Background— Endothelial lipase is a phospholipase with activity against high-density lipoprotein. Although a small number of mutations in LIPG have been described, the role of LIPG in protection against atherosclerosis is unclear. Methods and Results— We identified 8 loss-of-function (LOF) mutations in LIPG in individuals with high-density lipoprotein cholesterol. Functional analysis confirmed that most rare mutations abolish lipase activity in vitro, indicating complete LOF, whereas 2 more common mutations N396S and R476W reduce activity by ≈50%, indicating partial LOF and implying ≈50% and ≈75% remaining endothelial lipase function in heterozygous complete LOF and partial LOF mutation carriers, respectively. complete LOF mutation carriers had significantly higher plasma high-density lipoprotein cholesterol levels compared with partial LOF mutation carriers. Apolipoprotein B-depleted serum from complete LOF carriers showed significantly enhanced cholesterol efflux acceptor capacity, whereas only trends were observed in partial LOF carriers. Carriers of LIPG mutations exhibited trends toward reduced coronary artery disease in 4 independent cohorts (meta-analysis odds ratio, 0.7; P =0.04). Conclusions— Our data suggest that the impact of LIPG mutations is directly related to their effect on endothelial lipase function and support that antagonism of endothelial lipase function improves cardioprotection.
BackgroundCoronary heart disease (CHD) risk inversely associates with levels of high‐density lipoprotein cholesterol (HDL‐C). The protective effect of HDL is thought to depend on its functionality, such as its ability to induce cholesterol efflux.Materials and methodsWe compared plasma cholesterol efflux capacity between male familial hypercholesterolaemia (FH) patients with and without CHD relative to their non‐FH brothers, and examined HDL constituents including sphingosine‐1‐phosphate (S1P) and its carrier apolipoprotein M (apoM).ResultsSeven FH patients were asymptomatic and six had experienced a cardiac event at a mean age of 39 years. Compared to their non‐FH brothers, cholesterol efflux from macrophages to plasma from the FH patients without CHD was 16 ± 22% (mean ± SD) higher and to plasma from the FH patients with CHD was 7 ± 8% lower (P = 0·03, CHD vs. non‐CHD). Compared to their non‐FH brothers, FH patients without CHD displayed significantly higher levels of HDL‐cholesterol, HDL‐S1P and apoM, while FH patients with CHD displayed lower levels than their non‐FH brothers.ConclusionsA higher plasma cholesterol efflux capacity and higher S1P and apoM content of HDL in asymptomatic FH patients may play a role in their apparent protection from premature CHD.
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