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.

Pathogenetic, Prognostic, and Therapeutic Role of Fatty Acid Synthase in Human Hepatocellular Carcinoma

“…These feedback biochemical and metabolic events may contribute to HCC development. For instance, in the diethylnitrosamine (DEN) induced mouse HCC model, inhibition of lipogenesis via deletion of Acac1 and Acac2 genes in the liver led to an increased HCC development (58). Mechanistically, this unexpected finding was due to the marked increased in antioxidants, including increased NADPH and reduced glutathione, which protected hepatocytes from oxidant-mediated cell death.…”

Multi-omics Analysis of the Intermittent Fasting Response in Mice Identifies an Unexpected Role for HNF4α

“…For example, liver-specific ACC1/ACC2 (ACACA/ACACB) double knockouts have lower rates of fatty acid oxidation and higher rates of tumorigenesis (Chow et al, 2014;Nelson et al, 2017). Likewise, liver-specific FASN mutants display detrimental phenotypes compared to wild-type animals, including greatly increased steatosis after fasting (Chakravarthy et al, 2005).…”

M6A-mediated upregulation of LINC00958 increases lipogenesis and acts as a nanotherapeutic target in hepatocellular carcinoma

“…Mounting evidence indicates that abnormal lipid metabolism plays crucial parts in HCC development [22][23][24], and HDGF was recently reported to be a lipogenesis-associated gene in tumorigenesis [25]. We started to explore whether LINC00958 could affect lipogenesis in HCC cells.…”