Medizinische Universität Graz Austria/Österreich - Forschungsportal - Medical University of Graz
Gewählte Publikation:
SHR Neuro Krebs Kardio Lipid Stoffw Microb
Nelson, ME; Lahiri, S; Chow, JD; Byrne, FL; Hargett, SR; Breen, DS; Olzomer, EM; Wu, LE; Cooney, GJ; Turner, N; James, DE; Slack-Davis, JK; Lackner, C; Caldwell, SH; Hoehn, KL.
Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival.
Nat Commun. 2017; 8(6):14689-14689
Doi: 10.1038/ncomms14689
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- Lackner Karoline
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- 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.
- Find related publications in this database (using NLM MeSH Indexing)
- Acetyl-CoA Carboxylase - genetics
- Acetyl-CoA Carboxylase - metabolism
- Alkylating Agents - toxicity
- Animals -
- Antioxidants -
- Carcinogenesis - drug effects
- Carcinogenesis - metabolism
- Carcinoma, Hepatocellular - chemically induced
- Carcinoma, Hepatocellular - genetics
- Carcinoma, Hepatocellular - metabolism
- Cell Line, Tumor -
- Cell Survival - drug effects
- Cell Survival - genetics
- Diethylnitrosamine - toxicity
- Glutathione - metabolism
- Hep G2 Cells -
- Humans -
- Lipid Metabolism - drug effects
- Lipid Metabolism - genetics
- Lipogenesis - genetics
- Liver - drug effects
- Liver - metabolism
- Liver Neoplasms - genetics
- Liver Neoplasms - metabolism
- Liver Neoplasms, Experimental - chemically induced
- Liver Neoplasms, Experimental - genetics
- Liver Neoplasms, Experimental - metabolism
- Metabolomics -
- Mice -
- Mice, Knockout -
- NADP - metabolism