Hepatic PPARγ coactivator 1β drives mitochondrial and anabolic signatures that contribute to hepatocellular carcinoma progression

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Abstract

The peroxisome proliferator-activated receptor γ (PPARγ) coactivator-1β (PGC-1 β) coactivator is a master regulator of mitochondrial biogenesis and oxidative metabolism as well as of antioxidant defense. Specifically in the liver PGC-1β also promotes de novo lipogenesis, thus sustaining cellular anabolic processes. Given the relevant pathogenic role of mitochondrial and fatty acid metabolism in hepatocarcinoma (HCC), here we pointed to PGC-1β as a putative novel transcriptional player in the development and progression of HCC. For this purpose, we generated both hepatic-specific PGC-1β overexpressing (LivPGC-1β) and PGC-1β knockout (LivPGC-1βKO) mice, and we challenged them with both chemical and genetic models of hepatic carcinogenesis. Our results demonstrate a pivotal role of PGC-1β in driving liver tumor development. Indeed, whereas mice overexpressing PGC-1β show greater tumor susceptibility, PGC-1β knockout mice are protected from carcinogenesis. High levels of PGC-1β are able to boost ROS scavenger expression, therefore limiting the detrimental ROS accumulation and, consequently, apoptosis. Moreover, it supports tumor anabolism, enhancing the expression of genes involved in fatty acid and triglyceride synthesis. Accordingly, the specific hepatic ablation of PGC-1β promotes the accumulation of ROS-driven macromolecule damage, finally limiting tumor growth . The present data elect hepatic PGC-1β as a transcriptional gatekeeper of mitochondrial function and redox status in HCC, orchestrating different metabolic programs that allow tumor progression. This article is protected by copyright. All rights reserved.

Autore Pugliese

Tutti gli autori

  • MOSCHETTA A.;VILLANI G.

Titolo volume/Rivista

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Anno di pubblicazione

2018

ISSN

0270-9139

ISBN

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Numero di citazioni Wos

Nessuna citazione

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Numero di citazioni Scopus

2

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Settori ERC

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Codici ASJC

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