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Hormone-sensitive lipase

Open AccessPublished:October 01, 2002DOI:https://doi.org/10.1194/jlr.R200009-JLR200
      Hormone-sensitive lipase (HSL) is an intracellular neutral lipase that is capable of hydrolyzing triacylglycerols, diacylglycerols, monoacylglycerols, and cholesteryl esters, as well as other lipid and water soluble substrates. HSL activity is regulated post-translationally by phosphorylation and also by pretranslational mechanisms. The enzyme is highly expressed in adipose tissue and steroidogenic tissues, with lower amounts expressed in cardiac and skeletal muscle, macrophages, and islets. Studies of the structure of HSL have identified several amino acids and regions of the molecule that are critical for enzymatic activity and regulation of HSL. This has led to important insights into its function, including the interaction of HSL with other intracellular proteins, such as adipocyte lipid binding protein. Accumulating evidence has defined important functions for HSL in normal physiology, affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action; however, direct links between abnormal expression or genetic variations of HSL and human disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, await further clarification.
      The published reports examining the regulation, and function of HSL in normal physiology and disease are reviewed in this paper.
      Hormone-sensitive lipase (HSL) activity was first identified as an epinephrine-sensitive lipolytic activity in adipose tissue. Its name was coined to reflect the ability of hormones such as catecholamines, ACTH, and glucagon to stimulate the activity of this intracellular neutral lipase (
      • Vaughan M.
      • Berger J.E.
      • Steinberg D.
      Hormone-sensitive lipase and monoglycerol lipase activities in adipose tissue.
      ). Hormonal activation of HSL occurs via cyclic AMP dependent protein kinase (PKA), which phosphorylates HSL (
      • Yeaman S.J.
      Hormone-sensitive lipase - a multipurpose enzyme in lipid metabolism.
      ). As the enzyme responsible for the release of free fatty acids (FFA) from adipose tissue, HSL is felt to play a pivotal role in providing the major source of energy for most tissues. Although its expression is highest in adipose tissue, HSL is also expressed in adrenal, ovary, testis, and to a lesser extent in skeletal and cardiac muscle and macrophages (
      • Holm C.
      • Kirchgessner T.G.
      • Svenson K.L.
      • Fredrikson G.
      • Nilsson S.
      • Miller C.G.
      • Shively J.E.
      • Heinzmann C.
      • Sparkes R.S.
      • Mohandas T.
      • Lusis A.J.
      • Belfrage P.
      • Schotz M.C.
      Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3.
      ,
      • Kraemer F.B.
      • Patel S.
      • Saedi M.S.
      • Sztalryd C.
      Detection of hormone-sensitive lipase in various tissues. I. Expression of an HSL/bacterial fusion protein and generation of anti-HSL antibodies.
      ). Following the purification of the enzyme and the cloning of the cDNA encoding HSL, many research efforts have focused on understanding the activity, regulation, expression and function of this protein.

