormley A.K.
      • Gibson L.L.
      • Vongpatanasin W.
      • Chambliss K.L.
      • Hahner L.D.
      • Cummings M.L.
      • Kitchens R.L.
      • Marcel Y.L.
      • et al.
      High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
      ), (
      • Mineo C.
      • Yuhanna I.S.
      • Quon M.J.
      • Shaul P.W.
      High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases.
      )
      AMPKEndothelium, skeletal muscle, adipocyte(
      • Han R.
      • Lai R.
      • Ding Q.
      • Wang Z.
      • Luo X.
      • Zhang Y.
      • Cui G.
      • He J.
      • Liu W.
      • Chen Y.
      Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism.
      ), (
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ), (
      • Kimura T.
      • Tomura H.
      • Sato K.
      • Ito M.
      • Matsuoka I.
      • Im D.S.
      • Kuwabara A.
      • Mogi C.
      • Itoh H.
      • Kurose H.
      • et al.
      Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells.
      )
      CaMKKEndothelium(
      • Kimura T.
      • Tomura H.
      • Sato K.
      • Ito M.
      • Matsuoka I.
      • Im D.S.
      • Kuwabara A.
      • Mogi C.
      • Itoh H.
      • Kurose H.
      • et al.
      Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells.
      )
      LKB1Endothelium(
      • Kimura T.
      • Tomura H.
      • Sato K.
      • Ito M.
      • Matsuoka I.
      • Im D.S.
      • Kuwabara A.
      • Mogi C.
      • Itoh H.
      • Kurose H.
      • et al.
      Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells.
      )
      JAK2Macrophage(
      • Tang C.
      • Vaughan A.M.
      • Oram J.F.
      Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.
      )
      STAT3Macrophage(
      • Tang C.
      • Vaughan A.M.
      • Oram J.F.
      Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.
      )
      GSK3Skeletal muscle(
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      )
      Adenylate cyclaseFibroblast(
      • Haidar B.
      • Denis M.
      • Marcil M.
      • Krimbou L.
      • Genest Jr, J.
      Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter.
      )
      Cdc42Fibroblast(
      • Nofer J.R.
      • Remaley A.T.
      • Feuerborn R.
      • Wolinnska I.
      • Engel T.
      • von Eckardstein A.
      • Assmann G.
      Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter.
      )
      TABLE 2Protein or mediator abundance or activity modulated by apoA-I or HDL
      Protein or MediatorCell TypeReference
      Caspase 3 and 9 (downregulation)Endothelium, β cell(
      • Sugano M.
      • Tsuchida K.
      • Makino N.
      High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis.
      ), (
      • Nofer J.R.
      • Levkau B.
      • Wolinska I.
      • Junker R.
      • Fobker M.
      • von Eckardstein A.
      • Seedorf U.
      • Assmann G.
      Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids.
      ), (
      • Roehrich M.E.
      • Mooser V.
      • Lenain V.
      • Herz J.
      • Nimpf J.
      • Azhar S.
      • Bideau M.
      • Capponi A.
      • Nicod P.
      • Haefliger J.A.
      • et al.
      Insulin-secreting beta-cell dysfunction induced by human lipoproteins.
      )
      VCAM-1 (downregulation)Endothelium(
      • Cockerill G.W.
      • Rye K.A.
      • Gamble J.R.
      • Vadas M.A.
      • Barter P.J.
      High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.
      ), (
      • Kimura T.
      • Tomura H.
      • Mogi C.
      • Kuwabara A.
      • Damirin A.
      • Ishizuka T.
      • Sekiguchi A.
      • Ishiwara M.
      • Im D.S.
      • Sato K.
      • et al.
      Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells.
      )
      ICAM-1 (downregulation)Endothelium(
      • Cockerill G.W.
      • Rye K.A.
      • Gamble J.R.
      • Vadas M.A.
      • Barter P.J.
      High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.
      ), (
      • Kimura T.
      • Tomura H.
      • Mogi C.
      • Kuwabara A.
      • Damirin A.
      • Ishizuka T.
      • Sekiguchi A.
      • Ishiwara M.
      • Im D.S.
      • Sato K.
      • et al.
      Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells.
      )
      DHCR24 (upregulation)Endothelium(
      • Wu B.J.
      • Chen K.
      • Shrestha S.
      • Ong K.L.
      • Barter P.J.
      • Rye K.A.
      High-density lipoproteins inhibit vascular endothelial inflammation by increasing 3beta-hydroxysteroid-Delta24 reductase expression and inducing heme oxygenase-1.
      )
      HO-1 (upregulation)Endothelium(
      • Wu B.J.
      • Chen K.
      • Shrestha S.
      • Ong K.L.
      • Barter P.J.
      • Rye K.A.
      High-density lipoproteins inhibit vascular endothelial inflammation by increasing 3beta-hydroxysteroid-Delta24 reductase expression and inducing heme oxygenase-1.
      )
      E-selectin (downregulation)Endothelium(
      • Cockerill G.W.
      • Rye K.A.
      • Gamble J.R.
      • Vadas M.A.
      • Barter P.J.
      High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.
      )
      eNOS (upregulation)Endothelium, EPC(
      • Ramet M.E.
      • Ramet M.
      • Lu Q.
      • Nickerson M.
      • Savolainen M.J.
      • Malzone A.
      • Karas R.H.
      High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life.
      ), (
      • Noor R.
      • Shuaib U.
      • Wang C.X.
      • Todd K.
      • Ghani U.
      • Schwindt B.
      • Shuaib A.
      High-density lipoprotein cholesterol regulates endothelial progenitor cells by increasing eNOS and preventing apoptosis.
      )
      COX-2 (upregulation)VSM(
      • Vinals M.
      • Martinez-Gonzalez J.
      • Badimon J.J.
      • Badimon L.
      HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2).
      )
      MCP-1 (downregulation)VSM, adipocyte(
      • Tolle M.
      • Pawlak A.
      • Schuchardt M.
      • Kawamura A.
      • Tietge U.J.
      • Lorkowski S.
      • Keul P.
      • Assmann G.
      • Chun J.
      • Levkau B.
      • et al.
      HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
      ), (
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      )
      CD11b (downregulation)Monocyte, neutrophil(
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ), (
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      )
      Cytokines (downregulation)Monocyte, macrophage(
      • Carpintero R.
      • Gruaz L.
      • Brandt K.J.
      • Scanu A.
      • Faille D.
      • Combes V.
      • Grau G.E.
      • Burger D.
      HDL interfere with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production.
      ), (
      • Tang C.
      • Liu Y.
      • Kessler P.S.
      • Vaughan A.M.
      • Oram J.F.
      The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor.
      )
      NF-kB (downregulation)Endothelium(
      • Cheng A.M.
      • Handa P.
      • Tateya S.
      • Schwartz J.
      • Tang C.
      • Mitra P.
      • Oram J.F.
      • Chait A.
      • Kim F.
      Apolipoprotein A-I attenuates palmitate-mediated NF-kappaB activation by reducing Toll-like receptor-4 recruitment into lipid rafts.
      )
      Prostacyclin (upregulation)Endothelium(
      • Fleisher L.N.
      • Tall A.R.
      • Witte L.D.
      • Miller R.W.
      • Cannon P.J.
      Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins.
      )
      Platelet-activating factor (downregulation)Endothelium(
      • Sugatani J.
      • Miwa M.
      • Komiyama Y.
      • Ito S.
      High-density lipoprotein inhibits the synthesis of platelet-activating factor in human vascular endothelial cells.
      )
      Thromboxane A2 (downregulation)Endothelium(
      • Oravec S.
      • Demuth K.
      • Myara I.
      • Hornych A.
      The effect of high density lipoprotein subfractions on endothelial eicosanoid secretion.
      )
      Tissue factor (downregulation)Endothelium(
      • Viswambharan H.
      • Ming X.F.
      • Zhu S.
      • Hubsch A.
      • Lerch P.
      • Vergeres G.
      • Rusconi S.
      • Yang Z.
      Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase.
      )
      SOD1, SOD2 (upregulation)Macrophage(
      • Tabet F.
      • Lambert G.
      • Cuesta Torres L.F.
      • Hou L.
      • Sotirchos I.
      • Touyz R.M.
      • Jenkins A.J.
      • Barter P.J.
      • Rye K.A.
      Lipid-free apolipoprotein A-I and discoidal reconstituted high-density lipoproteins differentially inhibit glucose-induced oxidative stress in human macrophages.
      )
      Nox2 (downregulation)Macrophage(
      • Tabet F.
      • Lambert G.
      • Cuesta Torres L.F.
      • Hou L.
      • Sotirchos I.
      • Touyz R.M.
      • Jenkins A.J.
      • Barter P.J.
      • Rye K.A.
      Lipid-free apolipoprotein A-I and discoidal reconstituted high-density lipoproteins differentially inhibit glucose-induced oxidative stress in human macrophages.
      )
      Uncoupling protein I (upregulation)Brown adipocyte(
      • Ruan X.
      • Li Z.
      • Zhang Y.
      • Yang L.
      • Pan Y.
      • Wang Z.
      • Feng G.S.
      • Chen Y.
      Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat.
      )
      Adiponectin (upregulation)Adipocyte(
      • Van Linthout S.
      • Foryst-Ludwig A.
      • Spillmann F.
      • Peng J.
      • Feng Y.
      • Meloni M.
      • Van Craeyveld E.
      • Kintscher U.
      • Schultheiss H.P.
      • De Geest B.
      • et al.
      Impact of HDL on adipose tissue metabolism and adiponectin expression.
      )
      SAA3 (downregulation)Adipocyte(
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      )

