PUBLICATION

Deficient Cholesterol Esterification in Plasma of apoc2 Knockout Zebrafish and Familial Chylomicronemia Patients

Authors
Liu, C., Gaudet, D., Miller, Y.I.
ID
ZDB-PUB-170121-2
Date
2017
Source
PLoS One   12: e0169939 (Journal)
Registered Authors
Liu, Chao, Miller, Yury
Keywords
Zebrafish, Blood plasma, Cholesterol, Lipoproteins, In situ hybridization, Apolipoproteins, Cardiovascular diseases, Hydrolysis
MeSH Terms
  • Animals
  • Animals, Genetically Modified
  • Apolipoprotein C-II/genetics*
  • Cholesterol/metabolism*
  • Esterification
  • Humans
  • Hyperlipoproteinemia Type I/blood*
  • Zebrafish/genetics*
PubMed
28107429 Full text @ PLoS One
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.
Genes / Markers
Figures
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Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Antibodies
Orthology
Engineered Foreign Genes
Mapping