Hepatic Ketogenesis Regulates Lipid Homeostasis via ACSL1-mediated Fatty Acid Partitioning

Liver-derived ketone bodies play an essential role in energy homeostasis during fasting by supplying fuel to 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.

We used 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 histologic analyses. We further investigated the association between HMGCS2 expression, lipid re-esterification, and steatosis using human primary hepatocytes and liver samples from patients with metabolic dysfunction-associated steatohepatitis.

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 because of 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 metabolic dysfunction-associated steatohepatitis cases exhibiting impaired hepatic ketogenesis. We also demonstrate that L-carnitine, which buffers excess acetyl-CoA, reduces ER-associated ACSL1 and alleviates hepatic steatosis.

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