Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis
Objective: Aberrant ketogenesis is correlated with the degree of steatosis in non-alcoholic fatty liver disease (NAFLD) patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine...
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| Format: | Article |
| Language: | English |
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Elsevier
2022-07-01
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| Series: | Molecular Metabolism |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S2212877822000631 |
| _version_ | 1818232563372654592 |
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| author | Shaza Asif Ri Youn Kim Thet Fatica Jordan Sim Xiaoling Zhao Yena Oh Alix Denoncourt Angela C. Cheung Michael Downey Erin E. Mulvihill Kyoung-Han Kim |
| author_facet | Shaza Asif Ri Youn Kim Thet Fatica Jordan Sim Xiaoling Zhao Yena Oh Alix Denoncourt Angela C. Cheung Michael Downey Erin E. Mulvihill Kyoung-Han Kim |
| author_sort | Shaza Asif |
| collection | DOAJ |
| description | Objective: Aberrant ketogenesis is correlated with the degree of steatosis in non-alcoholic fatty liver disease (NAFLD) patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease. Methods: Loss- and gain-of-ketogenic function models, achieved by Hmgcs2 knockout and overexpression, respectively, were utilized to investigate the role of ketogenesis in the hepatic lipid accumulation during postnatal development and in a high-fat diet-induced NAFLD mouse model. Results: Ketogenic function was decreased in NAFLD mice with a reduction in Hmgcs2 expression. Mice lacking Hmgcs2 developed spontaneous fatty liver phenotype during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Hmgcs2 heterozygous adult mice, which exhibited lower ketogenic activity, were more susceptible to diet-induced NAFLD development, whereas HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis. Conclusions: Our study adds new knowledge to the field of ketone body metabolism and shows that Hmgcs2-mediated ketogenesis modulates hepatic lipid regulation under a fat-enriched nutritional environment. The regulation of hepatic ketogenesis may be a viable therapeutic strategy in the prevention and treatment of hepatosteatosis. |
| first_indexed | 2024-12-12T11:08:16Z |
| format | Article |
| id | doaj.art-541393ef70824562951e14381149227c |
| institution | Directory Open Access Journal |
| issn | 2212-8778 |
| language | English |
| last_indexed | 2024-12-12T11:08:16Z |
| publishDate | 2022-07-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Molecular Metabolism |
| spelling | doaj.art-541393ef70824562951e14381149227c2022-12-22T00:26:21ZengElsevierMolecular Metabolism2212-87782022-07-0161101494Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosisShaza Asif0Ri Youn Kim1Thet Fatica2Jordan Sim3Xiaoling Zhao4Yena Oh5Alix Denoncourt6Angela C. Cheung7Michael Downey8Erin E. Mulvihill9Kyoung-Han Kim10University of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, CanadaDepartment of Pathology and Laboratory Medicine, The Ottawa Hospital, Ottawa, ON, K1H 8M5, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, CanadaDepartment of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, K1H 8M5, CanadaGastroenterology and Hepatology, Department of Medicine, The Ottawa Hospital, Ottawa, ON, K1H 8M5, Canada; The Ottawa Hospital Research Institute, Chronic Disease Program, Ottawa, ON, K1Y 4E9, CanadaDepartment of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Ottawa Institute of Systems Biology, Ottawa, ON, K1H 8M5, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, CanadaUniversity of Ottawa Heart Institute, Ottawa, ON, K1Y 4W7, Canada; Department of Cellular and Molecular Medicine, Faculty of Medicine, University of Ottawa, Ottawa, ON, K1H 8M5, Canada; Corresponding author. University of Ottawa Heart Institute & Department of Cellular and Molecular Medicine, University of Ottawa, 40 Ruskin Street Ottawa, Rm H-3211A, ON, K1Y 4W7, Canada.Objective: Aberrant ketogenesis is correlated with the degree of steatosis in non-alcoholic fatty liver disease (NAFLD) patients, and an inborn error of ketogenesis (mitochondrial HMG-CoA synthase deficiency) is commonly associated with the development of the fatty liver. Here we aimed to determine the impact of Hmgcs2-mediated ketogenesis and its modulations on the development and treatment of fatty liver disease. Methods: Loss- and gain-of-ketogenic function models, achieved by Hmgcs2 knockout and overexpression, respectively, were utilized to investigate the role of ketogenesis in the hepatic lipid accumulation during postnatal development and in a high-fat diet-induced NAFLD mouse model. Results: Ketogenic function was decreased in NAFLD mice with a reduction in Hmgcs2 expression. Mice lacking Hmgcs2 developed spontaneous fatty liver phenotype during postnatal development, which was rescued by a shift to a low-fat dietary composition via early weaning. Hmgcs2 heterozygous adult mice, which exhibited lower ketogenic activity, were more susceptible to diet-induced NAFLD development, whereas HMGCS2 overexpression in NAFLD mice improved hepatosteatosis and glucose homeostasis. Conclusions: Our study adds new knowledge to the field of ketone body metabolism and shows that Hmgcs2-mediated ketogenesis modulates hepatic lipid regulation under a fat-enriched nutritional environment. The regulation of hepatic ketogenesis may be a viable therapeutic strategy in the prevention and treatment of hepatosteatosis.http://www.sciencedirect.com/science/article/pii/S2212877822000631KetogenesisHmgcs2NAFLDLipid accumulation |
| spellingShingle | Shaza Asif Ri Youn Kim Thet Fatica Jordan Sim Xiaoling Zhao Yena Oh Alix Denoncourt Angela C. Cheung Michael Downey Erin E. Mulvihill Kyoung-Han Kim Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis Molecular Metabolism Ketogenesis Hmgcs2 NAFLD Lipid accumulation |
| title | Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis |
| title_full | Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis |
| title_fullStr | Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis |
| title_full_unstemmed | Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis |
| title_short | Hmgcs2-mediated ketogenesis modulates high-fat diet-induced hepatosteatosis |
| title_sort | hmgcs2 mediated ketogenesis modulates high fat diet induced hepatosteatosis |
| topic | Ketogenesis Hmgcs2 NAFLD Lipid accumulation |
| url | http://www.sciencedirect.com/science/article/pii/S2212877822000631 |
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