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

Zhiguang Huang,Menglu Zhang,Abigail A. Plec,S. Estill,L. Cai,J. Repa,S. McKnight,B. Tu

Published 2018 in Proceedings of the National Academy of Sciences of the United States of America

ABSTRACT

Significance Animals lacking the ACSS2 enzyme are phenotypically normal when fed a standard chow diet. Surprisingly, when fed a high-fat diet, ACSS2-deficient animals become markedly less obese than their wild-type littermates. We further observe attenuation in the accumulation of fat in the livers of ACSS2-deficient mice. We show that the ACSS2 enzyme acts more like a transcription factor than a metabolic enzyme. It facilitates the dynamic reprogramming of gene expression in many different tissues to orchestrate the proper physiological adaptation of animals to the fed or fasted state. A potent and selective chemical inhibitor of the ACSS2 enzyme could represent a unique therapy for the treatment of both obesity and fatty liver disease. 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.

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