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

James S V Lally; Sarani Ghoshal; Danielle K DePeralta; Omeed Moaven; Lan Wei; Ricard Masia; Derek J Erstad; Naoto Fujiwara; Vivian Leong; Vanessa P Houde; Alexander E Anagnostopoulos; Alice Wang; Lindsay A Broadfield; Rebecca J Ford; Robert A Foster; Jamie Bates; Hailing Sun; Ting Wang; Henry Liu; Adrian S Ray; Asish K Saha; Jeremy Greenwood; Sathesh Bhat; Geraldine Harriman; Wenyan Miao; Jennifer L Rocnik; William F Westlin; Paola Muti; Theodoros Tsakiridis; H James Harwood Jr; Rosana Kapeller; Yujin Hoshida; Kenneth K Tanabe; Gregory R Steinberg; Bryan C Fuchs

doi:10.1016/j.cmet.2018.08.020

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

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

Authors

James S V Lally¹, Sarani Ghoshal², Danielle K DePeralta², Omeed Moaven², Lan Wei², Ricard Masia³, Derek J Erstad², Naoto Fujiwara⁴, Vivian Leong¹, Vanessa P Houde⁵, Alexander E Anagnostopoulos¹, Alice Wang¹, Lindsay A Broadfield¹, Rebecca J Ford¹, Robert A Foster⁶, Jamie Bates⁷, Hailing Sun⁷, Ting Wang⁷, Henry Liu⁷, Adrian S Ray⁷, Asish K Saha⁸, Jeremy Greenwood⁹, Sathesh Bhat⁹, Geraldine Harriman¹⁰, Wenyan Miao¹⁰, Jennifer L Rocnik¹⁰, William F Westlin¹⁰, Paola Muti¹¹, Theodoros Tsakiridis¹¹, H James Harwood Jr¹⁰, Rosana Kapeller¹⁰, Yujin Hoshida⁴, Kenneth K Tanabe², Gregory R Steinberg¹², Bryan C Fuchs¹³

Affiliations

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: [email protected].
¹³ Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA. Electronic address: [email protected].

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

Acetyl-CoA Carboxylase* / antagonists & inhibitors
Acetyl-CoA Carboxylase* / physiology
Animals
Carcinoma, Hepatocellular / metabolism*
Hep G2 Cells
Humans
Lipogenesis*
Liver Neoplasms / metabolism*
Male
Mice
Phosphorylation
Rats
Rats, Wistar

Substances

ACACA protein, human
ACC1 protein, mouse
Acacb protein, mouse
Acetyl-CoA Carboxylase

Abstract

Publication types

MeSH terms

Substances

Grants and funding