Curr Atheroscler Rep (2011) 13:257–265 DOI 10.1007/s11883-011-0175-2 Role of Hepatic Lipase and Endothelial Lipase in High-Density Lipoprotein–Mediated Reverse Cholesterol Transport Wijtske Annema & Uwe J. F. Tietge Published online: 22 March 2011 # The Author(s) 2011. This article is published with open access at Springerlink.com 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 cho- lesterol 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. Keywords Atherosclerosis . Bile . Cardiovascular disease . Cholesterol . Efflux . Endothelial lipase . Feces . Hepatic lipase . High density lipoproteins . Inflammation . Liver . Macrophage . Macrophage-to-feces . Phospholipase . Reverse cholesterol transport . Risk . Therapy . Triglycerides W. Annema : U. J. F. Tietge (*) Department of Pediatrics, Center for Liver, Digestive, and Metabolic Diseases, University Medical Center Groningen, University of Groningen, Hanzeplein 1, 9713 GZ, Groningen, The Netherlands e-mail: u_tietge@yahoo.com W. Annema e-mail: w.annema@med.umcg.nl Introduction Despite the widespread use of low-density lipoprotein (LDL) reduction therapies, atherosclerotic cardiovascular disease (CVD) remains a leading cause of morbidity and mortality in developed countries. Treatment with statins (HMG-CoA reductase inhibitors), for example, only decreases the risk of major coronary events by 15% to 40% even though these drugs consistently and efficiently lower LDL cholesterol [1]. This substantial residual risk indicates a potential clinical benefit of novel therapeutic strategies that look beyond LDL and focus on high-density lipoproteins (HDL). Plasma HDL cholesterol levels are strongly, inversely, and independently related to cardiovas- cular disease risk [2]. A major part of this atheroprotective potential of HDL conceivably consists of its key role in reverse cholesterol transport (RCT, see below for details) [2]. Among the factors modulating HDL metabolism, lipases such as hepatic lipase (HL) and endothelial lipase (EL) are of prime importance. HL and EL both belong to the triacylglycerol lipase family, which also includes lipoprotein lipase (LPL), but members of this family differ in their respective hydrolytic activities. Whereas LPL is almost exclusively a triglyceridase, HL uses both phospho- lipids and triglycerides as substrates, whereas EL possesses predominantly phospholipase and very little triglyceridase activity (Table 1) [3]. By decreasing the triglyceride and phospholipid content of HDL, HL and EL are both significant negative regulators of plasma HDL levels [2]. Therefore, pharmacologic inhibition of these lipases might represent a valid approach to increase HDL cholesterol. This review focuses on the impact of both HL and EL on HDL metabolism and RCT, but also addresses the con- sequences of modulating HL and EL expression and activity for atherosclerotic lesion development.