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Cell Metab. 2019 Jan 8;29(1):174-182.e5. doi: 10.1016/j.cmet.2018.08.020. Epub 2018 Sep 20.

Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma.

Author information

1
Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.
2
Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
3
Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.
4
Liver Tumor Translational Research Program, Harold C. Simmons Comprehensive Cancer Center, Division of Digestive and Liver Diseases, Department of Internal Medicine, University of Texas Southwestern Medical Center, 5323 Harry Hines Boulevard, Dallas, TX 75390, USA.
5
Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada; Department of Oncology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4L8, Canada.
6
Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON NIG 2W1, Canada.
7
Gilead Sciences, Foster City, CA 94404, USA.
8
Department of Medicine and Physiology, School of Medicine, Endocrinology, Diabetes, and Nutrition, Boston University, Boston, MA 02118, USA.
9
Schrodinger, 120 West 45th Street, New York, NY 10036, USA.
10
Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.
11
Department of Oncology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4L8, Canada.
12
Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada; Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada. Electronic address: gsteinberg@mcmaster.ca.
13
Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: bfuchs@mgh.harvard.edu.

Abstract

The incidence of hepatocellular carcinoma (HCC) is rapidly increasing due to the prevalence of obesity and non-alcoholic fatty liver disease, but the molecular triggers that initiate disease development are not fully understood. We demonstrate that mice with targeted loss-of-function point mutations within the AMP-activated protein kinase (AMPK) phosphorylation sites on acetyl-CoA carboxylase 1 (ACC1 Ser79Ala) and ACC2 (ACC2 Ser212Ala) have increased liver de novo lipogenesis (DNL) and liver lesions. The same mutation in ACC1 also increases DNL and proliferation in human liver cancer cells. Consistent with these findings, a novel, liver-specific ACC inhibitor (ND-654) that mimics the effects of ACC phosphorylation inhibits hepatic DNL and the development of HCC, improving survival of tumor-bearing rats when used alone and in combination with the multi-kinase inhibitor sorafenib. These studies highlight the importance of DNL and dysregulation of AMPK-mediated ACC phosphorylation in accelerating HCC and the potential of ACC inhibitors for treatment.

KEYWORDS:

NAFLD; NASH; cancer metabolism; fibrosis; fructose; inflammation; malonyl-CoA; non-alcoholic fatty liver disease; non-alcoholic steatohepatitis

PMID:
30244972
PMCID:
PMC6643297
[Available on 2020-01-08]
DOI:
10.1016/j.cmet.2018.08.020

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