title: Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia.
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 animal model to study hypertriglyceridemia and the mechanisms involved in the pathogenesis of associated human diseases.
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Chao
authors.initials: C
authors.lastname: Liu
authors.affiliation: Sanford Children's Health Research Center, Programs in Genetic Disease and Development and Aging, and Stem Cell and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: Keith P
authors.initials: KP
authors.lastname: Gates
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Longhou
authors.initials: L
authors.lastname: Fang
authors.affiliation: Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Marcelo J
authors.initials: MJ
authors.lastname: Amar
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Dina A
authors.initials: DA
authors.lastname: Schneider
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Honglian
authors.initials: H
authors.lastname: Geng
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Wei
authors.initials: W
authors.lastname: Huang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Jungsu
authors.initials: J
authors.lastname: Kim
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Pattison
authors.affiliation: State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Jian
authors.initials: J
authors.lastname: Zhang
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: Witztum
authors.affiliation: Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, NIH, Bethesda, MD, USA.
authors.forename: Alan T
authors.initials: AT
authors.lastname: Remaley
authors.affiliation: Sanford Children's Health Research Center, Programs in Genetic Disease and Development and Aging, and Stem Cell and Regenerative Biology, Sanford-Burnham Medical Research Institute, La Jolla, CA, USA.
authors.forename: P Duc
authors.initials: PD
authors.lastname: Dong
authors.affiliation: Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA yumiller@ucsd.edu.
authors.forename: Yury I
authors.initials: YI
authors.lastname: Miller
mesh_terms: D000375:Aging; D000595:Amino Acid Sequence; D000818:Animals; D053304:Apolipoprotein C-II / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics; D001483:Base Sequence; D001808:Blood Vessels / Q000187:drug effects / Q000378:metabolism; D004032:Diet; D004195:Disease Models, Animal; D004720:Endonucleases / Q000378:metabolism; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics* / Q000473:pathology; D007267:Injections; D007814:Larva; D008074:Lipoproteins / Q000378:metabolism; D008957:Models, Genetic; D008969:Molecular Sequence Data; D009154:Mutation / Q000235:genetics; D018919:Neovascularization, Physiologic; D010179:Pancreas / Q000187:drug effects / Q000254:growth & development / Q000473:pathology; D010455:Peptides / Q000494:pharmacology; D010641:Phenotype; D010949:Plasma / Q000378:metabolism; D015534:Trans-Activators / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D015027:Zebrafish / Q000235:genetics*; D029961:Zebrafish Proteins / Q000737:chemistry / Q000172:deficiency* / Q000235:genetics
chemical_list: C000606762:Apoc2 protein, zebrafish; D053304:Apolipoprotein C-II; D008074:Lipoproteins; D010455:Peptides; D015534:Trans-Activators; D014280:Triglycerides; D029961:Zebrafish Proteins; D004720:Endonucleases
keywords: APOC2; Apolipoprotein C-II; Hyperlipidemia; Lipoprotein lipase; Zebrafish