Dietary unsaturated fat improves high density lipoprotein function: opposing roles of apoE and apoCIII

Abstract

Cardiovascular disease is the leading cause of death worldwide. Atherosclerosis, the buildup of cholesterol-rich plaques in the arteries, is the pathophysiological process behind cardiovascular disease mortality. High density lipoproteins (HDL) are the body's only vehicle for removal and excretion of cholesterol from atherosclerotic plaques, a process called reverse cholesterol transport. Presumably as a result of this important function, plasma concentrations of HDL-cholesterol (-C) are one of the strongest inverse predictors of cardiovascular disease risk. However, therapeutics that increase HDL-C do not protect against cardiovascular disease mortality. This paradox has compelled a shift to improving HDL function rather than necessarily increasing plasma HDL-C. Emerging evidence suggests that the protein content of HDL, which largely has been underutilized in HDL research, could be leveraged to improve HDL function. Apolipoproteins (apo) E and CIII are two HDL proteins that have established roles in lipid metabolism. ApoE is essential for the clearance of triglyceride rich lipoproteins (TRL) from plasma, and it presumably serves a similar function on HDL. ApoCIII impedes the clearance of TRL and promotes the development of hypertriglyceridemia. HDL containing apoCIII no longer has a protective association with cardiovascular disease risk, suggesting that apoCIII makes HDL dysfunctional. ApoE and apoCIII form subpopulations, or subspecies, on HDL, and have opposing functions in vitro, in vivo, and in human metabolic studies of apoB-containing lipoproteins. Thus, my first aim was to verify that HDL subspecies have metabolic implications in humans, with the goal of finding a subspecies that was especially active in reverse cholesterol transport. Using a metabolic tracer study in humans, I tested if HDL subspecies defined by presence or absence of apoE/apoCIII had metabolic features typical of reverse cholesterol transport: increased synthesis into plasma, size expansion representing cholesterol uptake, and increased clearance from circulation. I found all of these features in a subspecies of HDL containing apoE but not apoCIII. Finally, unsaturated fat has demonstrated cardioprotective effects, but its role in HDL metabolism is unclear. Thus, my second aim was to determine the impact of dietary unsaturated fat on HDL metabolism, assessing its ability to promote reverse cholesterol transport in humans. Using a dietary intervention tracer study, I also tested if these HDL subspecies would respond metabolically to dietary intervention. I showed that dietary unsaturated fat primarily works through HDL containing apoE to make HDL more proficient in reverse cholesterol transport.