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

Area of Science:

• Biochemistry
• Metabolic disease research
• Hepatology

Background:

• Ketone bodies from the liver are vital for energy homeostasis during fasting.
• Ketogenesis prevents diet-induced hepatic steatosis by clearing excess acetyl-CoA.
• The role of ketogenesis in fasting-related liver lipid metabolism requires further investigation.

Purpose of the Study:

• To investigate the role of hepatic ketogenesis in fasting-induced hepatic steatosis.
• To determine how ACSL1-mediated esterification contributes to steatosis.
• To explore the therapeutic potential of L-carnitine.

Main Methods:

• Mice with liver-specific knockout of HMGCS2 were used.
• Biochemical assays, gene expression profiling, Western blotting, and histologic analyses were performed.
• Human primary hepatocytes and liver samples were analyzed.

Main Results:

• Ketogenic insufficiency worsened liver steatosis in mice.
• Hepatic steatosis resulted from increased fatty acid re-esterification mediated by ACSL1 at the ER.
• Impaired ketogenesis led to acetyl-CoA accumulation, increasing ER-localized ACSL1.
• L-carnitine reduced ER-associated ACSL1 and alleviated hepatic steatosis.

Conclusions:

• Hepatic ketogenesis is crucial for maintaining acetyl-CoA balance.
• Ketogenesis regulates lipid partitioning to prevent hepatic steatosis.
• Targeting ketogenesis or acetyl-CoA buffering may offer therapeutic strategies for fatty liver disease.