Review Article | Published:

Metabolic aspects in NAFLD, NASH and hepatocellular carcinoma: the role of PGC1 coactivators

Nature Reviews Gastroenterology & Hepatologyvolume 16pages160174 (2019) | Download Citation

Abstract

Alterations of hepatic metabolism are critical to the development of liver disease. The peroxisome proliferator-activated receptor-γ coactivators (PGC1s) are able to orchestrate, on a transcriptional level, different aspects of liver metabolism, such as mitochondrial oxidative phosphorylation, gluconeogenesis and fatty acid synthesis. As modifications affecting both mitochondrial and lipid metabolism contribute to the initiation and/or progression of liver steatosis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH) and hepatocellular carcinoma (HCC), a link between disrupted PGC1 pathways and onset of these pathological conditions has been postulated. However, despite the large quantity of studies, the scenario is still not completely understood, and some issues remain controversial. Here, we discuss the roles of PGC1s in healthy liver and explore their contribution to the pathogenesis and future therapy of NASH and HCC.

Key points

  • Peroxisome proliferator-activated receptor-γ coactivators (PGC1s) have a key role in liver metabolism and contribute to energy homeostasis.

  • PGC1α and PGC1β exert divergent functions on liver metabolism and regulate different pathways.

  • Although the hepatic expression of both PGC1α and PGC1β negatively correlates with nonalcoholic fatty liver disease (NAFLD) severity, hepatocellular carcinoma (HCC) development is inhibited by PGC1α and promoted by PGC1β.

  • Although direct coactivator targeting is problematic, pharmacological modulation of transcriptional and post-transcriptional activators of PGC1s is an appealing therapeutic avenue.

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Acknowledgements

A.M. is funded by the Italian Association for Cancer Research (AIRC, IG 18987), NR-NET FP7 Marie Curie ITN, FATMAL (HDHL-INTIMIC Joint Call) and the Italian Ministry of Health (Young Researchers Grant GR-2010-2314703).

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Nature Reviews Gastroenterology & Hepatology thanks J. Hakkola and the other anonymous reviewers for their contribution to the peer review of this work.

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Affiliations

  1. Department of Interdisciplinary Medicine, Aldo Moro University of Bari, Bari, Italy

    • Elena Piccinin
    •  & Antonio Moschetta
  2. INBB, National Institute for Biostructures and Biosystems, Rome, Italy

    • Elena Piccinin
  3. Department of Basic Medical Sciences, Neurosciences and Sense Organs, Aldo Moro University of Bari, Bari, Italy

    • Gaetano Villani
  4. National Cancer Center, IRCCS Istituto Tumori Giovanni Paolo II, Bari, Italy

    • Antonio Moschetta

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All authors contributed equally to all aspects of the manuscript.

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Correspondence to Antonio Moschetta.

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https://doi.org/10.1038/s41575-018-0089-3