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. RayAsish K. Saha, Jeremy Greenwood, Sathesh Bhat, Geraldine Harriman, Wenyan Miao, Jennifer L. Rocnik, William F. Westlin, Paola Muti, Theodoros Tsakiridis, H. James Harwood, Rosana Kapeller, Yujin Hoshida, Kenneth K. Tanabe, Gregory R. Steinberg, Bryan C. Fuchs

Research output: Contribution to journalArticle

35 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)174-182.e5
JournalCell Metabolism
Volume29
Issue number1
DOIs
StatePublished - Jan 8 2019

Keywords

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

ASJC Scopus subject areas

  • Physiology
  • Molecular Biology
  • Cell Biology

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  • Cite this

    Lally, J. S. V., Ghoshal, S., DePeralta, D. K., Moaven, O., Wei, L., Masia, R., Erstad, D. J., Fujiwara, N., Leong, V., Houde, V. P., Anagnostopoulos, A. E., Wang, A., Broadfield, L. A., Ford, R. J., Foster, R. A., Bates, J., Sun, H., Wang, T., Liu, H., ... Fuchs, B. C. (2019). Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma. Cell Metabolism, 29(1), 174-182.e5. https://doi.org/10.1016/j.cmet.2018.08.020