Virtual Issue: Exploring the nuances and complexity of lipoprotein clearance

Assembled by Brandon Davies

JLR cover

Brandon is an Associate Professor in the Department of Biochemistry at the University of Iowa and a member of the Fraternal Order of Eagles Diabetes Research Center. His research centers on plasma lipoprotein metabolism and lipid partitioning.

Plasma lipoproteins deliver lipids to and from tissues of the body. When, where, how, and how much of these lipids and lipoproteins are cleared from the bloodstream can have profound effects on metabolic homeostasis and overall health. Although many of the basic tenets of lipoprotein clearance have been known for decades, important new elements continue to be uncovered. In this virtual issue, we feature studies recently published in the Journal of Lipid Research that advance our understanding of lipoprotein clearance and illustrate the breadth and diversity of lipoprotein-clearance research. We also highlight some of the young investigators who are driving this important work.

The association of altered plasma lipoprotein levels with diseases such as atherosclerosis and diabetes has long been recognized, but the range of disease states with altered lipoprotein clearance continues to expand. Survivors of acute lymphoblastic leukemia display a high prevalence of dyslipidemia, including increased low-density lipoprotein (LDL) cholesterol and triglyceride levels and reduced high-density lipoprotein (HDL) cholesterol. Patients with sleep apnea have delayed clearance of triglyceride-rich lipoproteins.

Treatment of dyslipidemia is not always straightforward. Because the metabolism of different classes of lipoproteins are interconnected, drugs that target one class of lipoprotein, such as HDL, often will affect the clearance of other lipoproteins — and not always in predictable ways.

Clearance of LDL from the circulation by the LDL receptor (LDL-R) has been a textbook staple for years, but our understanding of this process continues to deepen. Major regulators of LDL-R have been uncovered, and the targeting of one of those regulators, PCSK9, has made the successful jump to clinical therapy. In turn, additional players that modulate the interactions of LDL, LDL-R and PCSK9 have been characterized. Defects in LDL clearance lead to the deposition and aggregation of LDL in the arterial wall. The mechanism by which macrophages digest aggregated LDL and subsequently become foam cells continues to be revealed, with recent evidence suggesting that ceramides play a regulatory role in this process.

Lipoprotein lipase (LPL) is the primary determinant of triglyceride clearance from triglyceride-rich lipoproteins. Although the role of LPL, once known as clearing factor, was identified over 60 years ago, fresh details of how its activity is regulated continue to emerge. Two members of the ANGPTL family of proteins, ANGPTL3 and ANGPTL8, recently have been shown to act together to regulate LPL activity and thus plasma triglyceride clearance. Moreover, in vitro data suggest that ANGPTL8 may act as a switch, modulating both the ability of ANGPTL3 and ANGPTL4 to inhibit LPL, but in opposite ways. The apolipoprotein ApoC-III has dual roles in reducing the clearance of triglyceride-rich lipoproteins. ApoC-III inhibits the LDL-R-mediated uptake of triglyceride-rich remnant lipoproteins by the liver, but antisense oligonucleotide studies confirm that ApoC-III also inhibits LPL activity, reducing lipolysis and plasma triglyceride clearance.

As the details of canonical clearance pathways have come into greater focus, evidence for new clearance pathways also has been uncovered. For example, there is increasing evidence that, under some circumstances, tissues other than the liver can internalize whole triglyceride-rich lipoproteins. On a smaller scale, structure–function studies continue to reveal the molecular details of plasma lipoprotein and lipid clearance — from the residues involved the Apo-CIII lipid binding to the potential mechanism by which APOA1 activates LCAT activity in HDL. In short, our knowledge of lipoprotein clearance continues to grow on all levels and continues to provide new therapeutic directions.

Cover Image

The cover art, by Luciana Giono, depicts different mechanisms acting to clear and modify lipoproteins on an assembly line representing the circulation.

