Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia

Chao Liu, Keith P. Gates, Longhou Fang, Marcelo J. Amar, Dina A. Schneider, Honglian Geng, Wei Huang, Jungsu Kim, Jennifer Pattison, Jian Zhang, Joseph L. Witztum, Alan T. Remaley, P. Duc Dong, Yury I. Miller

Research output: Contribution to journalArticle

32 Scopus citations

Abstract

Apolipoprotein C-II (APOC2) is an obligatory activator of lipoprotein lipase. Human patients with APOC2 deficiency display severe hypertriglyceridemia while consuming a normal diet, often manifesting xanthomas, lipemia retinalis and pancreatitis. Hypertriglyceridemia is also an important risk factor for development of cardiovascular disease. Animal models to study hypertriglyceridemia are limited, with no Apoc2-knockout mouse reported. To develop a genetic model of hypertriglyceridemia, we generated an apoc2 mutant zebrafish characterized by the loss of Apoc2 function. apoc2 mutants show decreased plasma lipase activity and display chylomicronemia and severe hypertriglyceridemia, which closely resemble the phenotype observed in human patients with APOC2 deficiency. The hypertriglyceridemia in apoc2 mutants is rescued by injection of plasma from wild-type zebrafish or by injection of a human APOC2 mimetic peptide. Consistent with a previous report of a transient apoc2 knockdown, apoc2 mutant larvae have a minor delay in yolk consumption and angiogenesis. Furthermore, apoc2 mutants fed a normal diet accumulate lipid and lipid-laden macrophages in the vasculature, which resemble early events in the development of human atherosclerotic lesions. In addition, apoc2 mutant embryos show ectopic overgrowth of pancreas. Taken together, our data suggest that the apoc2 mutant zebrafish is a robust and versatile animalmodel to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases.

Original languageEnglish (US)
Pages (from-to)989-998
Number of pages10
JournalDMM Disease Models and Mechanisms
Volume8
Issue number8
DOIs
StatePublished - Aug 1 2015

Keywords

  • APOC2
  • Apolipoprotein C-II
  • Hyperlipidemia
  • Lipoprotein lipase
  • Zebrafish

ASJC Scopus subject areas

  • Neuroscience (miscellaneous)
  • Medicine (miscellaneous)
  • Immunology and Microbiology (miscellaneous)
  • Biochemistry, Genetics and Molecular Biology(all)

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