      HDL AND CARDIOVASCULAR AND METABOLIC DISEASE

      Studies of the relationship between circulating concentrations of HDL and atherosclerosis and cardiovascular events have suggested that disease risk is inversely related to HDL level (
      • Fidge N.H.
      High density lipoprotein receptors, binding proteins, and ligands.
      ,
      • Gordon D.J.
      • Rifkind B.M.
      High-density lipoprotein–the clinical implications of recent studies.
      ). Even in patients treated aggressively with statins to decrease circulating low-density lipoprotein (LDL) cholesterol to less than 70 mg/dl, HDL levels may continue to be inversely related to the risk of major cardiovascular events (
      • Barter P.
      • Gotto A.M.
      • LaRosa J.C.
      • Maroni J.
      • Szarek M.
      • Grundy S.M.
      • Kastelein J.J.
      • Bittner V.
      • Fruchart J.C.
      HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
      ). However, genetic analyses of mechanisms that regulate plasma HDL have yielded conflicting results regarding the relationship between HDL abundance and disease risk (
      • Ridker P.M.
      • Pare G.
      • Parker A.N.
      • Zee R.Y.
      • Miletich J.P.
      • Chasman D.I.
      Polymorphism in the CETP gene region, HDL cholesterol, and risk of future myocardial infarction: genomewide analysis among 18 245 initially healthy women from the Women's Genome Health Study.
      ,
      • Voight B.F.
      • Peloso G.M.
      • Orho-Melander M.
      • Frikke-Schmidt R.
      • Barbalic M.
      • Jensen M.K.
      • Hindy G.
      • Holm H.
      • Ding E.L.
      • Johnson T.
      • et al.
      Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study.
      ), and the findings of studies of interventions aimed at raising HDL have also been mixed (
      • Barter P.
      • Gotto A.M.
      • LaRosa J.C.
      • Maroni J.
      • Szarek M.
      • Grundy S.M.
      • Kastelein J.J.
      • Bittner V.
      • Fruchart J.C.
      HDL cholesterol, very low levels of LDL cholesterol, and cardiovascular events.
      ,
      • Brown B.G.
      • Zhao X.Q.
      • Chait A.
      • Fisher L.D.
      • Cheung M.C.
      • Morse J.S.
      • Dowdy A.A.
      • Marino E.K.
      • Bolson E.L.
      • Alaupovic P.
      • et al.
      Simvastatin and niacin, antioxidant vitamins, or the combination for the prevention of coronary disease.
      ,
      • Rubins H.B.
      • Robins S.J.
      • Collins D.
      • Fye C.L.
      • Anderson J.W.
      • Elam M.B.
      • Faas F.H.
      • Linares E.
      • Schaefer E.J.
      • Schectman G.
      • et al.
      Gemfibrozil for the secondary prevention of coronary heart disease in men with low levels of high-density lipoprotein cholesterol. Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial Study Group.
      ,
      • Boden W.E.
      High-density lipoprotein cholesterol as an independent risk factor in cardiovascular disease: assessing the data from Framingham to the Veterans Affairs High-Density Lipoprotein Intervention Trial.
      • Boden W.E.
      • Probstfield J.L.
      • Anderson T.
      • Chaitman B.R.
      • Svignes-Nickens P.
      • Koprowicz K.
      • McBride R.
      • Teo K.
      • Weintraub W.
      Niacin in patients with low HDL cholesterol levels receiving intensive statin therapy.
      ). From a mechanistic perspective, HDL classically functions in RCT, removing cholesterol from peripheral tissues and cells, such as macrophages, and delivering it to the liver and to steroidogenic organs by binding of apoA-I to the high-affinity HDL receptor scavenger receptor, class B, type I (SR-BI) (
      • Krieger M.
      Charting the fate of the “good cholesterol”: identification and characterization of the high-density lipoprotein receptor SR-BI.
      ,
      • Connelly M.A.
      • Williams D.L.
      Scavenger receptor BI: a scavenger receptor with a mission to transport high density lipoprotein lipids.
      ). In mouse models of atherosclerosis, both apoA-I and SR-BI provide atheroprotection (
      • Braun A.
      • Trigatti B.L.
      • Post M.J.
      • Sato K.
      • Simons M.
      • Edelberg J.M.
      • Rosenberg R.D.
      • Schrenzel M.
      • Kriege M.
      Loss of SR-BI expression leads to the early onset of occlusive atherosclerotic coronary artery disease, spontaneous myocardial infarctions, severe cardiac dysfunction, and premature death in apolipoprotein E-deficient mice.
      ,
      • Rong J.X.
      • Li J.
      • Reis E.D.
      • Choudhury R.P.
      • Dansky H.M.
      • Elmalem V.I.
      • Fallon J.T.
      • Breslow J.L.
      • Fisher E.A.
      Elevating high-density lipoprotein cholesterol in apolipoprotein E-deficient mice remodels advanced atherosclerotic lesions by decreasing macrophage and increasing smooth muscle cell content.
      ), and the provision of apoA-I or HDL also attenuates neointima formation after artery injury in the context of experimental hypercholesterolemia (
      • Ameli S.
      • Hultgardh-Nilsson A.
      • Cercek B.
      • Shah P.K.
      • Forrester J.S.
      • Ageland H.
      • Nilsson J.
      Recombinant apolipoprotein A-I Milano reduces intimal thickening after balloon injury in hypercholesterolemic rabbits.
      ,
      • De Geest B.
      • Zhao Z.
      • Collen D.
      • Holvoet P.
      Effects of adenovirus-mediated human apo A-I gene transfer on neointima formation after endothelial denudation in apo E-deficient mice.
      ). The potential protective nature of HDL has been principally attributed to its ability to promote RCT by accepting cholesterol from lipid-laden macrophages (
      • Tall A.R.
      Cholesterol efflux pathways and other potential mechanisms involved in the athero-protective effect of high density lipoproteins.
      ,
      • Rosenson R.S.
      • Brewer Jr, H.B.
      • Davidson W.S.
      • Fayad Z.A.
      • Fuster V.
      • Goldstein J.
      • Hellerstein M.
      • Jiang X.C.
      • Phillips M.C.
      • Rader D.J.
      • et al.
      Cholesterol efflux and atheroprotection: advancing the concept of reverse cholesterol transport.
      ). However, there are other actions of the lipoprotein likely relevant to cardiovascular protection, including direct effects on endothelium (
      • Mineo C.
      • Shaul P.W.
      Novel biological functions of high-density lipoprotein cholesterol.
      ), vascular smooth muscle (
      • Vinals M.
      • Martinez-Gonzalez J.
      • Badimon J.J.
      • Badimon L.
      HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2).
      ,
      • Tamama K.
      • Tomura H.
      • Sato K.
      • Malchinkhuu E.
      • Damirin A.
      • Kimura T.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component.
      ,
      • Damirin A.
      • Tomura H.
      • Komachi M.
      • Liu J.P.
      • Mogi C.
      • Tobo M.
      • Wang J.Q.
      • Kimura T.
      • Kuwabara A.
      • Yamazaki Y.
      • et al.
      Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells.
      • Tolle M.
      • Pawlak A.
      • Schuchardt M.
      • Kawamura A.
      • Tietge U.J.
      • Lorkowski S.
      • Keul P.
      • Assmann G.
      • Chun J.
      • Levkau B.
      • et al.
      HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
      ), leukocytes (
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ,
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      ), and platelets (
      • Lerch P.G.
      • Spycher M.O.
      • Doran J.E.
      Reconstituted high density lipoprotein (rHDL) modulates platelet activity in vitro and ex vivo.
      ,
      • Calkin A.C.
      • Drew B.G.
      • Ono A.
      • Duffy S.J.
      • Gordon M.V.
      • Schoenwaelder S.M.
      • Sviridov D.
      • Cooper M.E.
      • Kingwell B.A.
      • Jackson S.P.
      Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux.
      ). Evaluations of HDL function have received considerable attention recently as potential means to interrogate the characteristics of the lipoprotein and how they relate to cardiovascular disease risk and severity. These include assessments of cholesterol efflux capacity from macrophages (
      • Khera A.V.
      • Cuchel M.
      • Llera-Moya M.
      • Rodrigues A.
      • Burke M.F.
      • Jafri K.
      • French B.C.
      • Phillips J.A.
      • Mucksavage M.L.
      • Wilensky R.L.
      • et al.
      Cholesterol efflux capacity, high-density lipoprotein function, and atherosclerosis.
      ,

      Li X. M. Tang W. H.Mosior M. K. Huang Y. Wu Y. Matter W. Gao V. Schmitt D. Didonato J. A. Fisher E. A.. Paradoxical association of enhanced cholesterol efflux with increased incident cardiovascular risks. Arterioscler. Thromb. Vasc. Biol., Epub ahead of print. March 21, 2013; doi:10.1161/ATVBAHA.113.301373.

