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Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival
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Journal Article
Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival
2017
Overview
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.
The lipogenic pathway is often upregulated in liver tumours and regarded as a therapeutic target. Here, the authors show instead that blocking lipogenesis via knockout of acetyl-CoA carboxylase genes results in increased susceptibility to liver tumorigenesis associated with an increased antioxidant defence.
Publisher
Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
Subject
/ 13/2
/ 13/51
/ 38/77
/ 82/1
/ 82/80
/ Acetyl-CoA Carboxylase - genetics
/ Acetyl-CoA Carboxylase - metabolism
/ Alkylating Agents - toxicity
/ Animals
/ Carcinogenesis - drug effects
/ Carcinoma, Hepatocellular - chemically induced
/ Carcinoma, Hepatocellular - genetics
/ Carcinoma, Hepatocellular - metabolism
/ Cell Survival - drug effects
/ Diethylnitrosamine - toxicity
/ Enzymes
/ Humanities and Social Sciences
/ Humans
/ Kinases
/ Lipid Metabolism - drug effects
/ Lipids
/ Liver Neoplasms - metabolism
/ Liver Neoplasms, Experimental - chemically induced
/ Liver Neoplasms, Experimental - genetics
/ Liver Neoplasms, Experimental - metabolism
/ Mice
/ Science
/ Tumors
