Cell Mol Gastroenterol Hepatol. 2025 Jul 19:101593. doi: 10.1016/j.jcmgh.2025.101593. Online ahead of print.

ABSTRACT

BACKGROUND AND AIMS: Liver-derived ketone bodies play an essential in energy homeostasis during fasting by supplying fuel to both the brain and peripheral tissues. Ketogenesis also helps to remove excess acetyl-CoA generated from fatty acid oxidation, thereby protecting against diet-induced hepatic steatosis. Despite this, the role of ketogenesis in fasting-associated hepatocellular lipid metabolism has not been thoroughly investigated.

METHODS: We utilized mice with liver-specific knockout of HMGCS2 mice to determine how ACSL1-mediated esterification contributes to fasting-induced steatosis and performed biochemical assays, gene expression profiling, Western blotting, and histological analyses. We further investigated the association between HMGCS2 expression, lipid re-esterification, and steatosis using human primary hepatocytes and liver samples from MASH patients.

RESULTS: We show that ketogenic insufficiency, achieved through disrupting hepatic HMGCS2, worsens liver steatosis in both fasted chow-fed and high-fat-fed mice. Our findings indicate that hepatic steatosis arises from increased fatty acid partitioning to the endoplasmic reticulum (ER) for re-esterification, a process mediated by acyl-CoA synthetase long-chain family member 1 (ACSL1). Mechanistically, the accumulation of acetyl-CoA due to impaired hepatic ketogenesis drives the elevated translocation of ACSL1 to the ER. Furthermore, our study reveals heightened ER-localized ACSL1 and lipid re-esterification in human MASH cases exhibiting impaired hepatic ketogenesis. We also demonstrate that L-carnitine, which buffers excess acetyl-CoA, reduces ER-associated ACSL1 and alleviates hepatic steatosis.

CONCLUSION: Hepatic ketogenesis plays a crucial role in maintaining intracellular acetyl-CoA balance, regulating lipid partitioning, and preventing the development of fasting-induced hepatic steatosis.

PMID:40692014 | DOI:10.1016/j.jcmgh.2025.101593

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