      ) and direct actions of HDL on endothelium (
      • Ansell B.J.
      • Navab M.
      • Hama S.
      • Kamranpour N.
      • Fonarow G.
      • Hough G.
      • Rahmani S.
      • Mottahedeh R.
      • Dave R.
      • Reddy S.T.
      • et al.
      Inflammatory/antiinflammatory properties of high-density lipoprotein distinguish patients from control subjects better than high-density lipoprotein cholesterol levels and are favorably affected by simvastatin treatment.
      ,
      • Besler C.
      • Heinrich K.
      • Rohrer L.
      • Doerries C.
      • Riwanto M.
      • Shih D.M.
      • Chroni A.
      • Yonekawa K.
      • Stein S.
      • Schaefer N.
      • et al.
      Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease.
      ).
      In addition to its relationship with atherosclerosis and cardiovascular events, there is a recognized association between HDL and insulin sensitivity, with low HDL levels and dysfunctional HDL associated with insulin resistance and type 2 diabetes (
      • Eckel R.H.
      • Grundy S.M.
      • Zimmet P.Z.
      The metabolic syndrome.
      ). Possible effects of HDL on glucose regulation are evident from studies in humans as well as experimental models. The administration of reconstituted HDL to patients with type 2 diabetes causes a fall in plasma glucose (
      • Drew B.G.
      • Duffy S.J.
      • Formosa M.F.
      • Natoli A.K.
      • Henstridge D.C.
      • Penfold S.A.
      • Thomas W.G.
      • Mukhamedova N.
      • de Courten B.
      • Forbes J.M.
      • et al.
      High-density lipoprotein modulates glucose metabolism in patients with type 2 diabetes mellitus.
      ), and apoA-I−/− mice have fasting hyperglycemia and hyperinsulinemia and abnormal glucose tolerance tests (
      • Han R.
      • Lai R.
      • Ding Q.
      • Wang Z.
      • Luo X.
      • Zhang Y.
      • Cui G.
      • He J.
      • Liu W.
      • Chen Y.
      Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism.
      ). In addition, HDL directly modifies the functions of cell types involved in glucose homeostasis, including pancreatic β cells (
      • Fryirs M.A.
      • Barter P.J.
      • Appavoo M.
      • Tuch B.E.
      • Tabet F.
      • Heather A.K.
      • Rye K.A.
      Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.
      ), skeletal muscle myocytes (
      • Han R.
      • Lai R.
      • Ding Q.
      • Wang Z.
      • Luo X.
      • Zhang Y.
      • Cui G.
      • He J.
      • Liu W.
      • Chen Y.
      Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism.
      ,
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ), and adipocytes (
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ). It has also been found that apoA-I has antiobesity effects, with transgenic mice overexpressing apoA-I and mice administered apoA-I mimetic D-4F demonstrating protection from increased adiposity caused by high-fat diet feeding (
      • Ruan X.
      • Li Z.
      • Zhang Y.
      • Yang L.
      • Pan Y.
      • Wang Z.
      • Feng G.S.
      • Chen Y.
      Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat.
      ). In ob/ob mice, the apoA-I mimetic L-4F attenuates adiposity and causes an improvement in glucose tolerance (
      • Peterson S.J.
      • Drummond G.
      • Kim D.H.
      • Li M.
      • Kruger A.L.
      • Ikehara S.
      • Abraham N.G.
      L-4F treatment reduces adiposity, increases adiponectin levels, and improves insulin sensitivity in obese mice.
      ). Conversely, type 2 diabetes and its associated hyperlipidemia and hyperglycemia negatively impact not only HDL abundance but also HDL quality, resulting in more glycated and triglyceride-rich HDL (
      • Taskinen M.R.
      Quantitative and qualitative lipoprotein abnormalities in diabetes mellitus.
      ,
      • Biesbroeck R.C.
      • Albers J.J.
      • Wahl P.W.
      • Weinberg C.R.
      • Bassett M.L.
      • Bierman E.L.
      Abnormal composition of high density lipoproteins in non-insulin-dependent diabetics.
      ). Mirroring the recent interest in evaluating HDL function in subjects with cardiovascular disease, the cellular actions of HDL isolated from diabetic and obese individuals have been studied (
      • Persegol L.
      • Verges B.
      • Foissac M.
      • Gambert P.
      • Duvillard L.
      Inability of HDL from type 2 diabetic patients to counteract the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation.
      ,
      • Persegol L.
      • Foissac M.
      • Lagrost L.
      • Athias A.
      • Gambert P.
      • Verges B.
      • Duvillard L.
      HDL particles from type 1 diabetic patients are unable to reverse the inhibitory effect of oxidised LDL on endothelium-dependent vasorelaxation.
      ,
      • Persegol L.
      • Verges B.
      • Gambert P.
      • Duvillard L.
      Inability of HDL from abdominally obese subjects to counteract the inhibitory effect of oxidized LDL on vasorelaxation.
      • Sorrentino S.A.
      • Besler C.
      • Rohrer L.
      • Meyer M.
      • Heinrich K.
      • Bahlmann F.H.
      • Mueller M.
      • Horvath T.
      • Doerries C.
      • Heinemann M.
      • et al.
      Endothelial-vasoprotective effects of high-density lipoprotein are impaired in patients with type 2 diabetes mellitus but are improved after extended-release niacin therapy.
      ). In the midst of attempts to better understand how HDL impacts both cardiovascular and metabolic health and how HDL function may be altered in various patient populations, diverse intracellular signaling events modulated by apoA-I or the lipoprotein have been identified.

