262 poorly lipidated apoA-I molecules that are rapidly cleared by the kidneys (Fig. 1) [3, 29]. Concomitantly, the CE within the remainder of the HDL particle is rendered more susceptible toward SR-BI—mediated selective uptake, a mechanism that is also a prerequisite for EL-induced HDL remodeling to continue [28 , 29]. This mechanism results in an increased hepatic cholesterol content without translating into altered biliary cholesterol secretion [30]. To put these data from experimental mouse models into perspective, an important question is if EL has a similar impact on HDL metabolism in humans and thereby might represent a potential therapeutic target. In a sample of 510 healthy individuals with a family history of premature coronary artery disease, post-heparin plasma mass levels of EL were positively correlated with small HDL and negatively with large HDL particles [31]. Selected common polymorphisms of EL were also found to be associated with HDL phenotypes [32, 33]. However, the strongest data supporting a negative impact of EL on plasma HDL cholesterol in humans come from a recent report demon- strating that the low-frequency Asn396Ser LIPG variant results in reduced lipolytic activity and is strongly associ- ated with increased plasma HDL cholesterol levels [34 ]. Another rare mutation in the EL gene, G26S, impairs secretion of the EL protein, leading to reduced EL plasma levels and thereby also to elevated plasma HDL cholesterol in African-American carriers [35]. However, the more common Thr111Ile EL variant, which had previously been variably and inconsistently associated with plasma HDL cholesterol phenotypes [36, 37], did not impact on EL function in vitro and failed to correlate with plasma HDL cholesterol levels in a comprehensive meta-analysis of five cohort studies [34 ]. Impact of EL on Selected Key Steps of RCT Only a few studies have examined the effect of EL on HDL-mediated cellular cholesterol efflux (the first step in RCT), and none have achieved conclusive results (Table 1). Decreased EL expression in vitro in macrophages caused a decline in efflux toward apoA-I (i.e., the part of the pathway mainly mediated by ABCA1), whereas over- expression of EL or addition of exogenous EL had an opposite effect [38]. Notably, both abolishing the catalytic activity or the bridging function of EL partially inhibited macrophage cholesterol efflux [38], indicating that these two properties of EL are relevant in this process. In contrast, using modification of the efflux acceptors by EL, one study noted no effect on the ABCA1-dependent pathway [39], whereas another group reported a 63% increase in ABCA1-mediated efflux toward HDL from EL-overexpressing mice [40]. However, increased efflux Curr Atheroscler Rep (2011) 13:257–265 toward plasma and HDL from EL knockout mice has also been observed, and an additive effect was seen in EL/HL double-knockout mice [6 ]. With respect to SR-BI–mediated efflux, a reduced capacity of EL-modified HDL [39] or of serum from EL-overexpressing mice [40] was described. Although it variably modulates cholesterol efflux, EL was consistently reported to enhance the second step in the RCT pathway, which is the uptake of HDL cholesterol into the liver (Table 1). While diminished selective uptake of CE was observed using HDL3 from EL-knockout mice [6 ], SR-BI—mediated selective uptake was enhanced from HDL from EL-overexpressing mice in vitro and in vivo [28 , 30]. This increase in selective uptake is dependent upon both the catalytic activity and the bridging function of EL [41]. Consequently, these properties of EL resulted in vivo in a significant increase in hepatic cholesterol content following EL overexpression [28 , 30]. However, the major pathway of cholesterol excretion from the body, namely biliary sterol secretion either as free cholesterol or after metabolic conversion into bile acids, remained essentially unchanged in EL-overexpressing mice (Table 1). Correspondingly, EL overexpression did not affect the mass fecal output of neutral sterols and bile acids (Table 1) [30]. EL and Macrophage-Specific RCT To date, two studies have explored the effect of EL on macrophage-specific RCT using 3H-cholesterol-labeled macrophage foam cells (Table 1). EL overexpression significantly decreased in vivo RCT and the same effect was observed with overexpression of profurin [42]. Profurin inhibits proprotein convertases, which in general mediate site-specific proteolysis and have specifically been shown to impact plasma HDL cholesterol levels via specific cleavage of EL resulting in inactivation of this lipase [42]; therefore, profurin overexpression has a similar metabolic effect than EL overexpression. In addition, angiopoietin-like 3 (ANGPTL3) has been dem- onstrated to be an endogenous inhibitor of EL, and consequently ANGPTL3 knockout mice have low plasma HDL cholesterol levels [3]. Therefore, the effect on RCT in ANGPTL3 knockouts would be expected to be the same as in mice overexpressing EL (namely, decreased), but this has not been experimentally tested thus far. On the other hand, overall RCT is unchanged in EL knockout mice [6 ]. However, EL knockouts had increased plasma levels of cholesterol originating from macrophages during the time course of the study, and this increase was significantly greater than in HL knockout mice [6 ]. No additive effect of the absence of both EL and HL on plasma counts or on overall RCT was observed [6 ], indicating that the effects