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(Circulation Research. 2008;103:159.)
© 2008 American Heart Association, Inc.

Molecular Medicine

Enhanced Cellular Uptake of Remnant High-Density Lipoprotein Particles

A Mechanism for High-Density Lipoprotein Lowering in Insulin Resistance and Hypertriglyceridemia

Changting Xiao, Takehiko Watanabe, Yi Zhang, Bernardo Trigatti, Linda Szeto, Phil W. Connelly, Santica Marcovina, Tomas Vaisar, Jay W. Heinecke, Gary F. Lewis

From the Departments of Medicine and Physiology (C.X., T.W., L.S., G.F.L.) and Department of Laboratory Medicine and Pathobiology (P.W.C.), University of Toronto, Ontario, Canada; Departments of Biochemistry and Biomedical Sciences (Y.Z., B.T.), McMaster University, Hamilton, Ontario, Canada; and Department of Medicine (S.M., T.V., J.W.H.), University of Washington School of Medicine, Seattle.

Correspondence to Dr. Gary F. Lewis, MD FRCPC, Room EN12-218, The Toronto General Hospital, 200 Elizabeth St, Toronto, ON, M5G 2C4, Canada. E-mail gary.lewis{at}uhn.on.ca

A low level of high-density lipoprotein (HDL) cholesterol is characteristic of insulin resistance and hypertriglyceridemia and likely contributes to the increased risk of cardiovascular disease associated with these conditions. One pathway involves enhanced clearance of lipolytically modified HDL particles, but the underlying mechanisms remain poorly understood. Here, we examine the effect of triglyceride enrichment and hepatic lipase hydrolysis on HDL binding, internalization, and degradation in cultured liver and kidney cells. Maximal binding of remnant HDL (HDL enriched with triglycerides followed by hepatic lipase hydrolysis), but not binding affinity, was markedly higher than native and triglyceride-rich HDL in both HepG2 cells and HEK293 cells. Compared with native and triglyceride-rich HDL, remnant HDL was internalized to a greater extent in both cell types and was more readily degraded in HEK293 cells. The increased binding of remnant HDL was not mediated by the low-density lipoprotein receptor or scavenger receptor class B type I (SR-BI), because enhanced remnant HDL binding was observed in low-density lipoprotein receptor–deficient cells with or without SR-BI overexpression. Disruption of cell surface heparan sulfate proteoglycans or blockage of apolipoprotein E–mediated lipoprotein binding also did not abolish the enhanced remnant HDL binding. Our observations indicate that remodeling of triglyceride-enriched HDL by hepatic lipase may result in enhanced binding, internalization, and degradation in tissues involved in HDL catabolism, contributing to rapid clearance and overall lowering of plasma HDL cholesterol in insulin resistance and hypertriglyceridemia.

Key Words: HDL • hepatic lipase • insulin resistance • hypertriglyceridemia

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