      HDL SIGNALING IN VASCULAR CELLS

      Endothelial cells

      Studies of the direct impact of HDL on endothelial cell apoptosis were some of the first to indicate that the lipoprotein alters intracellular signaling in endothelium. Oxidized LDL (OxLDL) causes a delayed but sustained increase in intracellular calcium in endothelial cells that results in cell death, and this is reversed by HDL via prevention of the increase in intracellular calcium. Purified apoA-I provides the same protection as native HDL, and it requires HDL binding to the cells and new protein synthesis (
      • Suc I.
      • Escargueil-Blanc I.
      • Troly M.
      • Salvayre R.
      • Negre-Salvayre A.
      HDL and ApoA prevent cell death of endothelial cells induced by oxidized LDL.
      ). Tumor necrosis factor-α (TNF-α)-induced endothelial cell apoptosis is also inhibited by HDL, and this is associated with diminished induction of caspase 3, which is a component of all primary apoptotic pathways (
      • Sugano M.
      • Tsuchida K.
      • Makino N.
      High-density lipoproteins protect endothelial cells from tumor necrosis factor-alpha-induced apoptosis.
      ). HDL also attenuates growth factor deprivation-related apoptosis of endothelial cells. This is due to blunting of the mitochondrial pathway of apoptosis, with HDL diminishing the dissipation of mitochondrial potential, oxygen-derived free-radical generation, cytochrome c release to the cytoplasm, and caspases 3 and 9 activation. HDL also activates Akt and causes phosphorylation of the Akt target BAD, which favors BAD disassociation from BCL-XL that is then free to inhibit mitochondria-mediated apoptosis. The HDL-associated lysophospholipids sphingosylphosphorylcholine (SPC) and lysosulfatide (LSF) protect endothelial cells from growth factor deprivation-related apoptosis via mechanisms paralleling those of native HDL (
      • Nofer J.R.
      • Levkau B.
      • Wolinska I.
      • Junker R.
      • Fobker M.
      • von Eckardstein A.
      • Seedorf U.
      • Assmann G.
      Suppression of endothelial cell apoptosis by high density lipoproteins (HDL) and HDL-associated lysosphingolipids.
      ). In addition, the lysophospholipid sphingosine-1-phosphate (S1P) enhances endothelial cell survival with effects comparable to those of native HDL, and these responses are inhibited by knockdown of the S1P receptor EDG-1/S1P1, by pertussis toxin, and by PI3 kinase and Erk pathway antagonists, suggesting that signaling by lysophospholipid components of HDL may be important for the inhibition of apoptosis (
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ). Although the vast majority of evidence for antiapoptotic action of HDL on endothelium comes from cell culture work, in studies of the apoA-I mimetic D-4F in a rat model of diabetes, the mimetic improved vascular reactivity and decreased endothelial cell fragmentation and sloughing (
      • Kruger A.L.
      • Peterson S.
      • Turkseven S.
      • Kaminski P.M.
      • Zhang F.F.
      • Quan S.
      • Wolin M.S.
      • Abraham N.G.
      D-4F induces heme oxygenase-1 and extracellular superoxide dismutase, decreases endothelial cell sloughing, and improves vascular reactivity in rat model of diabetes.
      ), suggesting that the antiapoptotic actions of HDL may be operative in vivo.
      In addition to its antiapoptotic actions on endothelial cells, it was recognized over 30 years ago that HDL directly stimulates endothelial cell proliferation (
      • Tauber J.P.
      • Cheng J.
      • Gospodarowicz D.
      Effect of high and low density lipoproteins on proliferation of cultured bovine vascular endothelial cells.
      ,
      • Tauber J.P.
      • Cheng J.
      • Massoglia S.
      • Gospodarowicz D.
      High density lipoproteins and the growth of vascular endothelial cells in serum-free medium.
      ) and that this occurs through calcium-dependent processes (
      • Tamagaki T.
      • Sawada S.
      • Imamura H.
      • Tada Y.
      • Yamasaki S.
      • Toratani A.
      • Sato T.
      • Komatsu S.
      • Akamatsu N.
      • Yamagami M.
      • et al.
      Effects of high-density lipoproteins on intracellular pH and proliferation of human vascular endothelial cells.
      ). In 1994 it was further reported that HDL stimulates endothelial cell migration independent of cell proliferation (
      • Murugesan G.
      • Sa G.
      • Fox P.L.
      High-density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor.
      ). The basis for the migration response has been somewhat controversial, with some reports indicating that pertussis toxin inhibits the response and others showing no effect of pertussis toxin (
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ,
      • Murugesan G.
      • Sa G.
      • Fox P.L.
      High-density lipoprotein stimulates endothelial cell movement by a mechanism distinct from basic fibroblast growth factor.
      ). The former studies further implicated the G protein-coupled S1P receptors EDG-1/S1P1 and EDG-3/S1P3 and the S1P-rich fraction of HDL, and dependence on PI3 kinase, p38 MAP kinase, and Rho kinase (
      • Kimura T.
      • Sato K.
      • Malchinkhuu E.
      • Tomura H.
      • Tamama K.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein stimulates endothelial cell migration and survival through sphingosine 1-phosphate and its receptors.
      ). Capillary tube formation stimulated by HDL in vitro has been found to be pertussis toxin-sensitive but independent of p38 MAP kinase, alternatively requiring p42/44 MAP kinase activity residing downstream of Ras (
      • Miura S.
      • Fujino M.
      • Matsuo Y.
      • Kawamura A.
      • Tanigawa H.
      • Nishikawa H.
      • Saku K.
      High density lipoprotein-induced angiogenesis requires the activation of Ras/MAP kinase in human coronary artery endothelial cells.
      ). It has also been observed that HDL stimulates endothelial cell migration in vitro via the activation of Rac GTPase; this process does not require HDL cargo molecules, and it is dependent on SR-BI and the activation of Src kinases, PI3-kinase, and p44/42 MAP kinases. Rapid initial stimulation of lamellipodia formation by the HDL/SR-BI tandem via Src kinases and Rac also occurs in cultured endothelial cells (
      • Seetharam D.
      • Mineo C.
      • Gormley A.K.
      • Gibson L.L.
      • Vongpatanasin W.
      • Chambliss K.L.
      • Hahner L.D.
      • Cummings M.L.
      • Kitchens R.L.
      • Marcel Y.L.
      • et al.
      High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
      ). Considering that few experiments have been done in vivo, the inconsistences in the implicated intracellular signaling events may relate to the diversity of endothelial cell types employed in cell culture studies and possibly also variance in the experimental conditions used. Along with promoting growth and migration and tube formation by differentiated endothelial cells, HDL action via SR-BI activates the same processes in endothelial progenitor cells (EPC). The responses in EPC are dependent on PI3 kinase, Akt, p42/44 MAP kinase, and endothelial nitric-oxide synthase (eNOS) (
      • Feng Y.
      • Van Eck M.
      • Van Craeyveld E.
      • Jacobs F.
      • Carlier V.
      • Van Linthout S.
      • Erdel M.
      • Tjwa M.
      • De Geest B.
      Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer.
      ,
      • Zhang Q.
      • Yin H.
      • Liu P.
      • Zhang H.
      • She M.
      Essential role of HDL on endothelial progenitor cell proliferation with PI3K/Akt/cyclin D1 as the signal pathway.
      ).
      A third category of direct impact of HDL on endothelium involves its anti-inflammatory actions. In particular, HDL attenuates the expression of the adhesion molecules vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), and E-selectin in cultured endothelial cells. This process is mediated by SR-BI and PI3 kinase and eNOS, and in some studies, also by S1P receptors, in the latter case implicating the involvement of HDL-associated S1P (
      • Cockerill G.W.
      • Rye K.A.
      • Gamble J.R.
      • Vadas M.A.
      • Barter P.J.
      High-density lipoproteins inhibit cytokine-induced expression of endothelial cell adhesion molecules.
      ,
      • Kimura T.
      • Tomura H.
      • Mogi C.
      • Kuwabara A.
      • Damirin A.
      • Ishizuka T.
      • Sekiguchi A.
      • Ishiwara M.
      • Im D.S.
      • Sato K.
      • et al.
      Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells.
      ). There is also evidence that lipid-free apoA-I and recombinant HDL inhibit endothelial cell adhesion molecule expression by upregulating the expression of 3β-hydroxysteriod-Δ24 reductase (DHCR24) and heme oxygenase-1 (HO-1), with the increased expression by HO-1 being mediated by DHCR24 upregulation and resulting activation of PI3 kinase and Akt (
      • Wu B.J.
      • Chen K.
      • Shrestha S.
      • Ong K.L.
      • Barter P.J.
      • Rye K.A.
      High-density lipoproteins inhibit vascular endothelial inflammation by increasing 3beta-hydroxysteroid-Delta24 reductase expression and inducing heme oxygenase-1.
      ). Other studies have indicated that HDL activation of AMP-activated protein kinase (AMPK) is required in HDL modulation of adhesion molecule expression and that the signaling events proximal to AMPK involve calcium/calmodulin-dependent protein kinase kinase (CaMKK) and liver kinase B1 (LKB1) (
      • Kimura T.
      • Tomura H.
      • Sato K.
      • Ito M.
      • Matsuoka I.
      • Im D.S.
      • Kuwabara A.
      • Mogi C.
      • Itoh H.
      • Kurose H.
      • et al.
      Mechanism and role of high density lipoprotein-induced activation of AMP-activated protein kinase in endothelial cells.
      ). Recognizing the key role of NF-κB in the modulation of cellular responses to inflammation, it has also been shown that apoA-I decreases NF-κB activation induced by palmitate in cultured endothelial cells (
      • Cheng A.M.
      • Handa P.
      • Tateya S.
      • Schwartz J.
      • Tang C.
      • Mitra P.
      • Oram J.F.
      • Chait A.
      • Kim F.
      Apolipoprotein A-I attenuates palmitate-mediated NF-kappaB activation by reducing Toll-like receptor-4 recruitment into lipid rafts.
      ).
      The capacity of HDL to activate eNOS, which was first described in 2001, may be the primary signaling mechanism that commonly underlies the capacity of the lipoprotein both to have antiapoptotic and anti-inflammatory action in endothelial cells and to promote their proliferation and migration (
      • Yuhanna I.S.
      • Zhu Y.
      • Cox B.E.
      • Hahner L.D.
      • Osborne-Lawrence S.
      • Lu P.
      • Marcel Y.L.
      • Anderson R.G.
      • Mendelsohn M.E.
      • Hobbs H.H.
      • et al.
      High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
      ). In cultured endothelial cells, potential apoA-I-eNOS interaction and perinuclear colocalization have been reported (
      • Drew B.G.
      • Fidge N.H.
      • Gallon-Beaumier G.
      • Kemp B.E.
      • Kingwell B.A.
      High-density lipoprotein and apolipoprotein AI increase endothelial NO synthase activity by protein association and multisite phosphorylation.
      ). However, eNOS enzyme activation has not been observed with lipid-free apoA-I, and corroborating evidence of this interaction is lacking. In isolated endothelial cell plasma membranes, where eNOS is localized in caveolae/lipid rafts (
      • Shaul P.W.
      • Smart E.J.
      • Robinson L.J.
      • German Z.
      • Yuhanna I.S.
      • Ying Y.
      • Anderson R.G.
      • Michel T.
      Acylation targets emdothelial nitric-oxide synthase to plasmalemmal caveolae.
      ), anti-apoA-I antibody blocks eNOS activation by HDL, whereas anti-apoA-II antibody causes enhanced eNOS stimulation by HDL. Thus, apoA-I is necessary but not sufficient for eNOS stimulation, and apoA-II may negatively influence eNOS activation by yet-to-be-determined mechanisms (
      • Yuhanna I.S.
      • Zhu Y.
      • Cox B.E.
      • Hahner L.D.
      • Osborne-Lawrence S.
      • Lu P.
      • Marcel Y.L.
      • Anderson R.G.
      • Mendelsohn M.E.
      • Hobbs H.H.
      • et al.
      High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
      ). The stimulation of eNOS enzymatic activity by HDL entails eNOS phosphorylation at Ser1179 via Akt, and this is mediated by Src family kinases and PI3 kinase. Enzyme activation by HDL also requires Src- and PI3 kinase-dependent activation of Erk1/2 MAP kinases (
      • Mineo C.
      • Yuhanna I.S.
      • Quon M.J.
      • Shaul P.W.
      High density lipoprotein-induced endothelial nitric-oxide synthase activation is mediated by Akt and MAP kinases.
      ). Paralleling these findings in cell culture, there is increased Akt and Erk1/2 phosphorylation in the aortas of apoA-I-transgenic mice and decreased abundance of the phosphorylated proteins in the aortas of apoA-I−/− mice (
      • Norata G.D.
      • Callegari E.
      • Marchesi M.
      • Chiesa G.
      • Eriksson P.
      • Catapano A.L.
      High-density lipoproteins induce transforming growth factor-beta2 expression in endothelial cells.
      ). It has further been shown using calcium chelation and other approaches that changes in intracellular calcium homeostasis in endothelial cells are required for nitric-oxide formation in response to HDL (
      • Honda H.M.
      • Wakamatsu B.K.
      • Goldhaber J.I.
      • Berliner J.A.
      • Navab M.
      • Weiss J.N.
      High-density lipoprotein increases intracellular calcium levels by releasing calcium from internal stores in human endothelial cells.
      ,
      • Nofer J.R.
      • van der Giet M.
      • Tolle M.
      • Wolinska I.
      • von Wnuck L.K.
      • Baba H.A.
      • Tietge U.J.
      • Godecke A.
      • Ishii I.
      • Kleuser B.
      • et al.
      HDL induces NO-dependent vasorelaxation via the lysophospholipid receptor S1P3.
      • Li X.A.
      • Titlow W.B.
      • Jackson B.A.
      • Giltiay N.
      • Nikolova-Karakashian M.
      • Uittenbogaard A.
      • Smart E.J.
      High density lipoprotein binding to scavenger receptor, class B, type I activates endothelial nitric-oxide synthase in a ceramide-dependent manner.
      ). Potentially further amplifying the impact of HDL on the capacity for nitric-oxide production by endothelial cells, the lipoprotein also increases eNOS protein abundance, not by altering gene transcription but by increasing the protein half-life through PI3 kinase, Akt, and p42/44 MAP kinase-dependent processes (
      • Ramet M.E.
      • Ramet M.
      • Lu Q.
      • Nickerson M.
      • Savolainen M.J.
      • Malzone A.
      • Karas R.H.
      High-density lipoprotein increases the abundance of eNOS protein in human vascular endothelial cells by increasing its half-life.
      ). HDL upregulation of eNOS protein has also been demonstrated in EPC (
      • Noor R.
      • Shuaib U.
      • Wang C.X.
      • Todd K.
      • Ghani U.
      • Schwindt B.
      • Shuaib A.
      High-density lipoprotein cholesterol regulates endothelial progenitor cells by increasing eNOS and preventing apoptosis.
      ).

