@article{841d5b4525414bff960a1f53f4fb1e80,
title = "Inhibition of Acetyl-CoA Carboxylase by Phosphorylation or the Inhibitor ND-654 Suppresses Lipogenesis and Hepatocellular Carcinoma",
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",
author = "Lally, {James S.V.} and Sarani Ghoshal and DePeralta, {Danielle K.} and Omeed Moaven and Lan Wei and Ricard Masia and Erstad, {Derek J.} and Naoto Fujiwara and Vivian Leong and Houde, {Vanessa P.} and Anagnostopoulos, {Alexander E.} and Alice Wang and Broadfield, {Lindsay A.} and Ford, {Rebecca J.} and Foster, {Robert A.} and Jamie Bates and Hailing Sun and Ting Wang and Henry Liu and Ray, {Adrian S.} and Saha, {Asish K.} and Jeremy Greenwood and Sathesh Bhat and Geraldine Harriman and Wenyan Miao and Rocnik, {Jennifer L.} and Westlin, {William F.} and Paola Muti and Theodoros Tsakiridis and Harwood, {H. James} and Rosana Kapeller and Yujin Hoshida and Tanabe, {Kenneth K.} and Steinberg, {Gregory R.} and Fuchs, {Bryan C.}",
note = "Funding Information: This work was supported by grants from the National Cancer Institute ( T32 CA071345 to D.K.D., O.M., and K.K.T. and K01 CA140861 to B.C.F.), the Uehara Memorial Foundation (N.F.), the National Institute of Diabetes and Digestive and Kidney Diseases ( DK099558 to Y.H.), the European Union ( ERC-2014-AdG-671231 HEPCIR to Y.H.), the Irma T. Hirschl Trust (Y.H.), the U.S. Department of Defense ( W81XWH-16-1-0363 to Y.H.), the Canadian Cancer Society Research and Innovation Fund (G.R.S.), the Canadian Institutes of Health Research (G.R.S. 125980-1 , 144625-1 ), Nimbus Therapeutics (to B.C.F.), and Gilead Sciences (to B.C.F.). A.E.G received a scholarship from the Canadian Liver Foundation . G.R.S. is supported by a Canada Research Chair and by the J. Bruce Duncan Chair in Metabolic Diseases . Publisher Copyright: {\textcopyright} 2018 Elsevier Inc.",
year = "2019",
month = jan,
day = "8",
doi = "10.1016/j.cmet.2018.08.020",
language = "English (US)",
volume = "29",
pages = "174--182.e5",
journal = "Cell Metabolism",
issn = "1550-4131",
publisher = "Cell Press",
number = "1",
}