Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice.

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Version: Final published version
License: CC BY 4.0
Serval ID
serval:BIB_978B8840BE0C
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Sex Dimorphism of Nonalcoholic Fatty Liver Disease (NAFLD) in Pparg-Null Mice.
Journal
International journal of molecular sciences
Author(s)
Schiffrin M., Winkler C., Quignodon L., Naldi A., Trötzmüller M., Köfeler H., Henry H., Parini P., Desvergne B., Gilardi F.
ISSN
1422-0067 (Electronic)
ISSN-L
1422-0067
Publication state
Published
Issued date
15/09/2021
Peer-reviewed
Oui
Volume
22
Number
18
Pages
9969
Language
english
Notes
Publication types: Journal Article
Publication Status: epublish
Abstract
Men with nonalcoholic fatty liver disease (NAFLD) are more exposed to nonalcoholic steatohepatitis (NASH) and liver fibrosis than women. However, the underlying molecular mechanisms of NALFD sex dimorphism are unclear. We combined gene expression, histological and lipidomic analyses to systematically compare male and female liver steatosis. We characterized hepatosteatosis in three independent mouse models of NAFLD, ob/ob and lipodystrophic fat-specific (PpargF <sup>Δ/Δ</sup> ) and whole-body PPARγ-null (Pparg <sup>Δ/Δ</sup> ) mice. We identified a clear sex dimorphism occurring only in Pparg <sup>Δ/Δ</sup> mice, with females showing macro- and microvesicular hepatosteatosis throughout their entire life, while males had fewer lipid droplets starting from 20 weeks. This sex dimorphism in hepatosteatosis was lost in gonadectomized Pparg <sup>Δ/Δ</sup> mice. Lipidomics revealed hepatic accumulation of short and highly saturated TGs in females, while TGs were enriched in long and unsaturated hydrocarbon chains in males. Strikingly, sex-biased genes were particularly perturbed in both sexes, affecting lipid metabolism, drug metabolism, inflammatory and cellular stress response pathways. Most importantly, we found that the expression of key sex-biased genes was severely affected in all the NAFLD models we tested. Thus, hepatosteatosis strongly affects hepatic sex-biased gene expression. With NAFLD increasing in prevalence, this emphasizes the urgent need to specifically address the consequences of this deregulation in humans.
Keywords
hepatic sex-biased gene expression, lipidomics, nonalcoholic fatty liver disease (NAFLD), sex dimorphism
Pubmed
Web of science
Open Access
Yes
Create date
29/09/2021 14:52
Last modification date
09/10/2021 6:38
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