      Structural and biochemical properties

      The HSL gene is located on chromosome 19q13.3 (
      • Holm C.
      • Kirchgessner T.G.
      • Svenson K.L.
      • Fredrikson G.
      • Nilsson S.
      • Miller C.G.
      • Shively J.E.
      • Heinzmann C.
      • Sparkes R.S.
      • Mohandas T.
      • Lusis A.J.
      • Belfrage P.
      • Schotz M.C.
      Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3.
      ) and was initially described to contain 9 exons spanning approximately 11 and 10 kB in human (
      • Langin D.
      • Laurell H.
      • Holst L.S.
      • Belfrage P.
      • Holm C.
      Gene organization and primary structure of human hormone-sensitive lipase: possible significance of a sequence homology with a lipase of Moraxella TA144, an antarctic bacterium.
      ) and mouse (
      • Li Z.
      • Sumida M.
      • Birchbauer A.
      • Schotz M.C.
      • Reue K.
      Isolation and characterization of the gene for mouse hormone-sensitive lipase.
      ), respectively, that encode an mRNA of ∼2.8 kB (
      • Grober J.
      • Laurell H.
      • Blaise R.
      • Fabry B.
      • Schaak S.
      • Holm C.
      • Langin D.
      Characterization of the promoter of human adipocyte hormone-sensitive lipase.
      ). Subsequently, two additional exons (termed A and B) that differentially encode 170 and 70 nt 5′ untranslated regions were identified approximately 12.5 and 1.5 kB upstream of exon 1, respectively (
      • Grober J.
      • Laurell H.
      • Blaise R.
      • Fabry B.
      • Schaak S.
      • Holm C.
      • Langin D.
      Characterization of the promoter of human adipocyte hormone-sensitive lipase.
      ). Only the smaller HSL mRNA product is expressed in human adipose tissue. In contrast, five different exons have been reported within 7 kB of the translation start site of exon 1 in mouse HSL, each of which can be alternatively utilized and expressed in mouse adipose tissue to varying degrees (
      • Laurin N.N.
      • Wang S.P.
      • Mitchell G.A.
      The hormone-sensitive lipase gene is transcibed from at least five alternative first exons in mouse adipose tissue.
      ). In addition to these alternative exons encoding 5′ untranslated regions, several isoforms of HSL have been reported. A testis specific exon 15.5 kB upstream of exon 1 of human adipocyte HSL yields a 3.9 kB testicular HSL mRNA and encodes a larger protein (
      • Stenson Holst L.
      • Langin D.
      • Mulder H.
      • Laurell H.
      • Grober J.
      • Bergh A.
      • Mohrenweiser H.W.
      • Edgren G.
      • Holm C.
      Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.
      ). A second testis specific exon was identified ∼12 kB upstream of exon 1 and encodes a protein identical to adipocyte HSL (
      • Mairal A.
      • Melaine N.
      • Laurell H.
      • Grober J.
      • Holst L.
      • Guillaudeux T.
      • Holm C.
      • Jegou B.
      • Langin D.
      Characterization of a novel testicular form of human hormone-sensitive lipase.
      ). β cells may have a specific exon (
      • Mulder H.
      • Holst L.
      • Svensson H.
      • Degerman E.
      • Sundler F.
      • Ahren B.
      • Rorsman P.
      • Holm C.
      Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.
      ) or an alternate translation start site may be 7 kB upstream of exon 1 (
      • Laurin N.N.
      • Wang S.P.
      • Mitchell G.A.
      The hormone-sensitive lipase gene is transcibed from at least five alternative first exons in mouse adipose tissue.
      ).
      The purified rat enzyme has a molecular weight of approximately 84,000 Da on SDS-PAGE, corresponding to the 768 amino acid protein with a molecular size of 82,820 Da predicted from the primary translation product of rat HSL cDNA (
      • Holm C.
      • Kirchgessner T.G.
      • Svenson K.L.
      • Fredrikson G.
      • Nilsson S.
      • Miller C.G.
      • Shively J.E.
      • Heinzmann C.
      • Sparkes R.S.
      • Mohandas T.
      • Lusis A.J.
      • Belfrage P.
      • Schotz M.C.
      Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3.
      ). The human HSL cDNA encodes a 775 amino acid protein with a molecular size of 84,032 Da, which corresponds to an 88 kDa immunoreactive protein seen on SDS-PAGE (
      • Langin D.
      • Laurell H.
      • Holst L.S.
      • Belfrage P.
      • Holm C.
      Gene organization and primary structure of human hormone-sensitive lipase: possible significance of a sequence homology with a lipase of Moraxella TA144, an antarctic bacterium.
      ). However, a truncated, catalytically inactive form of HSL due to alternative splicing which eliminates exon 6 has been described in human, but not rat, adipose tissue (
      • Laurell H.
      • Grober J.
      • Vindis C.
      • Lacome T.
      • Dauzats M.
      • Holm C.
      • Langin D.
      Species-specific alternative splicing generates a catalytically inactive form of human hormone-sensitive lipase.
      ). At least three additional isoforms of HSL have been reported. The testis appears to express two isoforms, one encoded by the larger testicular mRNA produces a protein with an additional 300 (rat) or 301 (human) amino acids N-terminal to the normal adipose form (
      • Stenson Holst L.
      • Langin D.
      • Mulder H.
      • Laurell H.
      • Grober J.
      • Bergh A.
      • Mohrenweiser H.W.
      • Edgren G.
      • Holm C.
      Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.
      ). So in addition to an 84 kDa protein that is similar to adipose HSL, a second larger isoform of ∼120–130 kDa is encoded by a unique testis mRNA (
      • Mairal A.
      • Melaine N.
      • Laurell H.
      • Grober J.
      • Holst L.
      • Guillaudeux T.
      • Holm C.
      • Jegou B.
      • Langin D.
      Characterization of a novel testicular form of human hormone-sensitive lipase.
      ). Islets and β cells have an HSL isoform that contains an additional 43 amino acids N-terminal to the normal adipose form (
      • Mulder H.
      • Holst L.
      • Svensson H.
      • Degerman E.
      • Sundler F.
      • Ahren B.
      • Rorsman P.
      • Holm C.
      Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.
      ). HSL exists as a functional dimer composed of homologous subunits; dimeric HSL has greater hydrolytic activity when compared with monomeric HSL but no difference in substrate affinity (
      • Shen W-J.
      • Patel S.
      • Kraemer F.B.
      Hormone-sensitive lipase functions as an oligomer.
      ).
      The primary sequence of HSL is unrelated to any of the other known mammalian lipases; however, it shares some sequence homology with lipase 2 of an antarctic bacterium, Moraxella TA144 (
      • Langin D.
      • Laurell H.
      • Holst L.S.
      • Belfrage P.
      • Holm C.
      Gene organization and primary structure of human hormone-sensitive lipase: possible significance of a sequence homology with a lipase of Moraxella TA144, an antarctic bacterium.
      ). This homology aided in locating a G-X-S-X-G motif, which represents a consensus lipid binding sequence that contains the active site serine in other lipases, such as pancreatic lipase. This region was proposed (
      • Hemilä H.
      • Koivula T.T.
      • Palva I.
      Hormone-sensitive lipase is closely related to several bacterial proteins, and distantly related to acetylcholinesterase and lipoprotein lipase: identification of a superfamily of esterases and lipases.
      ), and later shown by site-directed mutagenesis (
      • Holm C.
      • Davis R.C.
      • Østerlund T.
      • Schotz M.C.
      • Fredrikson G.
      Identification of the active site serine of hormone-sensitive lipase by site-directed mutagenesis.
      ), to contain the catalytically active serine at position 423 in rat HSL. Limited proteolysis and denaturation studies (
      • Østerlund T.
      • Danielsson B.
      • Degerman E.
      • Contreras J.A.
      • Edgren G.
      • Davis R.C.
      • Schotz M.C.
      • Holm C.
      Domain-structure analysis of recombinant rat hormone-sensitive lipase.
      ) suggested that HSL, like other lipases (
      • Wang H.
      • Schotz M.C.
      The lipase gene family.
      ) con-tains two major domains (Fig. 1). The N-terminal 320 amino acid domain is encoded by exons 1–4 and has no primary or secondary structural similarity with known proteins; however, the N-terminal domain has been shown to interact with adipocyte lipid-binding protein (ALBP) and has been proposed to function as a docking domain for protein-protein interactions (
      • Shen W-J.
      • Sridhar K.
      • Bernlohr D.A.
      • Kraemer F.B.
      Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein.
      ). The C-terminal portion of HSL is similar to acetylcholinesterase, bile salt-stimulated lipase and several fungal lipases, and is composed of α/β-hydrolase folds that accommodate the catalytic site. A significant advance in understanding the structure of HSL was made when it was observed that, even in the absence of primary sequence homology, the organization of the secondary structure predicted for the C-terminal ∼450 amino acids of HSL was similar to the secondary structure of acetylcholinesterase and of two fungal lipases from Geotrichum candidum and Candida rugosa (
      • Contreras J.A.
      • Karlsson M.
      • Østerlund T.
      • Laurell H.
      • Svensson A.
      • Holm C.
      Hormone-sensitive lipase is structurally related to acetylcholinesterase, bile salt-stimulated lipase, and several fungal lipases: building of a three-dimensional model for the catalytic domain of hormone-sensitive lipase.
      ). Using molecular modeling, it was proposed, and later confirmed by site-directed mutagenesis, that Ser-423, Asp-703, and His-733 (numbered for rat HSL) constitute the catalytic triad for HSL and are found within this C-terminal portion (
      • Østerlund T.
      • Contreras J.A.
      • Holm C.
      Identification of essential aspartic acid and histidine residues of hormone-sensitive lipase: apparent residues of the catalytic triad.
      ). Also located within the C-terminal portion is a 150 amino acid stretch that is not predicted to be composed of α helices or β sheets, but contains known phosphorylation sites and has been termed the regulatory module.
      Figure thumbnail gr1
      Fig. 1Schematic structure of rat HSL. The N-terminal 320 amino acids are depicted as a globular structure since its precise structure cannot currently be modeled. The C-terminal portion forms an α/β hydrolase structure and contains the catalytic triad: Ser-423, Asp 703, His-733. The α helices are denoted in purple and the β sheets in cyan. The C-terminal portion is interrupted by the 150 amino acid “regulatory module” which contains important serine residues that can be phosphorylated by the different kinases shown.
      HSL has broad substrate specificity; in addition to triacylglycerol, HSL can also catalyze the hydrolysis of diacylglycerol, 1(3) monoacylglycerol, cholesteryl esters, lipoidal esters of steroid hormones, and retinyl esters in adipose tissue, as well as water-soluble butyrate substrates (
      • Fredrikson G.
      • Stralfors P.
      • Nilsson N.O.
      • Belfrage P.
      Hormone-sensitive lipase of rat adipose tissue: purification and some properties.
      ,
      • Cook K.G.
      • Yeaman S.J.
      • Stralfors P.
      • Fredrikson G.
      • Belfrage P.
      Direct evidence that cholesteryl ester hydrolase from adrenal cortex is the same enzyme as hormone-sensitive lipase from adipose tissue.
      ,
      • Lee F.T.
      • Adams J.B.
      • Garton A.J.
      • Yeaman S.J.
      Hormone-sensitive lipase is involved in the hydrolysis of lipoidal derivatives of estrogens and other steroid hormones.
      ,
      • Wei S.
      • Lai K.
      • Patel S.
      • Piantedosi R.
      • Shen H.
      • Colantuoni V.
      • Kraemer F.B.
      • Blaner W.S.
      Retinyl ester hydrolysis and retinol efflux from BFC-1β adipocytes.
      ); however, in contrast to many other lipases, HSL has no phospholipase activity. The activity against diacylglycerol is about 10-fold and 5-fold higher than the activity against triacylglycerol and monoacylglycerol, respectively, whereas the activity against cholesteryl esters is about twice the activity toward triacylglycerol. The esterase activity against water-soluble substrates is more than 20-fold that of triacylglycerols. HSL shows a preference for the sn 1- or 3-ester bond over the sn 2-ester bond as its substrate, with the relative activity against the sn 3-ester bond three to four times higher than the sn 2-ester bond. Although fatty acids appear to be more readily mobilized from adipose cells as their chain length shortens (between 12–24 carbons) and as their degree of unsaturation increases, examination of the ability of recombinant HSL to release individual fatty acids from triacylglycerol substrates in vitro does not support a large contribution of HSL to this selective mobilization (
      • Raclot T.
      • Holm C.
      • Langin D.
      Fatty acid specificity of hormone-sensitive lipase: implication in the selective hydrolysis of triacylglycerols.
      ). Nonetheless, the relative hydrolysis of 12–24 carbon atom saturated fatty acids by HSL does increase with decreasing chain length (
      • Raclot T.
      • Holm C.
      • Langin D.
      A role for hormone-sensitive lipase in the selective mobilization of adipose tissue fatty acids.
      ), and there is a tendency for a decrease in release as the number of unsaturated bonds increases, except for C20 fatty acids (
      • Raclot T.
      • Holm C.
      • Langin D.
      Fatty acid specificity of hormone-sensitive lipase: implication in the selective hydrolysis of triacylglycerols.
      ). HSL may preferentially hydrolyze oxidized cholesteryl esters (at least 13-HODE cholesteryl ester) compared with cholesteryl linoleate (
      • Belkner J.
      • Stender H.
      • Holzhutter H.
      • Holm C.
      • Kuhn H.
      Macrophage cholesteryl ester hydrolases and hormone-sensitive lipase prefer specifically oxidized cholesteryl esters as substrates over their non-oxidized counterparts.
      ).
      One of the unique features of HSL that differentiates it from most other lipases is that its activity against triacylglycerol and cholesteryl ester substrates appears to be regulated by reversible phosphorylation; however, hydrolytic activity against diacylglycerol, monoacylglycerol and water-soluble substrates is unaffected by phosphorylation (
      • Yeaman S.J.
      Hormone-sensitive lipase - a multipurpose enzyme in lipid metabolism.
      ). PKA increases the hydrolytic activity of HSL by phosphorylation of a single site that was initially identified as S563 in rat HSL (
      • Yeaman S.J.
      Hormone-sensitive lipase - a multipurpose enzyme in lipid metabolism.
      ) and is located within the regulatory module (Fig. 1). Although evidence to support the phosphorylation of S563 by PKA has been provided from mutagenesis experiments (
      • Shen W-J.
      • Patel S.
      • Natu V.
      • Kraemer F.B.
      Mutational analysis of structural features of rat hormone-sensitive lipase.
      ), other investigators have reported that S659 and S660 were phosphorylated by PKA in vitro and were required for the phosphorylation-induced increase in hydrolytic activity against triacylglycerol substrate (
      • Anthonsen M.W.
      • Rönnstrandt L.
      • Wernstedt C.
      • Degerman E.
      • Holm C.
      Identification of novel phosphorylation sites in hormone-sensitive lipase that are phosphorylated in response to isoproterenol and govern activation properties in vitro.
      ). Additionally, lipolytic hormones not only can activate PKA, but also the mitogen activated protein kinase pathway and extracellular signal-regulated kinase (ERK). Activation of the ERK pathway appears to be able to regulate adipocyte lipolysis by phosphorylating HSL on S600 and increasing the activity of HSL (
      • Greenberg A.S.
      • Shen W-J.
      • Muliro K.
      • Patel S.
      • Souza S.C.
      • Roth R.A.
      • Kraemer F.B.
      Stimulation of lipolysis and hormone-sensitive lipase via the extracellular signal-regulated kinase pathway.
      ). In contrast to activation of activity seen with PKA or ERK phosphorylation, other kinases such as glycogen synthase kinase-4, Ca++/calmodulin-dependent protein kinase II, and AMP-activated protein kinase phosphorylate HSL at a secondary basal site S565 in rat HSL (
      • Yeaman S.J.
      Hormone-sensitive lipase - a multipurpose enzyme in lipid metabolism.
      ). Phosphorylation at S565 impairs the phosphorylation of S563 by PKA (
      • Yeaman S.J.
      Hormone-sensitive lipase - a multipurpose enzyme in lipid metabolism.
      ). HSL activity can be inactivated by protein phosphatases. The most active phosphatases against S563 are phosphatase 2A and 2C, while S565 is predominately dephosphorylated by phosphatase 2A (
      • Wood S.L.
      • Emmison N.
      • Borthwick A.C.
      • Yeaman S.J.
      The protein phosphatases responsible for dephosphorylation of hormone-sensitive lipase in isolated rat adipocytes.
      ). Thus, several different kinases phosphorylate HSL at unique serines within the regulatory module and modulate HSL activity.