      Vascular smooth-muscle cells

      HDL has numerous direct effects on intracellular signaling in vascular smooth-muscle (VSM) cells that are potentially important to the modulation of VSM function by the lipoprotein. HDL enhances VSM cell prostacyclin production, which results from the upregulation of cyclooxygenase type 2 (COX-2) expression (
      • Vinals M.
      • Martinez-Gonzalez J.
      • Badimon J.J.
      • Badimon L.
      HDL-induced prostacyclin release in smooth muscle cells is dependent on cyclooxygenase-2 (Cox-2).
      ). HDL also inhibits VSM cell migration via S1P-mediated processes (
      • Tamama K.
      • Tomura H.
      • Sato K.
      • Malchinkhuu E.
      • Damirin A.
      • Kimura T.
      • Kuwabara A.
      • Murakami M.
      • Okajima F.
      High-density lipoprotein inhibits migration of vascular smooth muscle cells through its sphingosine 1-phosphate component.
      ,
      • Damirin A.
      • Tomura H.
      • Komachi M.
      • Liu J.P.
      • Mogi C.
      • Tobo M.
      • Wang J.Q.
      • Kimura T.
      • Kuwabara A.
      • Yamazaki Y.
      • et al.
      Role of lipoprotein-associated lysophospholipids in migratory activity of coronary artery smooth muscle cells.
      ). Through its S1P cargo, HDL additionally blunts the expression of monocyte chemoattractant protein-1 (MCP-1) in VSM cells, and this is mediated by the S1P3 receptor for S1P, and an attenuation of reactive oxygen species (ROS) production, which regulates MCP-1 production. The influence of HDL on ROS production in VSM is through prevention of the activation of Rac1 and resulting inhibition of NAD(P)H oxidase (
      • Tolle M.
      • Pawlak A.
      • Schuchardt M.
      • Kawamura A.
      • Tietge U.J.
      • Lorkowski S.
      • Keul P.
      • Assmann G.
      • Chun J.
      • Levkau B.
      • et al.
      HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent monocyte chemoattractant protein-1 production.
      ).

      Leukocytes

      In addition to its anti-inflammatory actions on endothelial cells, HDL directly blunts monocytes/macrophage and neutrophil activation (
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ,
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      ). In monocytes, both native HDL and apoA-I dampen phorbol 12-myristate 13-acetate (PMA) induction of the integrin CD11b, which promotes adhesion and migration, thereby attenuating PMA-related enhancement of monocyte-endothelial cell interaction (
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      ). HDL also inhibits the binding of T-cell microparticles to monocytes, resulting in a diminution in proinflammatory cytokine production (
      • Carpintero R.
      • Gruaz L.
      • Brandt K.J.
      • Scanu A.
      • Faille D.
      • Combes V.
      • Grau G.E.
      • Burger D.
      HDL interfere with the binding of T cell microparticles to human monocytes to inhibit pro-inflammatory cytokine production.
      ). ApoA-I also attenuates dendritic cell differentiation from monocytes (
      • Kim K.D.
      • Lim H.Y.
      • Lee H.G.
      • Yoon D.Y.
      • Choe Y.K.
      • Choi I.
      • Paik S.G.
      • Kim Y.S.
      • Yang Y.
      • Lim J.S.
      Apolipoprotein A-I induces IL-10 and PGE2 production in human monocytes and inhibits dendritic cell differentiation and maturation.
      ). In macrophages, apoA-I actions mediated by Janus kinase 2 (JAK2) activation of STAT3 diminish the induction of inflammatory cytokines by LPS (
      • Tang C.
      • Liu Y.
      • Kessler P.S.
      • Vaughan A.M.
      • Oram J.F.
      The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor.
      ). Lipid-free apoA-I, reconstituted HDL, and native HDL also inhibit high-glucose-induced redox signaling in macrophages, with lipid-free apoA-I doing so through ABCG1-dependent increases in superoxide dismutase 1 and superoxide dismutase 2, and an attenuation in Nox2 expression (
      • Tabet F.
      • Lambert G.
      • Cuesta Torres L.F.
      • Hou L.
      • Sotirchos I.
      • Touyz R.M.
      • Jenkins A.J.
      • Barter P.J.
      • Rye K.A.
      Lipid-free apolipoprotein A-I and discoidal reconstituted high-density lipoproteins differentially inhibit glucose-induced oxidative stress in human macrophages.
      ). In neutrophils, native HDL and apoA-I decrease the surface expression of CD11b. In parallel, HDL and apoA-I decrease neutrophil spreading and migration and neutrophil-platelet interaction (
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ). HDL additionally inhibits the proliferation of hematopoietic stem cells and multipotential progenitor cells. Regarding the potential underlying signaling events, in bone marrow-derived cells HDL blunts Erk1,2 activation and Ras plasma membrane recruitment and activation by either IL-3 or GM-CSF (
      • Yvan-Charvet L.
      • Pagler T.
      • Gautier E.L.
      • Avagyan S.
      • Siry R.L.
      • Han S.
      • Welch C.L.
      • Wang N.
      • Randolph G.J.
      • Snoeck H.W.
      • et al.
      ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.
      ).

