Distinct Role of Nuclear Receptor Corepressor 1 Regulated de novo Fatty Acids Synthesis in Liver Regeneration and Hepatocarcinogenesis

Abstract

Means to improve liver regeneration is urgent to be found, but with risks to facilitate the development of tumor. NCoR1 is a co-repressor of nuclear receptors which regulates the expression level of metabolic genes, however, little is known about its potential contribution for liver regeneration and hepatocarcinogenesis. Here, we found liver-specific NCoR1 knock-out(NCoR1^Δhep) dramatically enhances liver regeneration after partial hepatectomy and surprisingly blocks the process of DEN-induced hepatocarcinogenesis. Both RNA-seq and metabolic assay results revealed exclusively improved expression of Fasn and Acc2 in NCoR1^Δhep mice, suggesting the critical role of de novo fatty acids synthesis(FAS) in liver regeneration. Continual enhanced de novo FAS in NCoR1^Δhep mice resulted in overwhelmed ATP and NADPH consumption and increased mitochondrial ROS production, which subsequently attenuated hepatocarcinogenesis through inducing apoptosis of hepatocytes at early stage after DEN administration. Conclusion: NCoR1 functions as a negative modulator for hepatic de novo FAS and mitochondria energy adaptation, playing distinct roles in either regeneration or carcinogenesis. This article is protected by copyright. All rights reserved.

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