      Physiological functions

      Adipose tissue

      The primary action attributed to HSL is hydrolysis of stored triacylglycerols in adipose tissue, i.e., lipolysis. The control of lipolysis is complex and involves multiple mechanisms (
      • Londos C.
      • Brasaemle D.L.
      • Schultz C.J.
      • Adler-Wailes D.C.
      • Levin D.M.
      • Kimmel A.R.
      • Rondinone C.M.
      On the control of lipolysis in adipocytes.
      ,
      • Holm C.
      • Osterlund T.
      • Laurell H.
      • Contreras J.A.
      Molecular mechanisms regulating hormone-sensitive lipase and lipolysis.
      ). These include lipolytic (β-adrenergic agonists, ACTH, etc.) and anti-lipolytic (insulin, adenosine, etc.) hormones, their cognate receptors and signaling pathways, lipid droplet-associated proteins such as perilipins, as well as HSL or other as yet unidentified lipases. In addition to the activation of HSL hydrolytic activity, other mechanisms involving HSL have been suggested to account for lipolysis. Evidence has been provided using subcellular fractionation to show that catecholamine-induced stimulation of lipolysis in vitro in 3T3-L1 adipocytes or in rat adipose cells is due to the translocation of phosphorylated HSL from an aqueous cytosolic compartment to the lipid droplet (
      • Egan J.J.
      • Greenberg A.S.
      • Chang M-K.
      • Wek S.A.
      • Moos Jr., M.C.
      • Londos C.
      Mechanism of hormone-stimulated lipolysis in adipocytes: translocation of hormone-sensitive lipase to the lipid storage droplet.
      ,
      • Clifford G.M.
      • Londos C.
      • Kraemer F.B.
      • Vernon R.G.
      • Yeaman S.J.
      Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes.
      ). Using immunofluorescence microscopy, HSL was observed diffusely distributed throughout the cytosol of 3T3-L1 adipocytes and, upon catecholamine stimulation, HSL translocated from the cytosol to the surfaces of intracellular lipid droplets concomitant with the onset of lipolysis (
      • Brasaemle D.L.
      • Levin D.M.
      • Adler-Wailes D.C.
      • Londos C.
      The lipolytic stimulation of 3T3–L1 adipocytes promotes the translocation of hormone-sensitive lipase to the surfaces of lipid storage droplets.
      ). It has been suggested that translocation of HSL to the lipid droplet is the critical event in regulating lipolysis induced by a variety of lipolytic agents, such as isoproterenol, forskolin, cyclic AMP, theophylline, and okadaic acid (
      • Morimoto C.
      • Kiyama A.
      • Kameda K.
      • Ninomiya H.
      • Tsujita T.
      • Okuda H.
      Mechanism of the stimulatory action of okadaic acid on lipolysis in rat fat cells.
      ,
      • Morimoto C.
      • Kameda K.
      • Tsujita T.
      • Okuda H.
      Relationships between lipolysis induced by various lipolytic agents and hormone-sensitive lipase in rat fat cells.
      ); however, this is not true for all physiological conditions, since translocation of HSL was not observed with lipolytic stimulation in adipocytes from old (
      • Clifford G.M.
      • Londos C.
      • Kraemer F.B.
      • Vernon R.G.
      • Yeaman S.J.
      Translocation of hormone-sensitive lipase and perilipin upon lipolytic stimulation of rat adipocytes.
      ) or lactating rats (
      • Clifford G.M.
      • Kraemer F.B.
      • Yeaman S.J.
      • Vernon R.G.
      Translocation of hormone-sensitive lipase and perilipin upon lipolytic stiumlation during the lactation cycle of the rat.
      ). Although the mechanisms mediating the translocation of HSL have not been well studied, disruption of microtubules or microfilaments appears to have minimal effects on isoproterenol-stimulated glycerol release and no visible effects on the translocation of HSL determined by immunofluorescence light microscopy (
      • Brasaemle D.L.
      • Levin D.M.
      • Adler-Wailes D.C.
      • Londos C.
      The lipolytic stimulation of 3T3–L1 adipocytes promotes the translocation of hormone-sensitive lipase to the surfaces of lipid storage droplets.
      ). However, a protein (lipotransin) was identified in a yeast two-hybrid screen that interacts with HSL and was proposed to be a potential participant in the process of the translocation of HSL to the lipid droplet (
      • Syu L-J.
      • Saltiel A.R.
      Lipotransin, a novel docking protein for hormone-sensitive lipase.
      ). Lipotransin is homologous to p60 katanin and is a member of the AAA protein superfamily, possessing ATPase and microtubule severing activities (
      • Hartman J.J.
      • Mahr J.
      • McNally K.
      • Okawa K.
      • Iwamatsu A.
      • Thomas S.
      • Cheesman S.
      • Heuser J.
      • Vale R.D.
      • McNally F.J.
      Katanin, a microtubule-severing protein, is a novel AAA ATPase that targets to the centrosome using a WD40-containing subunit.
      ). The function of lipotransin in interacting with HSL and influencing lipolysis has yet to be elucidated. A proposed model for hormone-induced lipolysis is depicted in Fig. 2.
      Figure thumbnail gr2
      Fig. 2Model of the mechanism of hormone-stimulated lipolysis. Under basal conditions HSL is not associated with the lipid droplet and is perhaps tethered to lipotransin, while perilipin decorates the lipid droplet and hinders access of the droplet to HSL. ALBP and other fatty acid binding proteins are found abundantly in the cytosol. Following hormonal stimulation, HSL and perilipin are phosphorylated and HSL translocates to the lipid droplet. ALBP binds to HSL, preventing fatty acid inhibition of the enzyme's hydrolytic activity, and sequesters and transports the released fatty acids.
      Fatty acids and monoacylglycerol exert product inhibition on HSL activity. This is interesting in light of the observation that HSL specifically interacts with ALBP, a member of the family of intracellular lipid-binding proteins which bind fatty acids and other hydrophobic ligands (
      • Shen W-J.
      • Sridhar K.
      • Bernlohr D.A.
      • Kraemer F.B.
      Interaction of rat hormone-sensitive lipase with adipocyte lipid-binding protein.
      ). Mutational analysis has identified several amino acids within the N-terminal domain of HSL (H194 and E199) as critical for mediating the interaction of HSL with ALBP (
      • Shen W-J.
      • Liang Y.
      • Hong R.
      • Patel S.
      • Natu V.
      • Sridhar K.
      • Jenkins A.
      • Bernlohr D.A.
      • Kraemer F.B.
      Characterization of the functional interaction of adipocyte lipid-binding protein with hormone-sensitive lipase.
      ). Incubation or co-expression of ALBP with HSL increased substrate hydrolysis, which was lost when the binding of ALBP to HSL was disrupted by mutagenesis. In addition, the ability of fatty acids to inhibit HSL hydrolytic activity was attenuated by co-incubation with ALBP. These observations suggest that ALBP and HSL constitute a lipolytic complex that increases the hydrolytic activity of HSL through the physical interaction of HSL with ALBP, and because ALBP sequesters fatty acids and prevents product inhibition. This is consistent with experiments in ALBP null mice where basal and isoproterenol-stimulated lipolysis are decreased ∼40% (
      • Coe N.R.
      • Simpson M.A.
      • Bernlohr D.A.
      Targeted disruption of the adipocyte lipid binding protein (aP2 protein) gene impairs fat cell lipolysis and increases cellular fatty acid levels.
      ).
      Indirect evidence has suggested that HSL is the rate limiting enzyme in intracellular lipolysis; overexpression of HSL in 3T3-F442A cells prevents differentiated adipocytes from accumulating triglyceride (
      • Sztalryd C.
      • Komaromy M.C.
      • Kraemer F.B.
      Overexpression of hormone-sensitive lipase prevents triglyceride accumulation in adipocytes.
      ). Recently, the functional significance of HSL in adipose tissue metabolism has begun to be clarified in studies using HSL null mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ,
      • Wang S.P.
      • Laurin N.
      • Himms-Hagen J.
      • Rudnicki M.A.
      • Levy E.
      • Robert M-F.
      • Pan L.
      • Oligny L.
      • Mitchell G.A.
      The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice.
      ,
      • Haemmerle G.
      • Zimmermann R.
      • Hayn M.
      • Theussl C.
      • Waeg G.
      • Wagner E.
      • Sattler W.
      • Magin T.M.
      • Wagner E.F.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.
      ). Inactivation of HSL by homologous recombination resulted in the complete absence of neutral cholesteryl ester hydrolase activity in adipose tissue (both white and brown); however, triacylglycerol lipase activity in white adipose tissue was reduced by only 40% and triacylglycerol lipase activity in brown adipose tissue was similar to wild-type mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ). Basal lipolysis, i.e., glycerol release, was reduced in isolated adipose cells from HSL null mice in one study (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ), but was unaffected and perhaps increased in another (