Featured research and reviews

Lipid and lipoprotein abnormalities in acute lymphoblastic leukemia survivors

Sophia Morel, Jade Leahy, Maryse Fournier, Benoit Lamarche, Carole Garofalo, Guy Grimard, Floriane Poulain, Edgard Delvin, Caroline Laverdière, Maja Krajinovic, Simon Drouin, Daniel Sinnett, Valérie Marcil, and Emile Levy
First Published on March 8, 2017

Sophia Morel

Sophia Morel is a Ph.D. candidate in nutrition at the Research Centre of the Sainte-Justine University Hospital, affiliated with University of Montreal, Canada. Her research is focused on gut microbiota and cardiometabolic complications, more specifically dyslipidemia, in survivors of childhood acute lymphoblastic leukemia. She is a registered nutritionist.

Obstructive sleep apnea and effects of continuous positive airway pressure on triglyceride-rich lipoprotein metabolism

Luciano F. Drager, Thauany M. Tavoni, Vanessa M. Silva, Raul D. Santos, Rodrigo P. Pedrosa, Luiz A. Bortolotto, Carmen G. Vinagre, Vsevolod Y. Polotsky, Geraldo Lorenzi-Filho, and Raul C. Maranhao
First published on April 8, 2018

Thauany Martins Tavoni

Thauany Martins Tavoni, Ph.D., is a researcher at the Lipid Metabolism Laboratory at the Heart Institute, University of São Paulo, in Brazil. Her research is focused on the metabolism of lipoproteins, blood glucose regulation, liver metabolism, diabetes and use of nanoparticles for drug delivery for the treatment of cancer and cardiovascular diseases.

Effects of CETP inhibition with anacetrapib on metabolism of VLDL-TG and plasma apolipoproteins C-II, C-III, and E

John S. Millar, Michael E. Lassman, Tiffany Thomas, Rajasekhar Ramakrishnan, Patricia Jumes, Richard L. Dunbar, Emil M. deGoma, Amanda L. Baer, Wahida Karmally, Daniel S. Donovan, Hashmi Rafeek, John A. Wagner, Stephen Holleran, Joseph Obunike, Yang Liu, Soumia Aoujil, Taylor Standiford, David E. Gutstein, Henry N. Ginsberg, Daniel J. Rader, and Gissette Reyes-Soffer
First published on March 17, 2017

Tiffany Thomas

Tiffany Thomas is an assistant professor in the department of pathology and cell biology at Columbia University Irving Medical Center. The goal of her research is to understand the relationships by which dietary lipids and lipoproteins affect red blood cell quality to try to identify potential mechanisms for creating better blood products. In addition to her academic career, Tiffany is an elite cyclist who competes in criteriums, road races, and cyclocross.

Cell-associated heparin-like molecules modulate the ability of LDL to regulate PCSK9 uptake

Adri M. Galvan and John S. Chorba
First published on November 21, 2018

Adri Galvan

Adri Galvan is a fourth-year medical student at Penn State College of Medicine. Her research was conducted during her Howard Hughes Medical Institute Medical Research Fellowship in Kevan Shokat's lab at the University of California, San Francisco, under the mentorship of John Chorba.

Ceramide activation of RhoA/Rho kinase impairs actin polymerization during aggregated LDL catabolism

Rajesh K. Singh, Abigail S. Haka, Alexandria Brumfield, Inna Grosheva, Priya Bhardwaj, Harvey F. Chin, Yuquan Xiong, Timothy Hla, and Frederick R. Maxfield
First Published on August 16, 2017

Rajesh Singh

Rajesh Singh is a postdoctoral associate at Weill Cornell Medicine in New York. His research has centered on how aggregated low-density lipoprotein clearance by macrophages activates inflammation during atherosclerosis. He is interested in how immune cell recruitment, activation and dysregulation results in inflammation in a variety of disease states. In his free time, he enjoys brewing beer and playing tennis.