      Platelets

      Studies in both humans and animal models indicate that HDL inhibits platelet activation (
      • Calkin A.C.
      • Drew B.G.
      • Ono A.
      • Duffy S.J.
      • Gordon M.V.
      • Schoenwaelder S.M.
      • Sviridov D.
      • Cooper M.E.
      • Kingwell B.A.
      • Jackson S.P.
      Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux.
      ,
      • Li D.
      • Weng S.
      • Yang B.
      • Zander D.S.
      • Saldeen T.
      • Nichols W.W.
      • Khan S.
      • Mehta J.L.
      Inhibition of arterial thrombus formation by ApoA1 Milano.
      ,
      • Pajkrt D.
      • Lerch P.G.
      • van der Poll T.
      • Levi M.
      • Illi M.
      • Doran J.E.
      • Arnet B.
      • van den Ende A.
      • Cate J.W.
      • van Deventer S.J.
      Differential effects of reconstituted high-density lipoprotein on coagulation, fibrinolysis and platelet activation during human endotoxemia.
      ). At least a portion of the underlying mechanisms in vivo are indirect, occurring via actions of HDL on the endothelium that include not only the activation of endothelial nitric oxide and prostacyclin production (
      • Yuhanna I.S.
      • Zhu Y.
      • Cox B.E.
      • Hahner L.D.
      • Osborne-Lawrence S.
      • Lu P.
      • Marcel Y.L.
      • Anderson R.G.
      • Mendelsohn M.E.
      • Hobbs H.H.
      • et al.
      High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
      ,
      • Fleisher L.N.
      • Tall A.R.
      • Witte L.D.
      • Miller R.W.
      • Cannon P.J.
      Stimulation of arterial endothelial cell prostacyclin synthesis by high density lipoproteins.
      ) but also the downregulation of platelet-activating factor (
      • Sugatani J.
      • Miwa M.
      • Komiyama Y.
      • Ito S.
      High-density lipoprotein inhibits the synthesis of platelet-activating factor in human vascular endothelial cells.
      ), thromboxane A2 (
      • Oravec S.
      • Demuth K.
      • Myara I.
      • Hornych A.
      The effect of high density lipoprotein subfractions on endothelial eicosanoid secretion.
      ), and tissue factor production by endothelium. The attenuation of endothelial cell tissue factor expression by HDL involves the inhibition of RhoA and activation of PI3 kinase (
      • Viswambharan H.
      • Ming X.F.
      • Zhu S.
      • Hubsch A.
      • Lerch P.
      • Vergeres G.
      • Rusconi S.
      • Yang Z.
      Reconstituted high-density lipoprotein inhibits thrombin-induced endothelial tissue factor expression through inhibition of RhoA and stimulation of phosphatidylinositol 3-kinase but not Akt/endothelial nitric oxide synthase.
      ). There is also evidence that HDL has direct action on platelets (
      • Lerch P.G.
      • Spycher M.O.
      • Doran J.E.
      Reconstituted high density lipoprotein (rHDL) modulates platelet activity in vitro and ex vivo.
      ,
      • Calkin A.C.
      • Drew B.G.
      • Ono A.
      • Duffy S.J.
      • Gordon M.V.
      • Schoenwaelder S.M.
      • Sviridov D.
      • Cooper M.E.
      • Kingwell B.A.
      • Jackson S.P.
      Reconstituted high-density lipoprotein attenuates platelet function in individuals with type 2 diabetes mellitus by promoting cholesterol efflux.
      ). Platelet aggregation stimulated by a variety of means, including by thrombin and ADP, is reduced by HDL, and the lipoprotein also decreases thromboxane A2 and 12-hydroxy-eicosatetraenoic acid release from platelets (
      • Korporaal S.J.
      • Akkerman J.W.
      Platelet activation by low density lipoprotein and high density lipoprotein.
      ,
      • Nofer J.R.
      • Brodde M.F.
      • Kehrel B.E.
      High-density lipoproteins, platelets and the pathogenesis of atherosclerosis.
      ). HDL activates p38MAPK in platelets (
      • Relou A.M.
      • Gorter G.
      • van Rijn H.J.
      • Akkerman J.W.
      Platelet activation by the apoB/E receptor-binding domain of LDL.
      ), and it attenuates intracellular calcium mobilization invoked by LDL cholesterol (
      • Knorr M.
      • Locher R.
      • Vogt E.
      • Vetter W.
      • Block L.H.
      • Ferracin F.
      • Lefkovits H.
      • Pletscher A.
      Rapid activation of human platelets by low concentrations of low-density lipoprotein via phosphatidylinositol cycle.
      ). ApoA-I-rich HDL may exert its actions on platelets via SR-BI, whereas responses to apoE-rich HDL are likely mediated by a splice variant of the LDL receptor family member apoER2 or Lrp8 (
      • Korporaal S.J.
      • Akkerman J.W.
      Platelet activation by low density lipoprotein and high density lipoprotein.
      ,
      • Nofer J.R.
      • Van E.M.
      HDL scavenger receptor class B type I and platelet function.
      ).

      HDL SIGNALING AND METABOLISM

      Adipocytes

      HDL promotes glucose uptake by adipocytes via processes that require SR-BI and possibly also Akt and AMPK activation (
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ). In brown adipocytes, apoA-I upregulates the expression of uncoupling protein I (
      • Ruan X.
      • Li Z.
      • Zhang Y.
      • Yang L.
      • Pan Y.
      • Wang Z.
      • Feng G.S.
      • Chen Y.
      Apolipoprotein A-I possesses an anti-obesity effect associated with increase of energy expenditure and up-regulation of UCP1 in brown fat.
      ), which participates in the control of energy expenditure (
      • Inokuma K.
      • Okamatsu-Ogura Y.
      • Omachi A.
      • Matsushita Y.
      • Kimura K.
      • Yamashita H.
      • Saito M.
      Indispensable role of mitochondrial UCP1 for antiobesity effect of beta3-adrenergic stimulation.
      ). In addition, in cultured adipocytes via PI3 kinase-dependent processes, HDL upregulates the expression of adiponectin, which is an adipokine that modulates a number of metabolic processes, including glucose regulation and fatty acid oxidation, and also has cardiovascular-protective actions (
      • Van Linthout S.
      • Foryst-Ludwig A.
      • Spillmann F.
      • Peng J.
      • Feng Y.
      • Meloni M.
      • Van Craeyveld E.
      • Kintscher U.
      • Schultheiss H.P.
      • De Geest B.
      • et al.
      Impact of HDL on adipose tissue metabolism and adiponectin expression.
      ). In adipocytes, apoA-I and HDL also have anti-inflammatory action, blunting MCP-1 and serum amyloid A3 (SAA3) expression and diminishing the translocation of NADPH oxidase 4 into lipid rafts, thereby attenuating ROS generation. These responses are dependent on ABCA1, ABCG1, and SR-BI (
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      ).

      Skeletal muscle myocytes

      ApoA-I/HDL stimulates glucose uptake in skeletal muscle myocytes via increasing AMPK activity (
      • Han R.
      • Lai R.
      • Ding Q.
      • Wang Z.
      • Luo X.
      • Zhang Y.
      • Cui G.
      • He J.
      • Liu W.
      • Chen Y.
      Apolipoprotein A-I stimulates AMP-activated protein kinase and improves glucose metabolism.
      ). Using L6 myotubes and myofibers studied ex vivo, it has been found that the effect of reconstituted HDL on glucose uptake is comparable to that observed with insulin, and that it is associated with increased plasma membrane GLUT4 (
      • Dalla-Riva J.
      • Stenkula K.G.
      • Petrlova J.
      • Lagerstedt J.O.
      Discoidal HDL and apoA-I-derived peptides improve glucose uptake in skeletal muscle.
      ). ApoA-I/HDL also promotes glycogen synthesis in myocytes in association with increases in glycogen synthase kinase 3 (GKS3) phosphorylation (
      • Zhang Q.
      • Zhang Y.
      • Feng H.
      • Guo R.
      • Jin L.
      • Wan R.
      • Wang L.
      • Chen C.
      • Li S.
      High density lipoprotein (HDL) promotes glucose uptake in adipocytes and glycogen synthesis in muscle cells.
      ).

      Pancreatic beta cells

      HDL promotes insulin secretion by pancreatic β cells through processes that involve ABCA1 when lipid-free apoA-I is the stimulus, and through ABCG1-dependent mechanisms when the stimulus is recombinant HDL. With either stimulus, SR-BI is required (
      • Fryirs M.A.
      • Barter P.J.
      • Appavoo M.
      • Tuch B.E.
      • Tabet F.
      • Heather A.K.
      • Rye K.A.
      Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.
      ). Via the activation of Akt, HDL also counteracts the proapoptotic actions of VLDL or LDL in β cells (
      • Roehrich M.E.
      • Mooser V.
      • Lenain V.
      • Herz J.
      • Nimpf J.
      • Azhar S.
      • Bideau M.
      • Capponi A.
      • Nicod P.
      • Haefliger J.A.
      • et al.
      Insulin-secreting beta-cell dysfunction induced by human lipoproteins.
      ).

      HDL SIGNALING MECHANISMS

      HDL signaling and cholesterol efflux

      As outlined above, HDL induces a variety of signaling events that underlie numerous actions of the lipoprotein in target cells (
      • Grewal T.
      • de Diego I.
      • Kirchhoff M.F.
      • Tebar F.
      • Heeren J.
      • Rinninger F.
      • Enrich C.
      High density lipoprotein-induced signaling of the MAPK pathway involves scavenger receptor type BI-mediated activation of Ras.
      ,
      • Nofer J.R.
      • Kehrel B.
      • Fobker M.
      • Levkau B.
      • Assmann G.
      • von Eckardstein A.
      HDL and arteriosclerosis: beyond reverse cholesterol transport.
      ). The molecular basis of HDL signaling that occurs independent of cargo molecules has been investigated by interrogation of the proximal mechanisms in HDL activation of eNOS. In cultured endothelial cells, short-term exposure to HDL or methyl-β-cyclodextrin causes eNOS stimulation of similar magnitude, whereas cholesterol-loaded methyl-β-cyclodextrin does not. Cholesterol-free Lp2A-I particles composed of lipid-free recombinant apoA-I and phosphatidylcholine also activate eNOS, whereas cholesterol-containing Lp2A-I particles do not. In addition, phosphatidylcholine-loaded HDL causes greater eNOS stimulation than native HDL, and blocking antibody to SR-BI, which retards cholesterol efflux, prevents eNOS activation. Furthermore, in a reconstitution system in COS-M6 cells, wild-type SR-BI mediates eNOS activation by both HDL and small unilamellar vesicles, whereas the SR-BI mutant AVI, which is incapable of efflux to small unilamellar vesicles, transmits signal only in response to HDL. Moreover, eNOS activation in response to either HDL or methyl-β-cyclodextrin is SR-BI dependent (
      • Assanasen C.
      • Mineo C.
      • Seetharam D.
      • Yuhanna I.S.
      • Marcel Y.L.
      • Connelly M.A.
      • Williams D.L.
      • Llera-Moya M.
      • Shaul P.W.
      • Silver D.L.
      Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initiated signaling.
      ). Since the capacity of methyl-β-cyclodextrin to invoke cholesterol efflux is not mediated by SR-BI or any other cell-surface protein, these cumulative findings in the context of eNOS regulation provided the first indication that signal initiation by HDL requires cholesterol efflux, that the apolipoprotein and phospholipid components of HDL are sufficient to initiate signaling, and that SR-BI may serve as a sensor of cholesterol movement in the plasma membrane.
      The participation of cholesterol efflux in HDL action has also been evaluated in nonendothelial cells and in processes besides eNOS regulation. In monocytes, HDL and methyl-β-cyclodextrin cause equal antagonism of CD11b expression, which contributes to HDL attenuation of monocyte-endothelial cell adhesion, whereas cholesterol-laden methyl-β-cyclodextrin has no effect (
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      ). In pancreatic β cells, insulin secretion in response to discoidal apoA-I-recombinant HDL is absent following ABCG1 knockdown (
      • Fryirs M.A.
      • Barter P.J.
      • Appavoo M.
      • Tuch B.E.
      • Tabet F.
      • Heather A.K.
      • Rye K.A.
      Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.
      ), and paralleling the actions of native HDL on β cells, there is an initiation of insulin secretion within 10 min of treatment with methyl-β-cyclodextrin, even in the absence of other insulin secretagogues (
      • Hao M.
      • Head W.S.
      • Gunawardana S.C.
      • Hasty A.H.
      • Piston D.W.
      Direct effect of cholesterol on insulin secretion: a novel mechanism for pancreatic beta-cell dysfunction.
      ). In adipocytes, the capacity of apoA-I and HDL to decrease MCP-1 expression and NADPH oxidase 4 plasma membrane translocation, which underlies NADPH oxidase 4 promotion of ROS generation, is associated with lowering of plasma membrane cholesterol content. In addition, these responses are mimicked by methyl-β-cyclodextrin, and they are dependent on ABCA1, ABCG1, and SR-BI (
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      ). These collective findings indicate that cholesterol efflux may be mechanistically involved in a variety of the actions of HDL in diverse target cells.

