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Nat Commun. 2018 May 29;9(1):2092. doi: 10.1038/s41467-018-04361-y.

The histone demethylase Phf2 acts as a molecular checkpoint to prevent NAFLD progression during obesity.

Author information

1
INSERM, U1016, Institut Cochin, Paris, France.
2
CNRS, UMR8104, Paris, France.
3
Université Paris Descartes, Sorbonne Paris Cité, Paris, France.
4
Plateau de lipidomique, Bio-Medical Federative Research Institute of Toulouse, INSERM, Plateforme MetaToul, Toulouse, France.
5
INRA-ToxAlim, Toxicologie Intégrative et Métabolisme, Toulouse, France.
6
Department of Chemistry and Molecular and Cell Biology, University of California, Berkeley, CA, 94720, USA.
7
Howard Hughes Medical Institute, University of California, Berkeley, CA, 94720, USA.
8
INSERM U1043-CPTP, Toulouse, F-31300, France.
9
CNRS, U5282, Toulouse, F-31300, France.
10
Université de Toulouse, UPS, Centre de Physiopathologie de Toulouse Purpan (CPTP), Toulouse, F-31300, France.
11
Institut de Recherche en Santé Digestive (IRSD), Université de Toulouse, ENVT, INPT, INRA UMR1416, INSERM UMR1220, UPS, Toulouse, France.
12
Department of Hepatology, Lille University Hospital, Lille, France.
13
Inserm, U 995, Lille, France.
14
INSERM, U859 Biotherapies for Diabetes, Lille, France.
15
European Genomic Institute for Diabetes, Lille University, Lille, France.
16
Department of Endocrine Surgery, Lille University Hospital, Lille, France.
17
INSERM, U1016, Institut Cochin, Paris, France. renaud.dentin@inserm.fr.
18
CNRS, UMR8104, Paris, France. renaud.dentin@inserm.fr.
19
Université Paris Descartes, Sorbonne Paris Cité, Paris, France. renaud.dentin@inserm.fr.

Abstract

Aberrant histone methylation profile is reported to correlate with the development and progression of NAFLD during obesity. However, the identification of specific epigenetic modifiers involved in this process remains poorly understood. Here, we identify the histone demethylase Plant Homeodomain Finger 2 (Phf2) as a new transcriptional co-activator of the transcription factor Carbohydrate Responsive Element Binding Protein (ChREBP). By specifically erasing H3K9me2 methyl-marks on the promoter of ChREBP-regulated genes, Phf2 facilitates incorporation of metabolic precursors into mono-unsaturated fatty acids, leading to hepatosteatosis development in the absence of inflammation and insulin resistance. Moreover, the Phf2-mediated activation of the transcription factor NF-E2-related factor 2 (Nrf2) further reroutes glucose fluxes toward the pentose phosphate pathway and glutathione biosynthesis, protecting the liver from oxidative stress and fibrogenesis in response to diet-induced obesity. Overall, our findings establish a downstream epigenetic checkpoint, whereby Phf2, through facilitating H3K9me2 demethylation at specific gene promoters, protects liver from the pathogenesis progression of NAFLD.

PMID:
29844386
PMCID:
PMC5974278
DOI:
10.1038/s41467-018-04361-y
[Indexed for MEDLINE]
Free PMC Article

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