      • Wang S.P.
      • Laurin N.
      • Himms-Hagen J.
      • Rudnicki M.A.
      • Levy E.
      • Robert M-F.
      • Pan L.
      • Oligny L.
      • Mitchell G.A.
      The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice.
      ). Nonetheless, there was a marked defect or complete absence of catecholamine-stimulated glycerol release in adipose cells from HSL null mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ,
      • Wang S.P.
      • Laurin N.
      • Himms-Hagen J.
      • Rudnicki M.A.
      • Levy E.
      • Robert M-F.
      • Pan L.
      • Oligny L.
      • Mitchell G.A.
      The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice.
      ), whereas catecholamine-stimulated FFA release was still observed, but attenuated (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ). This apparent discrepancy in the release of glycerol and FFA from adipose cells of HSL null mice has been clarified by the observation that diacylglycerol content increased markedly in adipose tissue of HSL null mice (
      • Haemmerle G.
      • Zimmermann R.
      • Hayn M.
      • Theussl C.
      • Waeg G.
      • Wagner E.
      • Sattler W.
      • Magin T.M.
      • Wagner E.F.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.
      ). In both white and brown adipose tissue from HSL null mice, catecholamine-stimulation caused the release of small amounts of FFA without any stimulated glycerol release, and a marked accumulation of diacylglycerol (
      • Haemmerle G.
      • Zimmermann R.
      • Hayn M.
      • Theussl C.
      • Waeg G.
      • Wagner E.
      • Sattler W.
      • Magin T.M.
      • Wagner E.F.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.
      ). Therefore, studies with HSL null mice appear to substantiate that HSL is the rate-limiting enzyme for diacylglycerol hydrolysis in adipose tissue and is essential for hormone stimulated lipolysis. The absence of HSL is not associated with the development of obesity; however, adipose cells from HSL null mice, while displaying size heterogeneity, tend to be hypertrophic (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ,
      • Wang S.P.
      • Laurin N.
      • Himms-Hagen J.
      • Rudnicki M.A.
      • Levy E.
      • Robert M-F.
      • Pan L.
      • Oligny L.
      • Mitchell G.A.
      The adipose tissue phenotype of hormone-sensitive lipase deficiency in mice.
      ). Moreover, due to defective lipolysis during fasting, there is a reduction in circulating FFA and a decreased hepatic production of VLDL triglyceride secondary to the diminished release of FFA from adipose tissue (
      • Haemmerle G.
      • Zimmermann R.
      • Strauss J.G.
      • Kratky D.
      • Riederer M.
      • Knipping G.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle.
      ). This is associated with an induction of LPL in white adipose tissue, as well as skeletal and cardiac muscle, but a decrease of LPL in brown adipose tissue (
      • Haemmerle G.
      • Zimmermann R.
      • Strauss J.G.
      • Kratky D.
      • Riederer M.
      • Knipping G.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice changes the plasma lipid profile by affecting the tissue-specific expression pattern of lipoprotein lipase in adipose tissue and muscle.
      ).
      Although HSL is primarily regulated by post-translational mechanisms, pretranslational mechanisms are important under some physiological settings. The expression of HSL protein and mRNA levels are lower in subcutaneous fat stores compared with internal fat depots in the rat (
      • Sztalryd C.
      • Kraemer F.B.
      Differences in hormone sensitive lipase expression in white adipose tissue from various anatomical locations of the rat.
      ), suggesting a possible basis for the differences in the rate of lipolysis among various fat depots. In contrast, subcutaneous fat in humans was reported to have higher HSL mRNA expression and HSL activity than omental fat. Human subcutaneous fat cells are larger and there is a positive correlation between fat cell size and HSL expression (
      • Reynisdottir S.
      • Dauzats M.
      • Thorne A.
      • Langin D.
      Comparison of hormone-sensitive lipase activity in visceral and subcutaneous human adipose tissue.
      ). When controlled for adipocyte cell size, the amount of HSL protein and HSL mRNA levels in subcutaneous adipocytes show a strong correlation with maximum lipolytic activity (
      • Large V.
      • Arner P.
      • Reynisdottir S.
      • Grober J.
      • Van Harmelen V.
      • Holm C.
      • Langin D.
      Hormone-sensitive lipase expression and activity in relation to lipolysis in human fat cells.
      ). A positive relationship between fat cell size and HSL expression was also seen with high fat feeding in rats, where fat feeding was associated with an increase in adipocyte cell size and an increase in both basal and stimulated HSL activity (
      • Berger J.J.
      • Barnard R.J.
      Effect of diet on fat cell size and hormone-sensitive lipase activity.
      ). In contrast, following several days of food deprivation in the rat, there is a ∼2-fold increase in HSL activity, immunoreactive protein, and mRNA levels in adipose tissue that is not observed with short term fasting and is associated with a reduction in fat cell size (
      • Sztalryd C.
      • Kraemer F.B.
      Regulation of hormone sensitive lipase during fasting.
      ). HSL mRNA levels have also been shown to be increased in adipose tissue in hibernating marmots during their time of fasting (
      • Wilson B.E.
      • Deeb S.
      • Florant G.L.
      Seasonal changes in hormone-sensitive and lipoprotein lipase messenger RNA concentrations in marmot white adipose tissue.
      ). Moreover, HSL activity, immunoreactive protein, and mRNA levels in adipose tissue were increased in response to streptozotocin-induced insulin deficiency in the rat, whereas short-term treatment with insulin returned HSL activity to normal without altering the increased amounts of HSL immunoreactive protein and mRNA (
      • Sztalryd C.
      • Kraemer F.B.
      Regulation of hormone-sensitive lipase in streptozotocin-treated rats.
      ). Thus, HSL activity appears to be regulated by pretranslational mechanisms under prolonged conditions, while short-term treatment with insulin controlled HSL by post-translational mechanisms. Using primary rat adipocytes, epinephrine, glucagon, growth hormone, and dexamethasone were all found to increase HSL activity, i.e., lipolysis, but only dexamethasone caused an increase in HSL mRNA levels (
      • Slavin B.G.
      • Ong J.M.
      • Kern P.A.
      Hormonal regulation of hormone-sensitive lipase activity and mRNA levels in isolated rat adipocytes.
      ), supporting a role for both post-translational and pretranslational mechanisms in controlling HSL expression and lipolysis. Glucose deprivation in adipocytes results in a decline in HSL expression, whereas incubation with glucose and insulin maintains HSL expression during adipocyte culture and results in an increase of basal and stimulated lipolysis (
      • Botion L.M.
      • Green A.
      Long-term regulation of lipolysis and hormone-sensitive lipase by insulin and glucose.
      ). Recently, a glucose-responsive region was mapped within the proximal promoter of human HSL and the involvement of upstream stimulatory factor 1 and 2 binding to a consensus E-box within this region was shown to be responsible for transcriptional regulation in response to glucose metabolism between glucose-6-phosphate and triose phosphates (
      • Smih F.
      • Rouet P.
      • Lucas S.
      • Mairal A.
      • Sengenes C.
      • Lafontan M.
      • Vaulont S.
      • Casado M.
      • Langin D.
      Transciptional regulation of adipocyte hormone-sensitive lipase by glucose.
      ). In contrast to induction of HSL, TNFα causes a marked reduction in HSL gene expression (
      • Ruan H.
      • Hacohen N.
      • Golub T.R.
      • Van Parijs L.
      • Lodish H.F.
      Tumor necrosis factor-α suppresses adipocyte-specific genes and activates expression of preadipocyte genes in 3T3–L1 adipocytes: Nuclear Factor-κB activation by TNF-α is obligatory.
      ), while stimulating lipolysis in adipocytes; the mechanisms appear to involve other components of the lipolytic machinery, particularly perilipin (
      • Souza S.C.
      • de Vargas L.M.
      • Yamamoto M.T.
      • Lien P.
      • Franciosa M.D.
      • Moss L.G.
      • Greenberg A.S.
      Overexpression of perilipin A and B blocks the ability of tumor necrosis factor α to increase lipolysis in 3T3–L1 adipocytes.
      ).