      ABCA1

      As mentioned above, the adenosine triphosphate-binding cassette (ABC) transporters ABCA1 and ABCG1, which are classically involved in cholesterol efflux to apoA-I and in nascent HDL particle assembly, have been implicated in certain cellular responses to apoA-I and HDL. ABCA1 mediates the direct effects of apoA-I in neutrophils (
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ) and monocytes (
      • Murphy A.J.
      • Woollard K.J.
      • Hoang A.
      • Mukhamedova N.
      • Stirzaker R.A.
      • McCormick S.P.
      • Remaley A.T.
      • Sviridov D.
      • Chin-Dusting J.
      High-density lipoprotein reduces the human monocyte inflammatory response.
      ), and ABCA1 and ABCG1 both participate in the actions of HDL in hematopoietic stem cells (
      • Yvan-Charvet L.
      • Pagler T.
      • Gautier E.L.
      • Avagyan S.
      • Siry R.L.
      • Han S.
      • Welch C.L.
      • Wang N.
      • Randolph G.J.
      • Snoeck H.W.
      • et al.
      ATP-binding cassette transporters and HDL suppress hematopoietic stem cell proliferation.
      ), pancreatic β cells (
      • Fryirs M.A.
      • Barter P.J.
      • Appavoo M.
      • Tuch B.E.
      • Tabet F.
      • Heather A.K.
      • Rye K.A.
      Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.
      ), and adipocytes (
      • Umemoto T.
      • Han C.Y.
      • Mitra P.
      • Averill M.M.
      • Tang C.
      • Goodspeed L.
      • Omer M.A.
      • Subramanian S.
      • Wang S.
      • Den Hartigh L.J.
      • et al.
      Apolipoprotein A-I and HDL have anti-inflammatory effects on adipocytes via cholesterol transporters: ATP-binding cassette (ABC) A-1, ABCG-1 and scavenger receptor B-1(SRB-1).
      ).
      In addition to regulating the primary functions of these various cell types, such as inflammation-related processes in neutrophils, there is evidence that signaling invoked by ABCA1 impacts its abundance and its capacity to mediate lipid transport to apoA-I. Via coupling to Gs, apoA-I binding to ABCA1 causes adenylate cyclase activation, cAMP production, and subsequent PKA-mediated ABCA1 phosphorylation, which results in increased lipidation of apoA-I (
      • Haidar B.
      • Denis M.
      • Marcil M.
      • Krimbou L.
      • Genest Jr, J.
      Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter.
      ). There is also evidence of a role for calcium in the modulation of ABCA1 function, with the removal of extracellular calcium or the chelation of intracellular calcium resulting in the attenuation of apoA-I lipidation (
      • Takahashi Y.
      • Smith J.D.
      Cholesterol efflux to apolipoprotein AI involves endocytosis and resecretion in a calcium-dependent pathway.
      ). In addition, protein kinase C (PKC) activation modulates both ABCA1 gene transcription and ABCA1 protein stability. Upon ABCA1 binding, apoA-I initially removes cellular free cholesterol, phosphatidylcholine, and sphingomyelin. The decrease in sphingomyelin in the plasma membrane then triggers phosphatidylcholine phospholipase activity, which catalyzes the hydrolysis of phosphatidylcholine to generate diacylglycerol (DAG). The DAG then activates PKC-α, which phosphorylates ABCA1, ultimately leading to protection of ABCA1 degradation by calpain (
      • Yamauchi Y.
      • Hayashi M.
      • Abe-Dohmae S.
      • Yokoyama S.
      Apolipoprotein A-I activates protein kinase C alpha signaling to phosphorylate and stabilize ATP binding cassette transporter A1 for the high density lipoprotein assembly.
      ). Interestingly, in response to LDL cholesterol, PKC-ζ activation induces its binding to the transcription factor specificity protein 1 (Sp1), and Sp1 interaction with LXR and RXR heterodimer and the ABCA1 promoter activates transcriptional transactivation of the ABCA1 gene (
      • Chen X.
      • Zhao Y.
      • Guo Z.
      • Zhou L.
      • Okoro E.U.
      • Yang H.
      Transcriptional regulation of ATP-binding cassette transporter A1 expression by a novel signaling pathway.
      ,
      • Thymiakou E.
      • Zannis V.I.
      • Kardassis D.
      Physical and functional interactions between liver X receptor/retinoid X receptor and Sp1 modulate the transcriptional induction of the human ATP binding cassette transporter A1 gene by oxysterols and retinoids.
      ). Along with activating PKA and PKC, the interaction of apoA-I with ABCA1 activates JAK2, resulting in both the enhancement of lipid removal from cells (
      • Tang C.
      • Vaughan A.M.
      • Oram J.F.
      Janus kinase 2 modulates the apolipoprotein interactions with ABCA1 required for removing cellular cholesterol.
      ) and the activation STAT3, which is anti-inflammatory in cell types such as macrophages (
      • Tang C.
      • Liu Y.
      • Kessler P.S.
      • Vaughan A.M.
      • Oram J.F.
      The macrophage cholesterol exporter ABCA1 functions as an anti-inflammatory receptor.
      ). Furthermore, Rho family small GTPases are also influenced by apoA-I binding to ABCA1. The activation of Cdc42 by apoA-I enhances apoA-I-mediated cholesterol efflux, which may involve the formation of a complex between Cdc42 and ABCA1 (
      • Nofer J.R.
      • Remaley A.T.
      • Feuerborn R.
      • Wolinnska I.
      • Engel T.
      • von Eckardstein A.
      • Assmann G.
      Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter.
      ,
      • Nofer J.R.
      • Feuerborn R.
      • Levkau B.
      • Sokoll A.
      • Seedorf U.
      • Assmann G.
      Involvement of Cdc42 signaling in apoA-I-induced cholesterol efflux.
      • Hirano K.
      • Matsuura F.
      • Tsukamoto K.
      • Zhang Z.
      • Matsuyama A.
      • Takaishi K.
      • Komuro R.
      • Suehiro T.
      • Yamashita S.
      • Takai Y.
      • et al.
      Decreased expression of a member of the Rho GTPase family, Cdc42Hs, in cells from Tangier disease - the small G protein may play a role in cholesterol efflux.
      ). ApoA-I binding also activates RhoA, which participates in the stabilization of ABCA1 (
      • Okuhira K.
      • Fitzgerald M.L.
      • Tamehiro N.
      • Ohoka N.
      • Suzuki K.
      • Sawada J.
      • Naito M.
      • Nishimaki-Mogami T.
      Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation.
      ).
      Structural features of ABCA1 involved in its capacity to alter intracellular signaling and in its modulation by intracellular signaling events have been elucidated. In studies of cAMP production and ABCA1 phosphorylation mediated by the apoA-I/ABCA1 tandem, it was found that mutations of ABCA1 associated with Tangier disease (C1477R, 2203X, and 2145X) cause the attenuation of both responses (
      • Haidar B.
      • Denis M.
      • Marcil M.
      • Krimbou L.
      • Genest Jr, J.
      Apolipoprotein A-I activates cellular cAMP signaling through the ABCA1 transporter.
      ). Mutation of one of the two most likely PKA phosphorylation sites on ABCA1, S2054, yields a transporter that is less capable of exporting cellular cholesterol (
      • See R.H.
      • Caday-Malcolm R.A.
      • Singaraja R.R.
      • Zhou S.
      • Silverston A.
      • Huber M.T.
      • Moran J.
      • James E.R.
      • Janoo R.
      • Savill J.M.
      • et al.
      Protein kinase A site-specific phosphorylation regulates ATP-binding cassette A1 (ABCA1)-mediated phospholipid efflux.
      ). It has additionally been determined that the C terminus of ABCA1 is required for its interaction with Cdc42, with C-terminal truncation of ABCA1 causing blunted Cdc42-dependent signaling (
      • Nofer J.R.
      • Remaley A.T.
      • Feuerborn R.
      • Wolinnska I.
      • Engel T.
      • von Eckardstein A.
      • Assmann G.
      Apolipoprotein A-I activates Cdc42 signaling through the ABCA1 transporter.
      ). There is also evidence that PDZ-RhoGEF binds to the C-terminal PDZ-binding motif of ABCA1 and prevents the degradation of the transporter by activating RhoA (
      • Okuhira K.
      • Fitzgerald M.L.
      • Tamehiro N.
      • Ohoka N.
      • Suzuki K.
      • Sawada J.
      • Naito M.
      • Nishimaki-Mogami T.
      Binding of PDZ-RhoGEF to ATP-binding cassette transporter A1 (ABCA1) induces cholesterol efflux through RhoA activation and prevention of transporter degradation.
      ). Furthermore, it has been determined that ABCA1 directly binds calmodulin in a calcium-dependent manner. The cytoplasmic loop of ABCA1 contains a calmodulin-binding sequence (residues 1245–1257), and its binding by calmodulin protects ABCA1 from proteolysis by calpain and thereby enhances apoA-I-mediated lipid release (
      • Iwamoto N.
      • Lu R.
      • Tanaka N.
      • Abe-Dohmae S.
      • Yokoyama S.
      Calmodulin interacts with ATP binding cassette transporter A1 to protect from calpain-mediated degradation and upregulates high-density lipoprotein generation.
      ).

