Background:Atherosclerotic cardiovascular disease is the main cause of mortality worldwide and is strongly influenced by circulating low-density lipoprotein (LDL) cholesterol levels. Only a few genes causally related to plasma LDL cholesterol levels have been identified so far, and only 1 gene, ANGPTL3, has been causally related to combined hypocholesterolemia. Here, our aim was to elucidate the genetic origin of an unexplained combined hypocholesterolemia inherited in 4 generations of a French family.Methods:Using next-generation sequencing, we identified a novel dominant rare variant in the LIPC gene, encoding for hepatic lipase, which cosegregates with the phenotype. We characterized the impact of this LIPC-E97G variant on circulating lipid and lipoprotein levels in family members using nuclear magnetic resonance–based lipoprotein profiling and lipidomics. To uncover the mechanisms underlying the combined hypocholesterolemia, we used protein homology modeling, measured triglyceride lipase and phospholipase activities in cell culture, and studied the phenotype of APOE*3.Leiden.CETP mice after LIPC-E97G overexpression.Results:Family members carrying the LIPC-E97G variant had very low circulating levels of LDL cholesterol and high-density lipoprotein cholesterol, LDL particle numbers, and phospholipids. The lysophospholipids/phospholipids ratio was increased in plasma of LIPC-E97G carriers, suggestive of an increased lipolytic activity on phospholipids. In vitro and in vivo studies confirmed that the LIPC-E97G variant specifically increases the phospholipase activity of hepatic lipase through modification of an evolutionarily conserved motif that determines substrate access to the hepatic lipase catalytic site. Mice overexpressing human LIPC-E97G recapitulated the combined hypocholesterolemic phenotype of the family and demonstrated that the increased phospholipase activity promotes catabolism of triglyceride-rich lipoproteins by different extrahepatic tissues but not the liver.Conclusions:We identified and characterized a novel rare variant in the LIPC gene in a family who presents with dominant familial combined hypocholesterolemia. This gain-of-function variant makes LIPC the second identified gene, after ANGPTL3, causally involved in familial combined hypocholesterolemia. Our mechanistic data highlight the critical role of hepatic lipase phospholipase activity in LDL cholesterol homeostasis and suggest a new LDL clearance mechanism.

中文翻译：

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鉴定功能获得性 LIPC 变体作为家族性联合低胆固醇血症的新原因

背景：动脉粥样硬化性心血管疾病是全世界死亡的主要原因，并且受循环低密度脂蛋白 (LDL) 胆固醇水平的强烈影响。迄今为止，仅鉴定出与血浆低密度脂蛋白胆固醇水平有因果关系的少数基因，并且只有 1 个基因ANGPTL3与联合低胆固醇血症有因果关系。在这里，我们的目的是阐明在一个法国家族中遗传了 4 代的不明原因的联合低胆固醇血症的遗传起源。与表型共分离。我们描述了这个LIPC的影响-使用基于核磁共振的脂蛋白分析和脂质组学对家庭成员循环脂质和脂蛋白水平的 E97G 变体。为了揭示联合低胆固醇血症的潜在机制，我们使用蛋白质同源性建模，测量细胞培养物中的甘油三酯脂肪酶和磷脂酶活性，并研究LIPC -E97G 过表达后 APOE*3.Leiden.CETP 小鼠的表型。结果：携带LIPC -E97G 变体的低密度脂蛋白胆固醇和高密度脂蛋白胆固醇、低密度脂蛋白颗粒数和磷脂的循环水平非常低。LIPC血浆中溶血磷脂/磷脂比率增加-E97G 携带者，提示对磷脂的脂解活性增加。体外和体内研究证实，LIPC -E97G 变体通过修饰决定底物进入肝脂肪酶催化位点的进化保守基序，特异性增加肝脂肪酶的磷脂酶活性。过表达人LIPC -E97G 的小鼠概括了该家族的联合低胆固醇血症表型，并证明增加的磷脂酶活性促进了不同肝外组织而非肝脏对富含甘油三酯的脂蛋白的分解代谢。结论：我们在LIPC中鉴定并表征了一种新的罕见变异出现显性家族性联合低胆固醇血症的家族中的基因。这种功能获得性变异使LIPC成为继ANGPTL3之后第二个被鉴定的基因，与家族性联合低胆固醇血症有因果关系。我们的机制数据强调了肝脂肪酶磷脂酶活性在低密度脂蛋白胆固醇稳态中的关键作用，并提出了一种新的低密度脂蛋白清除机制。