      Other tissues

      Macrophages

      HSL is definitely expressed in murine macrophages and macrophage cell lines (
      • Small C.A.
      • Rogers M.P.
      • Goodacre J.A.
      • Yeaman S.J.
      Phosphorylation and activation of hormone-sensitive lipase in isolated macrophages.
      ,
      • Khoo J.C.
      • Reue K.
      • Steinberg D.
      • Schotz M.C.
      Expression of hormone-sensitive lipase mRNA in macrophages.
      ); however, its expression in human monocytes and macrophages has been controversial, with some studies unable to detect HSL (
      • Contreras J.
      • Lasuncion M.
      Essential differences in cholesteryl ester metabolism between human monocyte-derived and J774 macrophages. Evidence against the presence of hormone-sensitive lipase in human macrophages.
      ,
      • Li F.
      • Hui D.Y.
      Modified low density lipoprotein enhances the secretion of bile salt-stimulated cholesterol esterase by human monocyte-macrophages. species-specific difference in macrophage cholesteryl ester hydrolase.
      ) and others documenting low levels of HSL expression (
      • Reue K.
      • Cohen R.D.
      • Schotz M.C.
      Evidence for hormone-sensitive lipase mRNA expression in human monocyte/macrophages.
      ,
      • Harte R.
      • Hulten L.
      • Lindmark H.
      • Reue K.
      • Schotz M.
      • Khoo J.
      • Rosenfeld M.
      Low level expression of hormone-sensitive lipase in arterial macrophage-derived foam cells: potential explanation for low rates of cholesteryl ester hydrolysis.
      ) or suggesting that the testicular HSL isoform is preferentially expressed (
      • Johnson W.
      • Jang S.
      • Bernard D.
      Hormone sensitive lipase mRNA in both monocyte and macrophage forms of the human THP-1 cell line.
      ). Further questioning a role for HSL in macrophages, neutral cholesteryl ester hydrolase activity has been reported to be unchanged in peritoneal macrophages isolated from HSL null mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ,
      • Contreras J.A.
      Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages.
      ), and cholesteryl ester stores in HSL null macrophages are mobilized similar to wild-type macrophages (
      • Contreras J.A.
      Hormone-sensitive lipase is not required for cholesteryl ester hydrolysis in macrophages.
      ), suggesting that HSL is not the major neutral cholesteryl ester hydrolase in macrophages. Nonetheless, it is possible that the findings with HSL null mice are due to a compensatory induction of other neutral cholesteryl ester hydrolases. HSL expression and neutral cholesteryl ester hydrolase activity are co-regulated in murine macrophages. Sterol loading of macrophages decreased HSL immunoreactive protein and neutral cholesteryl ester hydrolase activity (
      • Jepson C.A.
      • Harrison J.A.
      • Kraemer F.B.
      • Yeaman S.J.
      Down-regulation of hormone-sensitive lipase in sterol ester-laden J774.2 macrophages.
      ), whereas insulin has been reported to rapidly decrease and leptin to rapidly increase HSL activity (
      • O'Rourke L.
      • Yeaman S.J.
      • Shepherd P.R.
      Insulin and leptin acutely regulate cholesterol ester metabolism in macrophages by novel signaling pathways.
      ). Transgenic (
      • Escary J-L.
      • Choy H.A.
      • Reue K.
      • Schotz M.C.
      Hormone-sensitive lipase overexpression increases cholesteryl ester hydrolysis in macrophage foam cells.
      ) or adenovirus-mediated (
      • Okazaki H.
      • Osuga J-i.
      • Tsukamoto K.
      • Isoo N.
      • Kitamine T.
      • Tamura Y.
      • Tomita S.
      • Sekiya M.
      • Yahagi N.
      • Iizuka Y.
      • Ohashi K.
      • Harada K.
      • Gotoda T.
      • Shimano H.
      • Kimura S.
      • Nagai R.
      • Yamada N.
      • Ishibashi S.
      Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase.
      ) overexpression of HSL in macrophages results in an increase in the hydrolysis of cholesteryl ester stores and an increased cholesterol efflux, along with a decrease in the uptake of lipoproteins via scavenger receptors (
      • Okazaki H.
      • Osuga J-i.
      • Tsukamoto K.
      • Isoo N.
      • Kitamine T.
      • Tamura Y.
      • Tomita S.
      • Sekiya M.
      • Yahagi N.
      • Iizuka Y.
      • Ohashi K.
      • Harada K.
      • Gotoda T.
      • Shimano H.
      • Kimura S.
      • Nagai R.
      • Yamada N.
      • Ishibashi S.
      Elimination of cholesterol ester from macrophage foam cells by adenovirus-mediated gene transfer of hormone-sensitive lipase.
      ). Paradoxically, however, macrophage-specific transgenic expression of HSL resulted in more advanced atherosclerosis than in control mice fed a high fat, high cholesterol diet (
      • Escary J-L.
      • Choy H.A.
      • Reue K.
      • Wang X-P.
      • Castellani L.W.
      • Glass C.K.
      • Lusis A.J.
      • Schotz M.C.
      Paradoxical effect on atherosclerosis of hormone-sensitive lipase overexpression in macrophages.
      ), perhaps due to indirect effects on inflammation.

