ACAT3 controls hepatic cholesterol metabolism and modulates systemic energy homeostasis of male mice

Aims: Acetyl coenzyme A acetyltransferase (ACAT) family enzymes catalyses the conversion of acetyl-CoA into acetoacetyl-CoA that provides the substrate for ketone and cholesterol biosynthesis. In the present study, we aimed to assess the function of hepatic ACAT3 in cholesterol and bile acid homeostasis, and its effects on systemic energy metabolism. Materials and methods: We used genetic overexpression and knockout (KO) mouse models to liver-targeted access the function of ACAT3 in mouse liver. We then applied multiple analysis to investigate the changes in morphology, physiology, histology and molecular levels of the mice. Key findings: Acat3 is highly expressed in liver tissue of mice and its expression levels are downregulated during obesity, diabetes and aging. Hepatic Acat3 overexpression reduces body weight, fat mass and promotes glucose metabolism in mice. Mice with Acat3 overexpression have reduced serum lipid concentrations and adipose tissue weight. While Acat3 overexpression changed hepatic Cholesterol metabolic signaling and bile acid composition. Global and liver-specific (Acat3^Alb) Acat3 KO mice have reduced lean mass and energy expenditure. Liver-specific Acat3 KO reduces body weight, disrupts the gut microbiota and hepatic bile acid composition. Significance: Both overexpression and knockout of Acat3 lead to changes in hepatic cholesterol metabolic pathway, which alters bile acid synthesis and composition. These alterations in bile acid profiles subsequently influence intestinal microbiota, thereby modulating systemic energy homeostasis of mice. Modulation of ACAT3 or its downstream mechanisms alters bile acid profiles to improve glucose and lipid metabolism and develop new therapeutic strategies for clinical applications.