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Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease

Abstract

The liver is often thought of as a single functional unit, but both its structural and functional architecture make it highly multivalent and adaptable. In any given physiological situation, the liver can maintain metabolic homeostasis, conduct appropriate inflammatory responses, carry out endobiotic and xenobiotic transformation and synthesis reactions, as well as store and release multiple bioactive molecules. Moreover, the liver is a very resilient organ. This resilience means that chronic liver diseases can go unnoticed for decades, yet culminate in life-threatening clinical complications once the adaptive capacity of the liver is overwhelmed. Non-alcoholic fatty liver disease (NAFLD) predisposes individuals to cirrhosis and increases liver-related and cardiovascular disease-related mortality. This Review discusses the accumulating evidence of sexual dimorphism in NAFLD, which is currently rarely considered in preclinical and clinical studies. Increased awareness of the mechanistic causes of hepatic sexual dimorphism could lead to improved understanding of the biological processes that are dysregulated in NAFLD, to the identification of relevant therapeutic targets and to improved risk stratification of patients with NAFLD undergoing therapeutic intervention.

Key points

  • Liver pathophysiology is sexually dimorphic.

  • Male individuals predominantly show more severe stages of non-alcoholic fatty liver, non-alcoholic steatohepatitis (NASH) and fibrosis than do female individuals.

  • Individual variations in humans require large cohorts to identify sex-specific features of non-alcoholic fatty liver disease (NAFLD).

  • Preclinical and clinical investigations of NAFLD and of fibrosis rarely consider sex as a biological variable.

  • The time (and technologies) are ripe for investigating the sexual dimorphism of liver diseases in time and space.

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Fig. 1: Main physiological pathways involved in liver sexual dimorphism.
Fig. 2: Progression of NAFLD is influenced by sexual dimorphism.

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Acknowledgements

The authors’ research work was supported by grants from Agence Nationale pour la Recherche (ANR-16-RHUS-0006-PreciNASH and ANR-10-LBEX-46 to P.L. and B.S.), the European Union (FP6 Hepadip FP6-018734 and FP7 Resolve FP7-305707 to B.S.), Fondation de France (grant 2014 00047965 to P.L.), Fondation pour la Recherche Médicale (Equipe labellisée DEQ20150331724 to P.L.). B.S. is a recipient of an Advanced ERC Grant (694717).

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Glossary

Expandability

The capacity of adipocytes to proliferate and differentiate, particularly in a metabolically challenging environment.

Partially refractory

A general phenomenon in receptor biology whereby continuous activation of a signalling pathway renders it less active and resistant to further stimulation.

Pioneer transcription factors

Transcription factors that are able to install an open chromatin state, thus opening new methods or ways to regulate transcription.

X-escape genes

Genes on the inactivated X chromosome that are nonetheless transcribed to produce RNA levels ≥10% of the expression of their counterparts on the active X chromosome.

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Lefebvre, P., Staels, B. Hepatic sexual dimorphism — implications for non-alcoholic fatty liver disease. Nat Rev Endocrinol 17, 662–670 (2021). https://doi.org/10.1038/s41574-021-00538-6

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