      Muscle

      HSL of 84 kDa size has been reported to be expressed in cardiac (
      • Kraemer F.B.
      • Patel S.
      • Saedi M.S.
      • Sztalryd C.
      Detection of hormone-sensitive lipase in various tissues. I. Expression of an HSL/bacterial fusion protein and generation of anti-HSL antibodies.
      ) and skeletal muscle (
      • Peters S.J.
      • Dyck D.J.
      • Bonen A.
      • Spriet L.L.
      Effects of epinephrine on lipid metabolism in resting skeletal muscle.
      ,
      • Langfort J.
      • Ploug T.
      • Ihlemann J.
      • Saldo M.
      • Holm C.
      • Galbo H.
      Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle.
      ). In skeletal muscle the expression of HSL is higher in oxidative than glycolytic muscle (
      • Peters S.J.
      • Dyck D.J.
      • Bonen A.
      • Spriet L.L.
      Effects of epinephrine on lipid metabolism in resting skeletal muscle.
      ,
      • Langfort J.
      • Ploug T.
      • Ihlemann J.
      • Saldo M.
      • Holm C.
      • Galbo H.
      Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle.
      ), and HSL expression is reduced in 24-month-old rats (
      • Tucker M.Z.
      • Turcotte L.P.
      Impaired fatty acid oxidation in muscle of aging rats perfused under basal conditions.
      ), perhaps contributing to the increase in muscle triglyceride content observed with aging. HSL activity in muscle is stimulated by catecholamines (
      • Peters S.J.
      • Dyck D.J.
      • Bonen A.
      • Spriet L.L.
      Effects of epinephrine on lipid metabolism in resting skeletal muscle.
      ,
      • Langfort J.
      • Ploug T.
      • Ihlemann J.
      • Saldo M.
      • Holm C.
      • Galbo H.
      Expression of hormone-sensitive lipase and its regulation by adrenaline in skeletal muscle.
      ) acting via β-adrenergic receptors and cyclic AMP and by contraction acting independently of sympathetic tone or catecholamines (
      • Langfort J.
      • Ploug T.
      • Ihlemann J.
      • Holm C.
      • Galbo H.
      Stimulation of hormone-sensitive lipase activity by contractions in rat skeletal muscle.
      ). Exercise training does not affect the expression of HSL protein in muscle, but decreases the sensitivity of stimulation of muscle HSL activity by epinephrine (
      • Enevoldsen L.
      • Stallknecht B.
      • Langfort J.
      • Petersen L.
      • Holm C.
      • Ploug T.
      • Galbo H.
      The effect of exercise training on hormone-sensitive lipase in rat intra-abdominal adipose tissue and muscle.
      ). Heart-specific transgenic overexpression of HSL prevents the accumulation of cardiac triglyceride normally seen in fasted rodents (
      • Suzuki J.
      • Shen W-J.
      • Nelson B.D.
      • Patel S.
      • Veerkamp J.H.
      • Selwood S.P.
      • Murphy Jr., G.M.
      • Reaven E.
      • Kraemer F.B.
      Absence of cardiac lipid accumulation in transgenic mice with heart-specific HSL overexpression.
      ). In addition, heart-specific overexpression of HSL alters the expression of cardiac genes for fatty acid oxidation, transcription factors, signaling molecules, cytoskeletal proteins, and histocompatibility antigens. Thus, HSL in cardiac and skeletal muscle plays a role in controlling the accumulation of triglyceride droplets and in energy utilization.

      Adrenal

      The neutral cholesterol ester hydrolase activity purified from the adrenal has been shown to be identical to HSL purified from adipose tissue (
      • Cook K.G.
      • Yeaman S.J.
      • Stralfors P.
      • Fredrikson G.
      • Belfrage P.
      Direct evidence that cholesteryl ester hydrolase from adrenal cortex is the same enzyme as hormone-sensitive lipase from adipose tissue.
      ). Moreover, immunoreactive HSL (
      • Kraemer F.B.
      • Patel S.
      • Saedi M.S.
      • Sztalryd C.
      Detection of hormone-sensitive lipase in various tissues. I. Expression of an HSL/bacterial fusion protein and generation of anti-HSL antibodies.
      ,
      • Holm C.
      • Belfrage P.
      • Fredrikson G.
      Immunological evidence for the presence of hormone-sensitive lipase in rat tissue other than adipose tissue.
      ) and HSL mRNA (
      • Holm C.
      • Kirchgessner T.G.
      • Svenson K.L.
      • Fredrikson G.
      • Nilsson S.
      • Miller C.G.
      • Shively J.E.
      • Heinzmann C.
      • Sparkes R.S.
      • Mohandas T.
      • Lusis A.J.
      • Belfrage P.
      • Schotz M.C.
      Hormone-sensitive lipase: sequence, expression, and chromosomal localization to 19 cent-q13.3.
      ,
      • Kraemer F.B.
      • Tavangar K.
      • Hoffman A.R.
      Developmental regulation of hormone-sensitive lipase mRNA in the rat: changes in steroidogenic tissues.
      ) can be detected in adrenal, just as in adipose tissue. Less HSL is expressed in the glomerulosa than the inner cortex, and subfractionation of adrenals showed that immunoreactive HSL was prominently expressed in microsomes, with lesser amounts in the cytosol and little to no HSL in other fractions or the lipid droplet (
      • Kraemer F.B.
      • Shen W.-J.
      • Natu V.
      • Patel S.
      • Osuga J-i.
      • Ishibashi S.
      • Azhar S.
      Adrenal neutral cholesteryl hydrolase: identification, subcellular distribution and sex differences.
      ). HSL appears to be responsible for the vast majority, if not all, of the neutral cholesterol ester hydrolase activity in the adrenal since adrenals of HSL null mice have <2% of the neutral cholesterol ester hydrolase activity of wild-type mice (
      • Kraemer F.B.
      • Shen W.-J.
      • Natu V.
      • Patel S.
      • Osuga J-i.
      • Ishibashi S.
      • Azhar S.
      Adrenal neutral cholesteryl hydrolase: identification, subcellular distribution and sex differences.
      ). Although basal corticosterone levels are normal, the absence of HSL resulted in a reduction in corticosterone response to ACTH, suggesting that the actions of HSL are involved in the delivery of cholesterol for steroidogenesis.