ANGPTL8 requires ANGPTL3 to inhibit lipoprotein lipase and plasma triglyceride clearance

Jorge F. Haller, Ivory J. Mintah, Lisa M. Shihanian, Panayiotis Stevis, David Buckler, Corey A. Alexa-Braun, Sandra Kleiner, Serena Banfi, Jonathan C. Cohen, Helen H. Hobbs, George D. Yancopoulos, Andrew J. Murphy, Viktoria Gusarova, and Jesper Gromada
First published on April 15, 2017

On the mechanism of angiopoietin-like protein 8 for control of lipoprotein lipase activity

Oleg Kovrov, Kristian Kølby Kristensen, Erika Larsson, Michael Ploug, and Gunilla Olivecrona
First published on January 27, 2019

Oleg Kovrov

Oleg Kovrov completed his Ph.D. with Prof. Gunilla Olivecrona, studying the metabolism of triglyceride-rich lipoproteins. His focus was on the role of ANGPTL proteins in the regulation of lipoprotein lipase. He also worked on the development of an assay for studying various lipoprotein lipase regulators in close-to-natural conditions. In his spare time, he enjoys long distance cycling.

ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance

Bastian Ramms, Sohan Patel, Chelsea Nora, Ariane R. Pessentheiner, Max W. Chang, Courtney R. Green, Gregory J. Golden, Patrick Secrest, Ronald M. Krauss, Christian M. Metallo, Christopher Benner, Veronica J. Alexander, Joseph L. Witztum, Sotirios Tsimikas, Jeffrey D. Esko, and Philip L. S. M. Gordts
First published on: May 14, 2019

Bastian Ramms

Bastian Ramms recently completed his graduate studies at the University of California, San Diego, in collaboration with Bielefeld University in Germany. Today he is a postdoctoral researcher at the Sanford Consortium for Regenerative Medicine in San Diego. His research focuses on lipoprotein and glucose metabolism and how modulating their risk factors can improve the outcome of cardiovascular disease and diabetes. Outside of science, Bastian enjoys outdoor activities—everything from hiking in the mountains to relaxing at the beach.

Novel GPIHBP1-independent pathway for clearance of plasma TGs in Angptl4-/-Gpihbp1-/- mice

Emily M. Cushing, Kelli L. Sylvers, Xun Chi, Shwetha K. Shetty, and Brandon S. J. Davies
First published on May 8, 2018

Emily Cushing

Emily Cushing, Ph.D., is a postdoctoral research fellow at the University of Wisconsin-Madison in the lab of Alan Attie. Cushing earned her master’s degree in Chemistry at Georgia Tech and her doctorate in biochemistry at the University of Iowa. Her research is on metabolic disease and the regulation of diet-induced weight gain. In her downtime, she enjoys cooking and crocheting for friends and family.

Aromatic residues in the C terminus of apolipoprotein C-III mediate lipid binding and LPL inhibition

Nathan L. Meyers, Mikael Larsson, Evelina Vorrsjö, Gunilla Olivecrona, and Donald M. Small
First published on February 3, 2017

Nathan Meyers

Nathan Meyers is a staff scientist working with Melanie Ott in the department of virology & immunology at the Gladstone Institutes. The goal of his research is to characterize the effects of hepatitis C virus infection on its host cells. He has adapted a protocol to grow organoids from adult liver stem cells of viremic and nonviral donors, and he uses this system to identify novel host factors, generate new viral isolates, and test drug treatments. He is expanding this system to study hepatitis A virus and other hepatotropic pathogens.

A thumbwheel mechanism for APOA1 activation of LCAT activity in HDL

Allison L. Cooke, Jamie Morris, John T. Melchior, Scott E. Street, W. Gray Jerome, Rong Huang, Andrew B. Herr, Loren E. Smith, Jere P. Segrest, Alan T. Remaley, Amy S. Shah, Thomas B. Thompson, and W. Sean Davidson
First published on May 17, 2018

Allison Cooke

Allison Cooke is a scientist mentored by Gustavo Pesce and Richard Yu at Abalone Bio in Richmond, California. Her goal is to identify drug candidates for integral membrane proteins. Cooke earned her Ph.D. in pathology in W. Sean Davidson’s laboratory at the University of Cincinnati. There, she studied how the structure of apolipoprotein A-I on high-density lipoprotein modulates transient protein interactions in plasma. She is confident that investigating lipoprotein structure and function will lead to novel therapies for cardiovascular diseases. Cooke spends her weekends going on adventures in the Bay Area with her beloved dog, Lola Joe.