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- W4384661718 abstract "Liver-derived ketone bodies play a crucial role in fasting energy homeostasis by fueling the brain and peripheral tissues. Ketogenesis also acts as a conduit to remove excess acetyl-CoA generated from fatty acid oxidation and protects against diet-induced hepatic steatosis. Surprisingly, no study has examined the role of ketogenesis in fasting-associated hepatocellular lipid metabolism. Ketogenesis is driven by the rate-limiting mitochondrial enzyme 3-hydroxymethylglutaryl CoA synthase (HMGCS2) abundantly expressed in the liver. Here, we show that ketogenic insufficiency via disruption of hepatic HMGCS2 exacerbates liver steatosis in fasted chow and high-fat-fed mice. We found that the hepatic steatosis is driven by increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification via acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, acetyl-CoA accumulation from impaired hepatic ketogenesis is responsible for the elevated translocation of ACSL1 to the ER. Moreover, we show increased ER-localized ACSL1 and re-esterification of lipids in human NASH displaying impaired hepatic ketogenesis. Finally, we show that L-carnitine, which buffers excess acetyl-CoA, decreases the ER-associated ACSL1 and alleviates hepatic steatosis. Thus, ketogenesis via controlling hepatocellular acetyl-CoA homeostasis regulates lipid partitioning and protects against hepatic steatosis." @default.
- W4384661718 created "2023-07-20" @default.
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- W4384661718 date "2023-07-18" @default.
- W4384661718 modified "2023-09-25" @default.
- W4384661718 title "Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning" @default.
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- W4384661718 doi "https://doi.org/10.21203/rs.3.rs-3147009/v1" @default.
- W4384661718 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/37503004" @default.
- W4384661718 hasPublicationYear "2023" @default.
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