Hepatic ketogenesis regulates lipid homeostasis via ACSL1-mediated fatty acid partitioning

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.

Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation

“…These findings suggest that ketogenesis might be linked to the lipidomic remodeling of the liver that occurs in MASLD-MASH. Though numerous studies have linked ketogenesis to MASLD-MASH 19,[71][72][73][74] , the underlying mechanisms and consequences remain unclear. Prior studies from our group and others demonstrated ketogenic insufficiency increases the susceptibility to MASLD-MASH by increasing hepatic oxidative fluxes and provoking a DNL metabolic and transcriptomic signature 24,75 .…”