      SR-BI

      Sometimes independent of and sometimes in partnership with ABCA1 and/or ABCG1, SR-BI is required for the direct actions of apoA-I and HDL on certain cell types. SR-BI is required for HDL modulation of endothelial cell phenotype (
      • Seetharam D.
      • Mineo C.
      • Gormley A.K.
      • Gibson L.L.
      • Vongpatanasin W.
      • Chambliss K.L.
      • Hahner L.D.
      • Cummings M.L.
      • Kitchens R.L.
      • Marcel Y.L.
      • et al.
      High-density lipoprotein promotes endothelial cell migration and reendothelialization via scavenger receptor-B type I.
      ,
      • Kimura T.
      • Tomura H.
      • Mogi C.
      • Kuwabara A.
      • Damirin A.
      • Ishizuka T.
      • Sekiguchi A.
      • Ishiwara M.
      • Im D.S.
      • Sato K.
      • et al.
      Role of scavenger receptor class B type I and sphingosine 1-phosphate receptors in high density lipoprotein-induced inhibition of adhesion molecule expression in endothelial cells.
      ,
      • Yuhanna I.S.
      • Zhu Y.
      • Cox B.E.
      • Hahner L.D.
      • Osborne-Lawrence S.
      • Lu P.
      • Marcel Y.L.
      • Anderson R.G.
      • Mendelsohn M.E.
      • Hobbs H.H.
      • et al.
      High-density lipoprotein binding to scavenger receptor-BI activates endothelial nitric oxide synthase.
      ) and for the actions of HDL in EPC (
      • Feng Y.
      • Van Eck M.
      • Van Craeyveld E.
      • Jacobs F.
      • Carlier V.
      • Van Linthout S.
      • Erdel M.
      • Tjwa M.
      • De Geest B.
      Critical role of scavenger receptor-BI-expressing bone marrow-derived endothelial progenitor cells in the attenuation of allograft vasculopathy after human apo A-I transfer.
      ). SR-BI also mediates the actions of apoA-I and/or HDL in neutrophils (
      • Murphy A.J.
      • Woollard K.J.
      • Suhartoyo A.
      • Stirzaker R.A.
      • Shaw J.
      • Sviridov D.
      • Chin-Dusting J.P.
      Neutrophil activation is attenuated by high-density lipoprotein and apolipoprotein A-I in in vitro and in vivo models of inflammation.
      ), adipocytes (
      • Zhang Y.
      • McGillicuddy F.C.
      • Hinkle C.C.
      • O'Neill S.
      • Glick J.M.
      • Rothblat G.H.
      • Reilly M.P.
      Adipocyte modulation of high-density lipoprotein cholesterol.
      ), and pancreatic β cells (
      • Fryirs M.A.
      • Barter P.J.
      • Appavoo M.
      • Tuch B.E.
      • Tabet F.
      • Heather A.K.
      • Rye K.A.
      Effects of high-density lipoproteins on pancreatic beta-cell insulin secretion.
      ).
      The features of SR-BI required for signal initiation have been interrogated. Using SR-BII, which is a splice variant of SR-BI, and chimeric as well as mutant class B scavenger receptors, it has been shown that the C-terminal cytoplasmic PDZ-interacting domain and the C-terminal transmembrane domain of SR-BI are both required for HDL signaling. In addition, in studies employing a photoactivated derivative of cholesterol, direct binding of plasma membrane cholesterol to the C-terminal transmembrane domain was demonstrated (
      • Assanasen C.
      • Mineo C.
      • Seetharam D.
      • Yuhanna I.S.
      • Marcel Y.L.
      • Connelly M.A.
      • Williams D.L.
      • Llera-Moya M.
      • Shaul P.W.
      • Silver D.L.
      Cholesterol binding, efflux, and a PDZ-interacting domain of scavenger receptor-BI mediate HDL-initiated signaling.
      ). The C-terminal PDZ-interacting domain allows the receptor to bind to the adaptor molecule PDZK1, which comprises four PDZ domains. Whereas in certain contexts PDZK1 influences the stability of the SR-BI protein, such as in hepatocytes (
      • Kocher O.
      • Krieger M.
      Role of the adaptor protein PDZK1 in controlling the HDL receptor SR-BI.
      ), in endothelial cells PDZK1 does not impact SR-BI abundance, and alternatively, it is uniquely required for signal initiation by HDL and the resulting stimulation of eNOS and endothelial cell migration (
      • Zhu W.
      • Saddar S.
      • Seetharam D.
      • Chambliss K.L.
      • Longoria C.
      • Silver D.L.
      • Yuhanna I.S.
      • Shaul P.W.
      • Mineo C.
      The scavenger receptor class B type I adaptor protein PDZK1 maintains endothelial monolayer integrity.
      ).
      In recent studies, the functional implications of direct plasma membrane cholesterol binding to the C-terminal transmembrane domain of SR-BI were interrogated. In experiments performed in COS-M6 cells, mutation of a highly conserved C-terminal transmembrane domain glutamine to alanine (SR-BI-Q445A) decreased plasma membrane cholesterol interaction with the receptor by 71% without altering HDL binding or cholesterol uptake or efflux, and it yielded a receptor incapable of HDL-induced signaling. Signaling prompted by cholesterol efflux to methyl-β-cyclodextrin also was prevented, indicating that plasma membrane cholesterol interaction with the receptor enables it to serve as a plasma membrane cholesterol sensor. Using SR-BI-Q445A, it was further demonstrated that plasma membrane cholesterol sensing by SR-BI does not influence SR-BI-mediated RCT to the liver in mice. However, the plasma membrane cholesterol sensing does underlie apolipoprotein B intracellular trafficking in response to postprandial micelles or methyl-β-cyclodextrin in cultured enterocytes, and it is required for HDL activation of eNOS and migration in cultured endothelial cells and HDL-induced angiogenesis in vivo (
      • Saddar S.
      • Carriere V.
      • Lee W.R.
      • Tanigaki K.
      • Yuhanna I.S.
      • Parathath S.
      • Morel E.
      • Warrier M.
      • Sawyer J.K.
      • Gerard R.D.
      • et al.
      Scavenger receptor class B type I is a plasma membrane cholesterol sensor.
      ). Thus, through interaction with cholesterol, SR-BI serves as a plasma membrane cholesterol sensor, and the resulting intracellular signaling governs processes in both enterocytes and endothelial cells.

      UNANSWERED QUESTIONS

      Our present understanding of signaling mechanisms, as well as protein or mediator abundance or activity modulated by apoA-I or HDL, is summarized in TABLE 1, TABLE 2. The current unanswered questions in this aspect of HDL biology are multiple. First, although the role of HDL in RCT and the capacity of the lipoprotein to directly impact numerous cell types are well recognized, we do not know the relative importance of HDL modulation of global cholesterol homeostasis versus HDL modulation of intracellular signaling. Second, within the latter realm, we do not know to what extent each of the many cellular responses to apoA-I or HDL discussed in this review impacts cardiovascular and/or metabolic health. Third, recognizing that HDL subclasses differ greatly in their many chemical and physical properties and that HDL particles contain a large variety of lipid species and dozens of protein cargos (
      • Asztalos B.F.
      • Tani M.
      • Schaefer E.J.
      Metabolic and functional relevance of HDL subspecies.
      ), we do not know whether these many characteristics of HDL or its capacity to invoke lipid movement defines the actions of the lipoprotein of importance to health and disease. Finally, from a mechanistic standpoint, although we are improving our understanding of ABCA1, ABCG1, and SR-BI structure-function, we have much more to learn about the initiating events by which apoA-I binding to these cell-surface proteins causes lipid movement and coupling to intracellular signaling cascades. What we do now appreciate, however, is that the influence of HDL on physiologic and also pathophysiologic processes likely surpasses its classical participation in global cholesterol homeostasis. Further investigations of the bases for and implications of HDL and apoA-I modulation of intracellular signaling will potentially reveal new prophylactic and therapeutic strategies to optimize both cardiovascular and metabolic health.

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