ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 115; no. 40; pp. E9499 - E9506
• Main Authors: Huang, Zhiguang, Zhang, Menglu, Plec, Abigail A., Estill, Sandi Jo, Cai, Ling, Repa, Joyce J., McKnight, Steven L., Tu, Benjamin P.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 02.10.2018
• Series: PNAS Plus
• Subjects: Acetate-CoA Ligase - genetics; Acetate-CoA Ligase - metabolism; Acetic acid; Acetyl Coenzyme A - genetics; Acetyl Coenzyme A - metabolism; Adipose tissue; Adipose Tissue - metabolism; Adipose Tissue - pathology; Animal models; Animals; Biological Sciences; Body weight; Enzymes; Fat metabolism; Fatty liver; Fatty Liver - genetics; Fatty Liver - metabolism; Fatty Liver - pathology; Gene expression; Gene Expression Regulation; Gene regulation; Genes; Genotype & phenotype; Intestine; Lipid Metabolism; Lipids; Liver; Liver - metabolism; Liver - pathology; Liver cancer; Liver diseases; Metabolism; Mice; Mice, Knockout; Oxidation; Physiology; PNAS Plus; Rodents; Steatosis; Triglycerides; acetate; metabolism; epigenetics; obesity; fatty liver disease
• ISSN: 0027-8424; 1091-6490; 1091-6490
• DOI: 10.1073/pnas.1806635115

Acetyl-CoA synthetase 2 (ACSS2) is a conserved nucleocytosolic enzyme that converts acetate to acetyl-CoA. Adult mice lacking ACSS2 appear phenotypically normal but exhibit reduced tumor burdens in mouse models of liver cancer. The normal physiological functions of this alternate pathway of acetyl-CoA synthesis remain unclear, however. Here, we reveal that mice lacking ACSS2 exhibit a significant reduction in body weight and hepatic steatosis in a diet-induced obesity model. ACSS2 deficiency reduces dietary lipid absorption by the intestine and also perturbs repartitioning and utilization of triglycerides from adipose tissue to the liver due to lowered expression of lipid transporters and fatty acid oxidation genes. In this manner, ACSS2 promotes the systemic storage or metabolism of fat according to the fed or fasted state through the selective regulation of genes involved in lipid metabolism. Thus, targeting ACSS2 may offer a therapeutic benefit for the treatment of fatty liver disease.