      Testis

      The rat testis expresses a single 3.9 kB HSL mRNA due to a testis specific exon 15.5 kB upstream of exon 1 that encodes a ∼120–130 kDa immunoreactive protein, which contains an additional 300 amino acids N-terminal to the normal adipose form (
      • Stenson Holst L.
      • Langin D.
      • Mulder H.
      • Laurell H.
      • Grober J.
      • Bergh A.
      • Mohrenweiser H.W.
      • Edgren G.
      • Holm C.
      Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.
      ). The human testis contains both 3.9 kB and 3.3 kB HSL mRNAs, due to a testis specific exon 15.5 kB upstream of exon 1 that encodes a ∼120–130 kDa immunoreactive protein containing an additional 301 amino acids N-terminal to the normal adipose form and due to a second testis specific exon ∼12 kB upstream of exon 1 that encodes a protein identical to adipocyte HSL (
      • Mairal A.
      • Melaine N.
      • Laurell H.
      • Grober J.
      • Holst L.
      • Guillaudeux T.
      • Holm C.
      • Jegou B.
      • Langin D.
      Characterization of a novel testicular form of human hormone-sensitive lipase.
      ). HSL expression in the testis shows marked developmental changes. HSL mRNA is undetectable in testis in the first few weeks of age and increases 25-fold to stable adult levels between 20 and 90 days (
      • Kraemer F.B.
      • Tavangar K.
      • Hoffman A.R.
      Developmental regulation of hormone-sensitive lipase mRNA in the rat: changes in steroidogenic tissues.
      ). Whereas HSL activity appears to be regulated almost exclusively by post-translational mechanisms in most other tissues, treatment of sexually immature rats with chorionic gonadotropin increases neutral cholesteryl ester hydrolase activity by increasing HSL mRNA levels and the amount of HSL immunoreactive protein (
      • Kraemer F.B.
      • Patel S.
      • Singh-Bist A.
      • Gholami S.S.
      • Saedi M.S.
      • Sztalryd C.
      Detection of hormone-sensitive lipase in various tissues. II. Regulation in the rat testis by human chorionic gonadotropin.
      ). In the rat, HSL is not expressed in Leydig cells, but HSL is localized to Sertoli cells and spermatids after spermiation, where in situ hybridization and immunohistochemistry have shown the lowest intensity of labeling in stages III–VII and the highest intensity of labeling in elongated spermatids in stages X–XIV (
      • Stenson Holst L.
      • Langin D.
      • Mulder H.
      • Laurell H.
      • Grober J.
      • Bergh A.
      • Mohrenweiser H.W.
      • Edgren G.
      • Holm C.
      Molecular cloning, genomic organization, and expression of a testicular isoform of hormone-sensitive lipase.
      ,
      • Holst L.S.
      • Hoffmann A.M.
      • Mulder H.
      • Sundler F.
      • Holm C.
      • Bergh A.
      • Fredrikson G.
      Localization of hormone-sensitive lipase to rat Sertoli cells and its expression in developing and degenerating testes.
      ). In contrast, HSL has been observed by immunohistochemistry in Leydig cells, as well as Sertoli cells and sperm in guinea pig (
      • Kabbaj O.
      • Holm C.
      • Vitale M.L.
      • Pelletier R-M.
      Expression, activity, and subcellular localization of testicular hormone-sensitive lipase during postnatal development in the guinea pig.
      ) and human testes (
      • Mairal A.
      • Melaine N.
      • Laurell H.
      • Grober J.
      • Holst L.
      • Guillaudeux T.
      • Holm C.
      • Jegou B.
      • Langin D.
      Characterization of a novel testicular form of human hormone-sensitive lipase.
      ) where two HSL mRNA species are expressed. It appears that only the larger 120 kDa isoform is expressed in spermatids (
      • Mairal A.
      • Melaine N.
      • Laurell H.
      • Grober J.
      • Holst L.
      • Guillaudeux T.
      • Holm C.
      • Jegou B.
      • Langin D.
      Characterization of a novel testicular form of human hormone-sensitive lipase.
      ). The testis-specific and spermatid-specific, expression of HSL has been attributed to a possible germ cell-specific zinc finger transcription factor that binds between −46 and −29 base pairs upstream of the testis-specific promoter (
      • Blaise R.
      • Grober J.
      • Rouet P.
      • Tavernier G.
      • Daegelen D.
      • Langin D.
      Testis expression of hormone-sensitive lipase is conferred by a specific promoter that contains four regions binding testicular nuclear proteins.
      ,
      • Blaise R.
      • Guillaudeux T.
      • Tavernier G.
      • Daegelen D.
      • Evrard B.
      • Mairal A.
      • Holm C.
      • Jegou B.
      • Langin D.
      Testis hormone-sensitive lipase expression in spermatids is governed by a short promoter in transgenic mice.
      ). In studies of HSL null mice, no immunoreactive HSL was observed in testis and no neutral cholesteryl ester hydrolase activity could be detected in testis of HSL null mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ). Thus, it appears that HSL is responsible for all of the neutral cholesteryl ester hydrolase activity in testis even though previous reports have suggested that other lipases might be involved. Serum testosterone, LH, and FSH values were similar in HSL null and wild-type mice, which is consistent with HSL not being expressed in Leydig cells in rodents; however, HSL protein and enzymatic activity in interstitial tissue have been positively correlated with testosterone levels during development in the guinea pig (
      • Kabbaj O.
      • Holm C.
      • Vitale M.L.
      • Pelletier R-M.
      Expression, activity, and subcellular localization of testicular hormone-sensitive lipase during postnatal development in the guinea pig.
      ). The absence of HSL in the testis resulted in a 2-fold increase in testicular cholesteryl ester (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ) and diacylglycerol (
      • Haemmerle G.
      • Zimmermann R.
      • Hayn M.
      • Theussl C.
      • Waeg G.
      • Wagner E.
      • Sattler W.
      • Magin T.M.
      • Wagner E.F.
      • Zechner R.
      Hormone-sensitive lipase deficiency in mice causes diglyceride accumulation in adipose tissue, muscle, and testis.
      ) content, as well as severe oligospermia in HSL null mice (
      • Osuga J-i.
      • Ishibashi S.
      • Oka T.
      • Yagyu H.
      • Tozawa R.
      • Fujimoto A.
      • Shionoira F.
      • Yahagi N.
      • Kraemer F.B.
      • Tsutsumi O.
      • Yamada N.
      Targeted disruption of hormone-sensitive lipase results in male sterility and adipocyte hypertrophy, but not in obesity.
      ,
      • Chung S.
      • Wang S.
      • Pan L.
      • Mitchell G.
      • Trasler J.
      • Hermo L.
      Infertility and testicular defects in hormone-sensitive lipase-deficient mice.
      ). The sperm that do form display severe morphological abnormalities (
      • Chung S.
      • Wang S.
      • Pan L.
      • Mitchell G.
      • Trasler J.
      • Hermo L.
      Infertility and testicular defects in hormone-sensitive lipase-deficient mice.
      ). Therefore, consonant with its expression in germ cells, these observations from HSL null mice suggest that HSL plays an important role in supporting normal spermiogenesis.

      Islets

      HSL is predominantly expressed in pancreatic islets as a 3.1 kB mRNA encoding an ∼89 kDa isoform containing an additional 43 amino acids N-terminal to the adipocyte form of the protein, as well as the 2.8 kB mRNA encoding the 84 kDa adipocyte form (
      • Mulder H.
      • Holst L.
      • Svensson H.
      • Degerman E.
      • Sundler F.
      • Ahren B.
      • Rorsman P.
      • Holm C.
      Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.
      ). HSL immunoreactivity in islets is detected primarily in β cells, but some HSL is also observed in α cells (
      • Mulder H.
      • Holst L.
      • Svensson H.
      • Degerman E.
      • Sundler F.
      • Ahren B.
      • Rorsman P.
      • Holm C.
      Hormone-sensitive lipase, the rate-limiting enzyme in triglyceride hydrolysis, is expressed and active in beta-cells.
      ). Long term incubation of β cells or islets with high concentrations of glucose increases HSL mRNA and protein expression, as well as HSL activity (
      • Winzell M.S.
      • Svensson H.
      • Arner P.
      • Ahrén B.
      • Holm C.
      The expression of hormone-sensitive lipase in clonal β-cells and rat islets is induced by long-term exposure to high glucose.
      ). This induction of HSL expression appears to be regulated transcriptionally and to depend on the metabolism of glucose. Treatment of ob/ob mice with leptin increased HSL expression in islets, along with a decrease in islet triglyceride content and an improvement in insulin secretion (
      • Khan A.
      • Narangoda S.
      • Ahren B.
      • Holm C.
      • Sundler F.
      • Efendic S.
      Long-term leptin treatment of ob/ob mice improves glucose-induced insulin secretion.
      ). HSL is definitely functional in islets, since islet triglyceride content is increased 2–2.5-fold in HSL null mice compared with wild-type mice (
      • Roduit R.
      • Masiello P.
      • Wang S.P.
      • Li H.
      • Mitchell G.A.
      • Prentki M.
      A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice.
      ). Although HSL null mice are normoglycemic and normoinsulinemic when evaluated under fed and overnight fasted conditions, they are glucose intolerant and display a lack of rise in insulin in response to a glucose load (
      • Roduit R.
      • Masiello P.
      • Wang S.P.
      • Li H.
      • Mitchell G.A.
      • Prentki M.
      A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice.
      ). In addition, isolated islets from HSL null mice secrete higher amounts of insulin when exposed to basal glucose concentrations, but do not release insulin in response to glucose; however, their response to KCl-induced insulin secretion is normal (
      • Roduit R.
      • Masiello P.
      • Wang S.P.
      • Li H.
      • Mitchell G.A.
      • Prentki M.
      A role for hormone-sensitive lipase in glucose-stimulated insulin secretion: a study in hormone-sensitive lipase-deficient mice.
      ). These observations suggest that HSL might play an important role in glucose-induced insulin secretion and are consistent with the current view that fatty acid metabolites are critical for insulin secretion, but that excessive fatty acids can lead to lipotoxicity and dysfunction of β cell (
      • McGarry J.D.
      Banting Lecture 2001: Dysregulation of fatty acid metabolism in the etiology of type 2 diabetes.
      ). The exact function of HSL in insulin secretion from β cells awaits further study.

