Inhibition of hepatic lipogenesis enhances liver tumorigenesis by increasing antioxidant defence and promoting cell survival

Marin E Nelson,Kyle L Hoehn,Ellen M Olzomer,Jenny D Y Chow,David E James,Jill K Slack-Davis,Frances L Byrne,Stephen H Caldwell,Nigel Turner,Carolin Lackner,Sujoy Lahiri,Gregory J Cooney,Lindsay E Wu,David S Breen,Stefan R Hargett

doi:10.1038/ncomms14689

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.

Highlights

The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis
ACC2 catalyses the same reaction as ACC1; ACC2 is localized to the cytosolic surface of mitochondria where it produces malonyl-CoA that inhibits carnitine palmitoyltransferase 1 (CPT1) to decrease fat oxidation
We first investigated whether the mouse model of DEN-induced liver tumorigenesis demonstrated a lipogenic phenotype that was comparable to human hepatocellular carcinoma (HCC) tumours

Summary

Introduction

The metabolic pathway of de novo lipogenesis is frequently upregulated in human liver tumours, and its upregulation is associated with poor prognosis. Lipogenesisderived lipids are highly saturated and resistant to lipid peroxidation, saturated lipids may facilitate lipid raft formation to drive aberrant signal transduction pathways, de novo synthesized lipids may serve as endogenous ligands for transcription factors, and/or tumour cells may not be capable of scavenging enough extracellular lipids to support the increased rate of proliferation[11,12,13,14,15] It is currently unknown whether lipogenesis-derived lipids are required for tumorigenesis, or whether circulating lipids are sufficient to satisfy the metabolic and physical properties required for tumour cell growth and proliferation. ACC2 catalyses the same reaction as ACC1; ACC2 is localized to the cytosolic surface of mitochondria where it produces malonyl-CoA that inhibits carnitine palmitoyltransferase 1 (CPT1) to decrease fat oxidation Despite their distinct compartmentalization, ACC2 can compensate for the loss of ACC1 and drive lipogenesis in ACC1-deficient hepatocytes[16]. Blocking ACC activity conserved NADPH that would otherwise be used for lipogenesis, resulting in greater antioxidant defence that protected hepatocytes from oxidant-mediated cell death

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Conclusion