New Insights Into the Regulation of HDL Metabolism and Reverse Cholesterol Transport

Abstract

Abstract-The metabolism of high-density lipoproteins (HDL), which are inversely related to risk of atherosclerotic cardiovascular disease, involves a complex interplay of factors regulating HDL synthesis, intravascular remodeling, and catabolism. The individual lipid and apolipoprotein components of HDL are mostly assembled after secretion, are frequently exchanged with or transferred to other lipoproteins, are actively remodeled within the plasma compartment, and are often cleared separately from one another. HDL is believed to play a key role in the process of reverse cholesterol transport (RCT), in which it promotes the efflux of excess cholesterol from peripheral tissues and returns it to the liver for biliary excretion. This review will emphasize 3 major evolving themes regarding HDL metabolism and RCT. The first theme is that HDL is a universal plasma acceptor lipoprotein for cholesterol efflux from not only peripheral tissues but also hepatocytes, which are a major source of cholesterol efflux to HDL. Furthermore, although efflux of cholesterol from macrophages represents only a tiny fraction of overall cellular cholesterol efflux, it is the most important with regard to atherosclerosis, suggesting that it be specifically termed macrophage RCT. The second theme is the critical role that intravascular remodeling of HDL by lipid transfer factors, lipases, cell surface receptors, and non-HDL lipoproteins play in determining the ultimate metabolic fate of HDL and plasma HDL-c concentrations. The third theme is the growing appreciation that insulin resistance underlies the majority of cases of low HDL-c in humans and the mechanisms by which insulin resistance influences HDL metabolism. Progress in our understanding of HDL metabolism and macrophage reverse cholesterol transport will increase the likelihood of developing novel therapies to raise plasma HDL concentrations and promote macrophage RCT and in proving that these new therapeutic interventions prevent or cause regression of atherosclerosis in humans. Key Words: high density lipoprotein Ⅲ insulin resistance Ⅲ lipase Ⅲ lipoprotein Ⅲ reverse cholesterol transport P opulation studies have shown a highly consistent, inverse correlation between plasma concentrations of highdensity lipoprotein cholesterol (HDL-c) and its major protein apolipoprotein A-I (apoA-I) and atherosclerotic cardiovascular disease risk in humans. 1 HDL-c and apoA-I concentrations could simply be integrative markers of other atherosclerotic cardiovascular risk factors and not themselves causal in the disease process. However, studies in animals strongly suggest Dr Gary Lewis has acted as a consultant to the following pharmaceutical companies that are involved in the lipid-lowering and diabetes therapeutics fields: Pfizer, Merck Frosst, Astra Zeneca, Eli Lilly, Fournier Pharma, Bristol Myers Squibb.Correspondence that HDL and apoA-I have direct antiatherogenic properties. HDL metabolism is somewhat more complex than that of the other major lipoprotein fractions, in that the individual lip...

Ezetimibe: cholesterol lowering and beyond

“…Cholesterol synthesis in peripheral tissues also contributes to the hepatic cholesterol pool through the transfer of cholesterol to the liver in a process mediated by HDL particles (peripheral, or sometimes referred to as 'reverse' cholesterol transport) (FIGURES 3 & 4) [13]. Free cholesterol is transferred from peripheral tissues to pre-β-HDL-C particles via the ATP-binding cassette transporter 1 (ABCA1) pathway.…”

“…Secretion of nascent, pre-β-HDL particles by the intestine into the circulation promotes cholesterol and phospholipid efflux from peripheral cells to these particles [13,16], and thus may enhance cholesterol flux to the liver.…”

The expression of ATP-binding cassette transporter A1 in Chinese overweight and obese patients

“…1 Specifically, cholesterol efflux from macrophages represents only a small fraction of overall cellular cholesterol efflux, but it is probably the most important with regard to atherosclerosis, and it has recently been termed macrophage RCT, as excess lipid accumulation within macrophages in peripheral artery wall may lead to foam cell formation. 1 ATP-binding cassette transporters (ABCA1, ABCG1) and scavenger receptor class B type I (SR-BI) are the three best characterized cellular transporters/ receptor that are involved in mediating macrophage cholesterol efflux in animal models and in vitro experiments.…”

High-density lipoprotein metabolism in human apolipoprotein B100transgenic/brown adipose tissue deficient mice: a model of obesity-induced hyperinsulinemia

“…ApoA-I accounts for ∼70% of total proteins in HDL particles (Lewis and Rader 2005) and its absence in mice leads to extremely low levels of plasma HDL-C levels along with increased atherosclerosis (Lewis and Rader 2005;Moore et al 2005). Hepatic SR-BI mediates the selective uptake of cholesteryl ester from the HDL particles and thus increased expression of SR-BI in mice increases HDL uptake into the liver, lowering plasma HDL-C levels (Kozarsky et al 1997).…”

“…Hepatic lipase (HL) is another important enzyme whose action affects the rate of apoA-I catabolism by primarily hydrolyzing triglycerides in HDL particles. HL activity is increased when HDL particles are triglyceride-rich (Lewis and Rader 2005).…”