Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia
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...
| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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The Company of Biologists
2015-08-01
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| Series: | Disease Models & Mechanisms |
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| Online Access: | http://dmm.biologists.org/content/8/8/989 |
| _version_ | 1818303717179392000 |
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| author | 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 |
| author_facet | 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 |
| author_sort | Chao Liu |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-12-13T05:59:14Z |
| format | Article |
| id | doaj.art-0e8f7229942e490c806f467aa4dab7cb |
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| issn | 1754-8411 1754-8403 |
| language | English |
| last_indexed | 2024-12-13T05:59:14Z |
| publishDate | 2015-08-01 |
| publisher | The Company of Biologists |
| record_format | Article |
| series | Disease Models & Mechanisms |
| spelling | doaj.art-0e8f7229942e490c806f467aa4dab7cb2022-12-21T23:57:22ZengThe Company of BiologistsDisease Models & Mechanisms1754-84111754-84032015-08-018898999810.1242/dmm.019836019836Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemiaChao Liu0Keith P. Gates1Longhou Fang2Marcelo J. Amar3Dina A. Schneider4Honglian Geng5Wei Huang6Jungsu Kim7Jennifer Pattison8Jian Zhang9Joseph L. Witztum10Alan T. Remaley11P. Duc Dong12Yury I. Miller13 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA 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 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, NIH, Bethesda, MD, USA Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA State Key Laboratory of Molecular Developmental Biology, Institute of Genetics and Developmental Biology, Chinese Academy of Sciences, Beijing, China Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA Lipoprotein Metabolism Section, Cardiopulmonary Branch, NHLBI, NIH, Bethesda, MD, USA 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 Division of Endocrinology and Metabolism, Department of Medicine, University of California, San Diego, La Jolla, CA, USA 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.http://dmm.biologists.org/content/8/8/989ZebrafishApolipoprotein C-IIAPOC2Lipoprotein lipaseHyperlipidemia |
| spellingShingle | 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 Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia Disease Models & Mechanisms Zebrafish Apolipoprotein C-II APOC2 Lipoprotein lipase Hyperlipidemia |
| title | Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia |
| title_full | Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia |
| title_fullStr | Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia |
| title_full_unstemmed | Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia |
| title_short | Apoc2 loss-of-function zebrafish mutant as a genetic model of hyperlipidemia |
| title_sort | apoc2 loss of function zebrafish mutant as a genetic model of hyperlipidemia |
| topic | Zebrafish Apolipoprotein C-II APOC2 Lipoprotein lipase Hyperlipidemia |
| url | http://dmm.biologists.org/content/8/8/989 |
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