Curr Atheroscler Rep (2011) 13:257–265 of absence of EL and HL on overall RCT in mice are minor. EL and Atherosclerosis Studies exploring the role of EL in experimental athero- genesis have not yielded conclusive results thus far (Table 1). One study reported that targeted disruption of EL in apoE knockout mice attenuated atherosclerotic lesion formation by approximately 70% on chow and to a lesser degree on a Western-type diet [43]. Interestingly, the lack of EL resulted in increased plasma levels of antiatherogenic HDL as well as proatherogenic very low-density lipoprotein and LDL cholesterol [43]. Therefore, the authors rather proposed reduced monocyte adhesion to the vascular wall via heparan sulfate proteoglycans as an underlying mech- anism for decreased atherosclerosis development in apoE/ EL double knockout mice [43]. On the contrary, in another comprehensive study, no differences in atherosclerotic lesion size and lesion macrophage content were detected between mice expressing or lacking EL either on the apoE knockout or the LDL-receptor knockout background [44]. Also, this report noted a slight but consistent increase in plasma levels of both cholesterol within HDL as well as apoB-containing lipoproteins [44]. Inflammation plays an important role in the development of atherosclerosis, and a link between EL and inflammation has been suggested. Expression of EL is substantially upregulated in cultured endothelial cells in response to proinflammatory cytokines and in humans during acute experimental inflammation [3]. Although EL has been shown to enhance monocyte adhesion to the vessel wall [43], another report suggested that EL decreases endothelial adhesion molecule expression by generating peroxisome proliferator—activated receptor α (PPARα) ligands from HDL phospholipids [3]. Therefore, although EL expression is upregulated by inflammatory stimuli, it is currently unclear if EL itself exerts anti- or proinflammatory activity. In analogy to other secreted phospholipases [45], however, it could also be conceivable that EL expression induces endothelial dysfunction and thereby the susceptibility to atherosclerotic CVD, although this concept has not been experimentally addressed thus far. In humans, the association between atherosclerotic cardiovascular disease and EL levels or variants of the EL gene has been investigated (summarized in Table 2). As indirect evidence, a significant positive correlation was found between coronary artery calcification scores and EL mass levels in pre-heparin (odds ratio= 1.67) and post-heparin (odds ratio= 2.42) plasma among apparently healthy indi- viduals that persisted even after adjustment for plasma lipids, vasoactive medication, and established risk factors 263 [31]. A report on a relatively small group of patients with end-stage renal disease on hemodialysis suggested that during a 2-year follow-up, patients experiencing CVD events had higher serum EL levels compared with event- free patients [46]. Two small case-control studies from Japan and China noted that the common Thr111Ile EL variant was related to a decreased risk of acute myocardial infarction and coronary artery disease, respectively [47, 48]. However, the Thr111Ile variant was shown in in vitro assays to be indiscernible from wild-type EL [34 ]. Subsequently, three larger Caucasian study populations could not confirm an impact of the Thr111Ile variant on cardiovascular risk [49]. More recent data from two independent, prospective, nested- control studies reported that out of five single nucleotide polymorphism in LIPG, only the Thr111Ile variant was modestly associated with higher HDL cholesterol, higher apoA-I levels, and a higher concentration of larger HDL particles, whereas none of the EL variants tested proved to be a risk factor for atherosclerotic cardiovascular disease [50]. Clearly, more studies are needed that relate plasma levels and/or activity of EL to hard endpoints of CVD. Conclusions HL and EL are both negative regulators of plasma HDL cholesterol levels. For both lipases, variable effects on cholesterol efflux, which is the first step in RCT, have been reported. HL and EL increase hepatic cholesterol content, but this does not impact biliary sterol secretion. Overall, EL overexpression decreases macrophage-to-feces RCT, whereas EL as well as HL knockout did not affect RCT. In terms of establishing these lipases as targets for therapeutic intervention, increases in RCT upon inhibition are not likely to be expected; however, a decrease in RCT might not occur either. More work seems required on the impact of HL and EL on atherosclerotic disease, including measurements of plasma mass and activity. In addition, exploring other biological properties of these lipases, such as their role in modulating inflammatory pathways, might prove useful in deciding whether HL and EL are suitable targets for pharmacologic inhibition as a therapeutic strategy against atherosclerotic CVD. Disclosure The authors report no potential conflicts of interest relevant to this article. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which per- mits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.