258 Table 1 Characteristics of hepatic lipase and endothelial lipase Structural features Tissue expression Lipolytic activity Substrates Impact on plasma HDL cholesterol levels Impact on cholesterol efflux Impact on hepatic uptake of HDL cholesterol Impact on biliary cholesterol secretion Impact on fecal neutral sterol and bile acid excretion Impact on macrophage-to-feces RCT Impact on atherosclerosis Hepatic lipase 65-kD glycoprotein Hepatocytes, macrophages TG > PL All lipoproteins Knockout ↑ Overexpression ↓ Knockout ↑ ↔ Knockout ↓ Overexpression ↑ Knockout ↔ Knockout ↔ Knockout ↔ Knockout ↑ ↓ Overexpression ↓ Macrophage expression ↑ Macrophage knockout ↑ Curr Atheroscler Rep (2011) 13:257–265 Endothelial lipase 68-kD glycoprotein Endothelial cells, macrophages, thyroid gland, hepatocytes, kidney, lung, ovary, testis, and placenta PL > TG HDL Knockout ↑ Overexpression ↓ Knockout ↓ ↑ Overexpression ↑ ↓ Knockout ↓ Overexpression ↑ Overexpression ↔ Overexpression ↔ Knockout ↔ Overexpression ↓ Knockout ↓ ↔ TG triglycerides, PL phospholipids, RCT reverse cholesterol transport; ↑ = increased; ↓ = decreased; ↔ = not affected. Multiple arrows per condition indicate divergent reports in literature Role of High-Density Lipoproteins in Reverse Cholesterol Transport HDL plays a central role in RCT (Fig. 1) [2]. The first step in RCT involves the efflux of cholesterol from peripheral cells, most importantly macrophage foam cells within atherosclerotic plaques, toward either apolipoprotein (apo) A-I, which is mainly ATP-binding cassette transporter A1 (ABCA1)-mediated, or HDL, a process mainly driven by ABCG1. Lecithin:cholesterol acyltransferase (LCAT) then catalyzes the formation of mature spherical HDL by converting free cholesterol to apolar cholesterol ester, which moves to the core of the HDL particle. In addition to ABCA1 and ABCG1, the scavenger receptor class B type I (SR-BI) might also contribute to net cholesterol efflux. The cholesterol originating from peripheral cells is subsequently taken up into the liver in several distinct pathways that are all relevant for RCT: 1) selective uptake mediated by SR-BI, 2) holoparticle uptake involving the extracellularly localized β-chain of the mitochondrial F1 ATPase as well as P2Y13 receptors, and 3) in species such as humans, rabbits, hamsters, and monkeys, but not mice and rats, transfer to apoB-containing lipoproteins by cholesteryl ester transfer protein (CETP) followed by uptake via LDL receptors. The major pathway for disposal of hepatic cholesterol from the body is generally believed to be its secretion into bile in the form of either free cholesterol or bile acids. Eventually, neutral sterols (cho- lesterol and its metabolites) and bile acids are excreted via the feces. The RCT pathway has been reviewed in more detailed elsewhere [2]. Hepatic Lipase HL is a 65-kD glycoprotein synthesized and secreted primarily by hepatocytes and to a lesser extent by macro- phages (Table 1) [4]. In the liver, HL is anchored via heparan sulfate proteoglycans to hepatocytes in the Space of Disse and to the sinusoidal endothelial cell surface [4]. Virtually all lipoprotein subclasses are substrates for HL, resulting in the generation of smaller and denser particles (Table 1) [5]. In addition, independent of its catalytic activity, HL anchored to cell surface proteoglycans also has a bridging function promoting receptor-mediated uptake of lipoproteins [4]. HL and HDL Metabolism By hydrolyzing triglycerides and phospholipids, HL con- verts lipid-rich large HDL2 to smaller, more dense HDL3. Mice lacking HL characteristically display increased plas- ma levels of larger, phospholipid- and triglyceride-enriched