Curr Atheroscler Rep (2011) 13:257–265 259 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 HDL (Table 1) [6 ]. In turn, in mice and in rabbits, overexpression of human HL resulted in a marked decrease in HDL cholesterol due to an increased catabolic rate [5]. HL can also impact on HDL metabolism independent of its lipolytic properties, as adenovirus-mediated overexpression of catalytically inactive HL in HL knockout mice led to a reduction in plasma HDL levels, though to a lesser extent than observed in mice overexpressing similar levels of wild-type HL [5]. HL deficiency in humans also results in elevated levels of larger HDL2 particles, an enrichment of HDL with triglycerides, and hyperalphalipoproteinemia attributable to slower catabolism of apoA-I [7]. Consistent- ly, certain polymorphisms in the HL gene such as S267F, C-480T, and C-514T that result in lower HL expression and activity are firmly associated with higher plasma HDL cholesterol [8, 9]. These combined data support a key role for HL as a negative regulator of plasma HDL levels. 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 secre- tion 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 Impact of HL on Selected Key Steps in RCT Cholesterol efflux is a critical first step in RCT [2]. Plasma as well as HDL from HL-deficient mice has an increased capacity to elicit cholesterol efflux from lipid-laden macro- phages in vitro (Table 1), which was ascribed to phospho- lipid enrichment of HDL from the HL knockouts [6 ]. However, in humans with a complete deficiency of HL, the ability of plasma or isolated HDL to promote cholesterol efflux from normal human skin fibroblasts was not altered [7]. Thus, the impact of HL on macrophage cholesterol efflux remains to be elucidated. It would be interesting to also study the effect of HL overexpression, because HL increases the formation of preβ-HDL, an important medi- ator of ABCA1-mediated macrophage cholesterol efflux [5]. In addition, the impact of macrophage HL on cholesterol efflux has not been explored yet.