Journal
MOLECULAR METABOLISM
Volume 61, Issue -, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.molmet.2022.101494
Keywords
Ketogenesis; Hmgcs2; NAFLD; Lipid accumulation
Categories
Funding
- University of Ottawa Heart Institute [RGPIN-2021-03887]
- National New Investigator Award from the Heart and Stroke Foundation of Canada (HSFC)
- Canada Graduate Scholarships Master Award (CGS-M) by the Canadian Institutes of Health Research
- Queen Elizabeth II Graduate Scholarship in Science and Technology
- University of Ottawa Cardiology Research Endowment Fund
- National Research Foundation of Korea
- Frederick Banting and Charles Best Canada Graduate Scholarships Doctoral Award (CGS-D)
- Natural Sciences and Engineering Research Council of Canada (NSERC)
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This study demonstrates the impact of Hmgcs2-mediated ketogenesis on the development and treatment of fatty liver disease, suggesting that the regulation of hepatic ketogenesis may be a viable therapeutic strategy for 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 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. (c) 2022 The Author(s). Published by Elsevier GmbH. This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
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