Liu Chao, Gaudet Daniel, Miller Yury I
Department of Medicine, University of California San Diego, La Jolla, California, United States of America.
Department of Medicine, ECOGENE-21 Clinical and Translational Research Center and Lipidology Unit, Université de Montréal, Chicoutimi, Quebec, Canada.
PLoS One. 2017 Jan 20;12(1):e0169939. doi: 10.1371/journal.pone.0169939. eCollection 2017.
Hypertriglyceridemia is an independent risk factor for cardiovascular disease. Apolipoprotein C-II (APOC2) is an obligatory cofactor for lipoprotein lipase (LPL), the major enzyme catalyzing plasma triglyceride hydrolysis. We have created an apoc2 knockout zebrafish model, which mimics the familial chylomicronemia syndrome (FCS) in human patients with a defect in the APOC2 or LPL gene. In this study, we measured plasma levels of free cholesterol (FC) and cholesterol esters (CE) and found that apoc2 mutant zebrafish have a significantly higher FC to CE ratio (FC/CE), when compared to the wild type. Feeding apoc2 mutant zebrafish a low-fat diet reduced triglyceride levels but not the FC/CE ratio. In situ hybridization and qPCR results demonstrated that the hepatic expression of lecithin-cholesterol acyltransferase (lcat), the enzyme responsible for esterifying plasma FC to CE, and of apolipoprotein A-I, a major protein component of HDL, were dramatically decreased in apoc2 mutants. Furthermore, the FC/CE ratio was significantly increased in the whole plasma and in a chylomicron-depleted fraction of human FCS patients. The FCS plasma LCAT activity was significantly lower than that of healthy controls. In summary, this study, using a zebrafish model and human patient samples, reports for the first time the defect in plasma cholesterol esterification associated with LPL deficiency.
高甘油三酯血症是心血管疾病的独立危险因素。载脂蛋白C-II（APOC2）是脂蛋白脂肪酶（LPL）的必需辅因子，LPL是催化血浆甘油三酯水解的主要酶。我们构建了一个apoc2基因敲除斑马鱼模型，该模型模拟了人类患者中因APOC2或LPL基因缺陷导致的家族性乳糜微粒血症综合征（FCS）。在本研究中，我们测量了血浆中游离胆固醇（FC）和胆固醇酯（CE）的水平，发现与野生型相比，apoc2突变斑马鱼的FC与CE比值（FC/CE）显著更高。给apoc2突变斑马鱼喂食低脂饮食可降低甘油三酯水平，但不会降低FC/CE比值。原位杂交和qPCR结果表明，apoc2突变体中负责将血浆FC酯化为CE的卵磷脂胆固醇酰基转移酶（lcat）以及高密度脂蛋白的主要蛋白质成分载脂蛋白A-I的肝脏表达显著降低。此外，人类FCS患者的全血浆和乳糜微粒耗尽部分的FC/CE比值均显著升高。FCS患者血浆LCAT活性显著低于健康对照组。总之，本研究使用斑马鱼模型和人类患者样本，首次报道了与LPL缺乏相关的血浆胆固醇酯化缺陷。
