Hepatic Lipase and Endothelial Lipase
HDL is ﬁrst remodeled in the circulation and subsequently catabolized by cells and tissues. Hepatic lipase (HL) and endothelial lipase (EL) are two plasma lipases playing an important role in HDL remodeling (Fig. 8a). HL and EL have speciﬁcity primarily for phospholipids and to a lesser extend for triglycerides of apoBcontaining lipoprotein remnants and large HDL (Maugeais et al. 2003a; Santamarina-Fojo et al. 2004). HL-deﬁcient mice exhibit elevated levels of large HDL particles enriched in phospholipids and apoE (Homanics et al. 1995) and reduced atherosclerosis in the background of apoE-/mice (Karackattu et al. 2006; Mezdour et al. 1997). In contrast, overexpression of HL in mice reduced plasma HDL levels (Braschi et al. 1998). A rat liver perfusion of human native HDL2 or triglyceride-enriched HDL promoted the formation of the preβ1-HDL subspecies and a reduction of the α-HDL2 (Barrans et al. 1994). These changes were attributed to the triglyceride lipase activity of HL (Barrans et al. 1994). Characterization of preβ1-HDL showed that these particles contain one to two molecules of apoA-I, associated with phospholipids, and some free and esteriﬁed cholesterol (Guendouzi et al. 1999). When compared to triglyceride-rich HDL2, remnant-HDL2 had lost on the average one molecule of apoA-I, 60 % of triglycerides, and 15 % of phospholipids. The estimated composition supported the hypothesis that HL had splitted the initial particle into one preβ1-HDL and one remnant-HDL2. RemnantHDL2 had different composition and properties from HDL3, suggesting that HL did not promote the direct conversion of HDL2 to HDL3 (Guendouzi et al. 1999). Analysis of HL transgenic rabbits suggested that HL reduces the size of α-migrating HDL and increases the rate of catabolism of apoA-I (Kee et al. 2002). Cell studies showed that HL promotes selective HDL3 cholesterol ester uptake independent from SR-BI and that proteoglycans are needed for the HL action on selective CE uptake (Brundert et al. 2003). Earlier studies in mice deﬁcient in both HL and EL suggested an additive effect of HL and EL on plasma HDL levels but not on macrophage-mediated reverse cholesterol transport in mice (Brown et al. 2010). However, a recent study demonstrated that targeted inactivation of both HL and EL in mice promoted macrophage-to-feces RCT and enhanced HDL antioxidant properties (Escola-Gil et al. 2013).
HL-deﬁcient patients have elevated plasma concentrations of cholesterol in the HDL and β-VLDL and increased concentration of triglycerides and phospholipids in the LDL and HDL (Breckenridge et al. 1982). Analyses carried out in complete and partial HL-deﬁcient subjects as well as in normotriglyceridemic and hypertriglyceridemic controls suggested that HL activity is important for physiologically balanced HDL metabolism (Ruel et al. 2004). However, the presence of HL may not be necessary for normal HDL-mediated reverse cholesterol transport process and is not associated with pro-atherogenic changes in HDL composition and metabolism (Ruel et al. 2004). In addition, another Mendelian randomization study showed that subjects with loss-of-function genetic variants of HL have elevated levels of HDL cholesterol, but are not associated with risk of ischemic cardiovascular disease and therefore may not be protected against ischemic cardiovascular disease (Johannsen et al. 2009).
Endothelial lipase (EL) has phospholipase activity (mostly PLA1 activity) and low levels of triglyceride lipase activity (Jaye et al. 1999). Overexpression of EL in mice markedly decreased plasma HDL cholesterol and apoA-I levels, had a modest effect on apoB-containing lipoproteins, and increased 2.5–3-fold the uptake of the HDL by the kidney and the liver (Ishida et al. 2003; Maugeais et al. 2003a). In contrast, the EL deﬁciency in mice increased HDL cholesterol levels (Ishida et al. 2003; Ma et al. 2003) and reduced atherosclerosis in the background of apoE-/mice (Ishida et al. 2004). Analysis of atherosclerosis prone LDLR-/x ApoB(100/100) mice suggested that EL and the HDL cholesterol levels were regulated by SREBPs and VEGF-A (Kivela et al. 2012). Overexpression of EL in mice markedly decreased plasma HDL cholesterol and apoA-I levels and had a modest effect on apoB-containing lipoproteins (Maugeais et al. 2003b; Ishida et al. 2003). Furthermore, the HDL phospholipid and cholesteryl ester content decreased, while HDL triglyceride content increased (Nijstad et al. 2009) and the free cholesterol content remained unaltered. Fast protein liquid chromatography analysis and agarose gel electrophoresis showed that the expression of EL resulted in the generation of small preβ-HDL particles (Nijstad et al. 2009). In addition, overexpression of EL increased the selective uptake of hepatic HDL cholesteryl ester by SR-BI as well as hepatic holoparticle uptake. This resulted in a dramatic increase in the uptake of the HDL protein, but not the cholesteryl ester moieties, into the kidneys (Nijstad et al. 2009). These data support a model in which EL-mediated phospholipid hydrolysis of HDL destabilizes the particle, resulting in the shedding of poorly lipidated apoA-I from the particle surface, which are preferentially cleared by the kidneys and via increased selective uptake by SR-BI. Several genetic EL variants have been reported to be associated with plasma HDL-C levels (deLemos et al. 2002; Edmondson et al. 2009), and genome-wide association studies have shown that single-nucleotide polymorphisms (SNPs) near LIPG (EL) are associated with plasma HDL-C levels (Kathiresan et al. 2008a, 2009; Teslovich et al. 2010). However, the relationship of genetic variation in the EL locus with the risk for coronary artery disease remains uncertain (Vergeer et al. 2010b). A newer study showed that carriers of an EL mutant characterized by complete loss of function had signiﬁcantly higher plasma HDL cholesterol levels compared to carriers having partial loss-of-function mutations (Singaraja et al. 2013). Apolipoprotein B-depleted serum from carriers of HL with complete loss of function had signiﬁcantly enhanced capacity to promote cholesterol efﬂux as compared to apoB-depleted serum obtained from HL carriers with partial loss of function (Singaraja et al. 2013). In the same study, it was reported that carriers of certain EL mutations exhibited trends toward reduced coronary artery disease in
four independent cohorts (Singaraja et al. 2013).