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

Acetyl-CoA Carboxylase / antagonists & inhibitors Animals Carcinoma, Hepatocellular / metabolism Hep G2 Cells Humans Lipogenesis Liver Neoplasms / metabolism Male Mice Phosphorylation Rats Rats, Wistar
NAFLD NASH cancer metabolism fibrosis fructose inflammation malonyl-CoA non-alcoholic fatty liver disease non-alcoholic steatohepatitis

Journal

Cell metabolism
ISSN: 1932-7420
Titre abrégé: Cell Metab
Pays: United States
ID NLM: 101233170

Informations de publication

Date de publication:
08 01 2019
Historique:
received: 05 04 2017
revised: 12 03 2018
accepted: 22 08 2018
pubmed: 25 9 2018
medline: 25 2 2020
entrez: 25 9 2018
Statut: ppublish

Résumé

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.

Identifiants

DOI: 10.1016/j.cmet.2018.08.020 PMID: 30244972 PMC: PMC6643297
pubmed: 30244972
pii: S1550-4131(18)30521-7
doi: 10.1016/j.cmet.2018.08.020
pmc: PMC6643297
mid: NIHMS1507681
pii:
doi:

Substances chimiques

ACACA protein, human EC 6.4.1.2
ACC1 protein, mouse EC 6.4.1.2
Acacb protein, mouse EC 6.4.1.2
Acetyl-CoA Carboxylase EC 6.4.1.2

Types de publication

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

Langues

eng

Sous-ensembles de citation

IM

Pagination

174-182.e5

Subventions

Organisme : NCI NIH HHS
ID : K01 CA140861
Pays : United States
Organisme : European Research Council
ID : 671231
Pays : International
Organisme : CIHR
ID : 144625-1
Pays : Canada
Organisme : NCI NIH HHS
ID : T32 CA071345
Pays : United States
Organisme : NIDDK NIH HHS
ID : R01 DK099558
Pays : United States
Organisme : CIHR
ID : 125980-1
Pays : Canada

Informations de copyright

Copyright © 2018 Elsevier Inc. All rights reserved.

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Auteurs

James S V Lally (JSV)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Sarani Ghoshal (S)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Danielle K DePeralta (DK)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Omeed Moaven (O)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Lan Wei (L)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Ricard Masia (R)

Department of Pathology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Derek J Erstad (DJ)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Naoto Fujiwara (N)

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.

Vivian Leong (V)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Vanessa P Houde (VP)

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.

Alexander E Anagnostopoulos (AE)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Alice Wang (A)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Lindsay A Broadfield (LA)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Rebecca J Ford (RJ)

Department of Medicine, McMaster University, 1280 Main Street West, Hamilton, ON L8S 4L8, Canada.

Robert A Foster (RA)

Department of Pathobiology, Ontario Veterinary College, University of Guelph, Guelph, ON NIG 2W1, Canada.

Jamie Bates (J)

Gilead Sciences, Foster City, CA 94404, USA.

Hailing Sun (H)

Gilead Sciences, Foster City, CA 94404, USA.

Ting Wang (T)

Gilead Sciences, Foster City, CA 94404, USA.

Henry Liu (H)

Gilead Sciences, Foster City, CA 94404, USA.

Adrian S Ray (AS)

Gilead Sciences, Foster City, CA 94404, USA.

Asish K Saha (AK)

Department of Medicine and Physiology, School of Medicine, Endocrinology, Diabetes, and Nutrition, Boston University, Boston, MA 02118, USA.

Jeremy Greenwood (J)

Schrodinger, 120 West 45th Street, New York, NY 10036, USA.

Sathesh Bhat (S)

Schrodinger, 120 West 45th Street, New York, NY 10036, USA.

Geraldine Harriman (G)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

Wenyan Miao (W)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

Jennifer L Rocnik (JL)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

William F Westlin (WF)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

Paola Muti (P)

Department of Oncology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4L8, Canada.

Theodoros Tsakiridis (T)

Department of Oncology, McMaster University, 1280 Main St. W., Hamilton, ON L8S 4L8, Canada.

H James Harwood (HJ)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

Rosana Kapeller (R)

Nimbus Therapeutics, 30 Prospect Street, Cambridge, MA 02139, USA.

Yujin Hoshida (Y)

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.

Kenneth K Tanabe (KK)

Divison of Surgical Oncology, Massachusetts General Hospital Cancer Center and Harvard Medical School, 55 Fruit Street, Boston, MA 02114, USA.

Gregory R Steinberg (GR)

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.

Bryan C Fuchs (BC)

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.

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Classifications MeSH

Recherchemedicale.com › Enzymes et coenzymes › Enzymes › Enzymes multifonctionnelles › Acetyl-coA carboxylase › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Eucaryotes › Animaux › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Carcinome hépatocellulaire › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Cellules › Cellules épithéliales › Hépatocytes › Cellules HepG2 › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Métabolisme › Métabolisme lipidique › Lipogenèse › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Maladies de l'appareil digestif › Maladies du foie › Tumeurs du foie › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Souris › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Métabolisme › Phosphorylation › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Inhibition of Acetyl-CoA Carboxylase by...
Recherchemedicale.com › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Rodentia › Muridae › Murinae › Rats › Rat Wistar › Inhibition of Acetyl-CoA Carboxylase by...