Role of hepatic lipase and endothelial lipase in high-density lipoprotein-mediated reverse cholesterol transport

Abstract

Reverse cholesterol transport (RCT) constitutes a key part of the atheroprotective properties of high-density lipoproteins (HDL). Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol levels. Although overexpression of EL decreases overall macrophage-to-feces RCT, knockout of both HL and EL leaves RCT essentially unaffected. With respect to important individual steps of RCT, current data on the role of EL and HL in cholesterol efflux are not conclusive. Both enzymes increase hepatic selective cholesterol uptake; however, this does not translate into altered biliary cholesterol secretion, which is regarded the final step of RCT. Also, the impact of HL and EL on atherosclerosis is not clear cut; rather it depends on respective experimental conditions and chosen models. More mechanistic insights into the diverse biological properties of these enzymes are therefore required to firmly establish EL and HL as targets for the treatment of atherosclerotic cardiovascular disease.

Fig. 1

Schematic depicting the impact of hepatic lipase (HL) and endothelial lipase (EL) on reverse cholesterol transport (RCT). Small discoidal high-density lipoprotein (HDL) particles are generated by the liver (about 70% contribution) and by the intestine (about 30% contribution). Free cholesterol (FC) from macrophage foam cells is effluxed toward these particles by ATP-binding cassette transporter A1 (ABCA1). Through the action of lecithin:cholesterol acyltransferase (LCAT), these particles mature and become spherical; ABCG1 and scavenger receptor class B type I (SR-BI) add more cholesterol onto these larger HDL. EL and HL hydrolyze HDL phospholipids and phospholipids/triglycerides (TG), respectively, thereby destabilizing the particle, resulting in shedding of poorly lipidated apolipoprotein (apo) A-I that is subject to clearance by the kidneys. Cholesteryl ester from these HDL particles becomes more susceptible towards SR-BI—mediated selective uptake. In turn, selective uptake is also required for HDL remodeling by these lipases to continue. Via SR-BI, HDL cholesterol enters the hepatic cholesterol pool and can either be directly secreted as free cholesterol into bile and feces or after metabolic conversion into bile acids. Cholesteryl ester transfer protein (CETP), expressed in humans but not in mice and rats, mediates the hetero-exchange of cholesteryl ester (CE) originating from HDL with triglycerides originating from apoB-containing lipoproteins. TG-enrichment of HDL makes the particle a better substrate for HL. On the other hand, cholesterol transferred to apoB-containing lipoproteins can be taken up into the liver via low-density lipoprotein receptors (LDLR) and then also enters the hepatic cholesterol pool. EL and HL expression consistently results in lower plasma HDL levels, increased hepatic cholesterol content, but unchanged biliary cholesterol secretion rates. Results regarding the impact of these lipases on cholesterol efflux are variable. The net effect of the absence of HL and EL on overall RCT is minimal, whereas overexpression of EL has been shown to decrease RCT. VLDL—very low-density lipoprotein