Abstract
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.
Highlights
Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and human genetic studies suggest that reduced triglyceride (TG) levels in the carriers of APOC3 and ANGPTL4 loss-of-function mutations correlate with the decreased risk of heart attack [1,2,3,4]
We found a significant increase in the plasma ratio of free cholesterol (FC) to cholesterol esters (CE) (FC/CE) in apoc2 mutant zebrafish and in human familial chylomicronemia syndrome (FCS) patients, which was associated with reduced lcat expression in zebrafish and reduced Lecithin:cholesterol acyltransferase (LCAT) activity in human plasma
We found a disproportionate increase in the levels of FC, as compared to CE, and, the FC to CE ratio (FC/CE) ratio was higher in apoc2 mutants than in WT (Fig 1B and 1C)
Summary
Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and human genetic studies suggest that reduced triglyceride (TG) levels in the carriers of APOC3 and ANGPTL4 loss-of-function mutations correlate with the decreased risk of heart attack [1,2,3,4]. We found a significant increase in the plasma ratio of FC to CE (FC/CE) in apoc2 mutant zebrafish and in human FCS patients, which was associated with reduced lcat expression in zebrafish and reduced LCAT activity in human plasma. In situ hybridization of 5.3 dpf zebrafish showed no changes in the liver cetp mRNA expression, but lcat was dramatically decreased in the liver of apoc2 mutants (Fig 3A).
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