title: Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival.
abstract: The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Blocking lipogenesis in cultured liver cancer cells is sufficient to decrease cell viability; however, it is not known whether blocking lipogenesis in vivo can prevent liver tumorigenesis. Herein, we inhibit hepatic lipogenesis in mice by liver-specific knockout of acetyl-CoA carboxylase (ACC) genes and treat the mice with the hepatocellular carcinogen diethylnitrosamine (DEN). Unexpectedly, mice lacking hepatic lipogenesis have a twofold increase in tumour incidence and multiplicity compared to controls. Metabolomics analysis of ACC-deficient liver identifies a marked increase in antioxidants including NADPH and reduced glutathione. Importantly, supplementing primary wild-type hepatocytes with glutathione precursors improves cell survival following DEN treatment to a level indistinguishable from ACC-deficient primary hepatocytes. This study shows that lipogenesis is dispensable for liver tumorigenesis in mice treated with DEN, and identifies an important role for ACC enzymes in redox regulation and cell survival.
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Marin E
authors.initials: ME
authors.lastname: Nelson
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Sujoy
authors.initials: S
authors.lastname: Lahiri
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Jenny D Y
authors.initials: JD
authors.lastname: Chow
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Frances L
authors.initials: FL
authors.lastname: Byrne
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Stefan R
authors.initials: SR
authors.lastname: Hargett
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: David S
authors.initials: DS
authors.lastname: Breen
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Ellen M
authors.initials: EM
authors.lastname: Olzomer
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Lindsay E
authors.initials: LE
authors.lastname: Wu
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.|School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.|School of Medicine, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Cooney
authors.affiliation: School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.
authors.forename: Nigel
authors.initials: N
authors.lastname: Turner
authors.affiliation: Charles Perkins Centre, The University of Sydney, Sydney, New South Wales 2006, Australia.|School of Life and Environmental Sciences, The University of Sydney, Sydney, New South Wales 2006, Australia.|School of Medicine, The University of Sydney, Sydney, New South Wales 2006, Australia.
authors.forename: David E
authors.initials: DE
authors.lastname: James
authors.affiliation: Department of Microbiology, Immunology and Cancer Biology, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Jill K
authors.initials: JK
authors.lastname: Slack-Davis
authors.affiliation: Institute of Pathology, Medical University of Graz, 8010 Graz, Austria.
authors.forename: Carolin
authors.initials: C
authors.lastname: Lackner
authors.affiliation: Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.|Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Stephen H
authors.initials: SH
authors.lastname: Caldwell
authors.affiliation: Department of Pharmacology, University of Virginia, Charlottesville, Virginia 22908, USA.|School of Biotechnology and Biomolecular Sciences, University of New South Wales, Sydney, New South Wales 2052, Australia.|Department of Medicine, University of Virginia, Charlottesville, Virginia 22908, USA.|Emily Couric Clinical Cancer Center, University of Virginia, Charlottesville, Virginia 22908, USA.
authors.forename: Kyle L
authors.initials: KL
authors.lastname: Hoehn
mesh_terms: D000103:Acetyl-CoA Carboxylase / Q000235:genetics* / Q000378:metabolism; D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D000975:Antioxidants; D063646:Carcinogenesis / Q000187:drug effects / Q000378:metabolism*; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects / Q000235:genetics*; D004052:Diethylnitrosamine / Q000633:toxicity; D005978:Glutathione / Q000378:metabolism; D056945:Hep G2 Cells; D006801:Humans; D050356:Lipid Metabolism / Q000187:drug effects / Q000235:genetics; D050155:Lipogenesis / Q000235:genetics*; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D008113:Liver Neoplasms / Q000235:genetics / Q000378:metabolism*; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000235:genetics / Q000378:metabolism*; D055432:Metabolomics; D051379:Mice; D018345:Mice, Knockout; D009249:NADP / Q000378:metabolism
chemical_list: D000477:Alkylating Agents; D000975:Antioxidants; D004052:Diethylnitrosamine; D009249:NADP; C000588423:ACACA protein, human; C520105:ACACB protein, human; C000616953:ACC1 protein, mouse; C498191:Acacb protein, mouse; D000103:Acetyl-CoA Carboxylase; D005978:Glutathione