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

Zhiguang Huang, Menglu Zhang, Abigail A. Plec, Sandi Jo Estill, Ling Cai, Joyce J. Repa, Steven L. McKnight, Benjamin P. Tu

Research output: Contribution to journalArticle

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Abstract

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.

Original languageEnglish (US)
Pages (from-to)E9499-E9506
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number40
DOIs
StatePublished - Oct 2 2018

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Acetate-CoA Ligase
Lipid Metabolism
Fats
Genes
Acetyl Coenzyme A
Lipids
Liver
Fatty Liver
Liver Neoplasms
Tumor Burden
Intestines
Adipose Tissue
Liver Diseases
Triglycerides
Acetates
Fatty Acids
Obesity
Body Weight
Diet
Enzymes

Keywords

  • Acetate
  • Epigenetics
  • Fatty liver disease
  • Metabolism
  • Obesity

ASJC Scopus subject areas

  • General

Cite this

ACSS2 promotes systemic fat storage and utilization through selective regulation of genes involved in lipid metabolism. / Huang, Zhiguang; Zhang, Menglu; Plec, Abigail A.; Estill, Sandi Jo; Cai, Ling; Repa, Joyce J.; McKnight, Steven L.; Tu, Benjamin P.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 40, 02.10.2018, p. E9499-E9506.

Research output: Contribution to journalArticle

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AU - Zhang, Menglu

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AU - Estill, Sandi Jo

AU - Cai, Ling

AU - Repa, Joyce J.

AU - McKnight, Steven L.

AU - Tu, Benjamin P.

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