      Pathophysiology

      Although HSL has not been identified as a major gene that is responsible for a unique metabolic disease, diminished activity of HSL or genetic polymorphisms of HSL have been described in various metabolic disorders. For instance, maximum enzymatic activity of HSL was reported to be decreased ∼40% in 10 patients with familial combined hyperlipidemia in Sweden (
      • Reynisdottir S.
      • Eriksson M.
      • Angelin B.
      • Arner P.
      Impaired activation of adipocyte lipolysis in familial combined hyperlipidemia.
      ,
      • Reynisdottir S.
      • Angelin B.
      • Langin D.
      • Lithell H.
      • Eriksson M.
      • Holm C.
      • Arner P.
      Adipose tissue lipoprotein lipase and hormone-sensitive lipase: contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome.
      ); however, no differences in HSL activity were demonstrated in 48 subjects with familial combined hyperlipidemia in Finland when compared with normolipidemic spouses (
      • Ylitalo K.
      • Large V.
      • Pajukanta P.
      • Reynisdottir S.
      • Porkka K.
      • Vakkilainen J.
      • Nuotio I.
      • Taskinen M.
      • Arner P.
      Reduced hormone-sensitive lipase activity is not a major metabolic defect in Finnish FCHL families.
      ). Moreover, no differences in steady state HSL mRNA levels in adipose tissue (
      • Ylitalo K.
      • Nuotio I.
      • Viikari J.
      • Auwerx J.
      • Vidal H.
      • Taskinen M.
      C3, hormone-sensitive lipase, and peroxisome proliferator-activated receptor gamma expression in adipose tissue of familial combined hyperlipidemia patients.
      ) or in the frequency of a −60C/G polymorphism in the HSL promoter (
      • Pihlajamaki J.
      • Valve R.
      • Karjalainen L.
      • Karhapaa P.
      • Vauhkonen I.
      • Laakso M.
      The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.
      ) were observed in Finnish subjects with familial combined hyperlipidemia. Nonetheless, a sib-pair linkage analysis using a CA dinucleotide repeat in intron 7 of HSL demonstrated a linkage between HSL and plasma triglyceride levels in 126 dizygotic pairs of women twins (
      • Friedlander Y.
      • Talmud P.J.
      • Edwards K.L.
      • Humphries S.E.
      • Austin M.A.
      Sib-pair linkage analysis of longitudinal changes in lipoprotein risk factors and lipase genes in women twins.
      ). Thus, it is unclear whether variations in HSL expression and activity are related to familial combined hyperlipidemia. Maximum stimulated lipolysis, and by inference HSL, was initially reported to be markedly reduced in adipocytes from subjects with insulin resistance (
      • Reynisdottir S.
      • Ellerfeldt K.
      • Wahrenberg H.
      • Lithell H.
      • Arner P.
      Multiple lipolysis defects in the insulin resistance (metabolic) syndrome.
      ); however, this difference was not observed later by the same investigators (
      • Reynisdottir S.
      • Angelin B.
      • Langin D.
      • Lithell H.
      • Eriksson M.
      • Holm C.
      • Arner P.
      Adipose tissue lipoprotein lipase and hormone-sensitive lipase: contrasting findings in familial combined hyperlipidemia and insulin resistance syndrome.
      ). Three polymorphisms in the coding region of HSL, Arg262Met, Glu620Asp, and Ser681Ile, do not contribute measurably to biological variation of insulin sensitivity (
      • Stumvoll M.
      • Wahl H.G.
      • Jacob S.
      • Rettig A.
      • Machicao F.
      • Häring H.
      Two novel prevalent polymorphisms in the hormone-sensitive lipase gene have no effect on insulin sensitivity of lipolysis and glucose disposal.
      ). Nonetheless, the −60C/G polymorphism in the HSL promoter does appear to have effects on insulin sensitivity with the −60G variant displaying increased insulin stimulated glucose uptake (
      • Pihlajamaki J.
      • Valve R.
      • Karjalainen L.
      • Karhapaa P.
      • Vauhkonen I.
      • Laakso M.
      The hormone sensitive lipase gene in familial combined hyperlipidemia and insulin resistance.
      ) or lower insulin or FFA levels (
      • Talmud P.
      • Palmen J.
      • Luan J.
      • Flavell D.
      • Byrne C.
      • Waterworth D.
      • Wareham N.
      Variation in the promoter of the human hormone sensitive lipase gene shows gender specific effects on insulin and lipid levels: results from the Ely study.
      ).
      As with familial combined hyperlipidemia and insulin resistance, there are varying data as to the relationship of HSL with obesity. Thus, HSL protein and mRNA expression, as well as maximum lipolytic capacity of subcutaneous adipocytes, has been reported to be reduced in obese men and women (
      • Large V.
      • Reynisdottir S.
      • Langin D.
      • Fredby K.
      • Klannemark M.
      • Holm C.
      • Arner P.
      Decreased expression and function of adipocyte hormone-sensitive lipase in subcutaneous fat cells of obese subjects.
      ). Furthermore, non-obese subjects with a family history of obesity have been reported to have a reduced maximum lipolytic capacity when compared with lean subjects without a family history of obesity (
      • Hellstrom L.
      • Reynisdottir S.
      Influence of heredity for obesity on adipocyte liplysis in lean and obese subjects.
      ); however, steady state mRNA levels of HSL were not different (
      • Hellstrom L.
      • Langin D.
      • Reynisdottir S.
      • Dauzats M.
      • Arner P.
      Adipocyte lipolysis in normal weight subjects with obesity among first-degree relatives.
      ). Middle-aged men have an increase in percentage body fat compared with young men, and their fat cells have a lower maximal lipolytic response; yet HSL mRNA levels are higher in adipocytes from middle-aged men (
      • Imbeault P.
      • Vidal H.
      • Tremblay A.
      • Vega N.
      • Nadeau A.
      • Despres J-P.
      • Mauriege P.
      Age-related differences in messenger ribonucleic acid expression of key proteins involved in adipose cell differentiation and metabolism.
      ). A CA dinucleotide polymorphism within intron 7 of HSL has been reported to be associated with abdominal obesity in patients with type 2 diabetes (
      • Klannemark M.
      • Orho M.
      • Langin D.
      • Laurell H.
      • Holm C.
      • Reynisdottir S.
      • Arner P.
      • Groop L.
      The putative role of the hormone-sensitive lipase gene in the pathogenesis of Type II diabetes mellitus and abdominal obesity.
      ); however, no linkage was found between an intragenic marker of HSL and morbid obesity (
      • Clément K.
      • Dina C.
      • Basdevant A.
      • Chastang N.
      • Pelloux V.
      • Lahlou N.
      • Berlan M.
      • Langin D.
      • Guy-Grand B.
      • Froguel P.
      A sib-pair analysis study of 15 candidate genes in French families with morbid obesity: indication for linkage with islet 1 locus on chromosome 5q.
      ). In addition, the −60C/G polymorphism in the HSL promoter, which results in a ∼40% lower transcriptional activity of the −60G promoter (
      • Talmud P.J.
      • Palmen J.
      • Walker M.
      Identification of genetic variation in the human hormone-sensitive lipase gene and 5′ sequences: homology of 5′ sequences with mouse promoter and identification of potential regulatory elements.
      ), is associated with BMI, fat mass, and percentage body fat in women, but not in men. The −60G polymorphism has a positive relationship in black women and a negative relationship in white women that was lost after adjusting for fasting insulin concentrations (
      • Garenc C.
      • Perusse L.
      • Chagnon Y.
      • Rankinen T.
      • Gagnon J.
      • Borecki I.
      • Leon A.
      • Skinner J.
      • Wilmore J.
      • Rao D.
      • Bouchard C.
      The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study.
      ). Interestingly, a polymorphism of a CA dinucleotide repeat in intron 6 has been reported to be associated with obesity and with type 2 diabetes (
      • Magré J.
      • Laurell H.
      • Fizames C.
      • Antoine P.J.
      • Dib C.
      • Vigouroux C.
      • Bourut C.
      • Capeau J.
      • Weissenbach J.
      • Langin D.
      Human hormone-sensitive lipase: genetic mapping, identification of a new dinucleotide repeat, and association with obesity and NIDDM.
      ). Importantly, this polymorphism is associated with a 50% decrease in the lipolytic rate of subcutaneous abdominal adipocytes (
      • Hoffstedt J.
      • Arner P.
      • Schalling M.
      • Pedersen N.L.
      • Sengul S.
      • Ahlberg S.
      • Iliadou A.
      • Lavebratt C.
      A common hormone-sensitive lipase i6 gene polymorphism is associated with decreased human adipocyte lipolytic function.
      ).
      Therefore, accumulating evidence has defined important functions for HSL in normal physiology, affecting adipocyte lipolysis, steroidogenesis, spermatogenesis, and perhaps insulin secretion and insulin action; however, direct links between abnormal expression or genetic variations of HSL and human disorders, such as obesity, insulin resistance, type 2 diabetes, and hyperlipidemia, await further clarification.

      Acknowledgments

      This work was supported in part by research grants from the Research Service of the Department of Veterans Affairs (F.B.K.), by grant DK 46942 (F.B.K.) from the National Institutes of Health, and a Research Award from the American Diabetes Association (W.J.S.).

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