Hepatocyte-specific loss of GPS2 in mice reduces non-alcoholic steatohepatitis via activation of PPAR\u03b1

Ning Liang,Tarja Schröder,Saioa Goñi,Fawaz Alzaïd ,Sven Francque,Zhiqiang Huang,Anthony N Hollenberg ,Osman Ahmed,Anastasius Damdimopoulos,Arturo Mendoza,Lise‐Lotte Vedin ,Tomas Jakobsson,Luc Van Gaal,Serena Barilla,Marco Giudici,Paolo Parini,Bart Staels,Nicolas Venteclef,Eckardt Treuter,Raoul V Kuiper ,Philippe Lefèbvre ,Matteo Pedrelli,Rongrong Fan

doi:10.1038/s41467-019-09524-z

Abstract

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. Here we demonstrate that G protein pathway suppressor 2 (GPS2), a subunit of the nuclear receptor corepressor (NCOR) and histone deacetylase 3 (HDAC3) complex, has a central role in these alterations and accelerates the progression of NAFLD towards non-alcoholic steatohepatitis (NASH). Hepatocyte-specific Gps2 knockout in mice alleviates the development of diet-induced steatosis and fibrosis and causes activation of lipid catabolic genes. Integrative cistrome, epigenome and transcriptome analysis identifies the lipid-sensing peroxisome proliferator-activated receptor α (PPARα, NR1C1) as a direct GPS2 target. Liver gene expression data from human patients reveal that Gps2 expression positively correlates with a NASH/fibrosis gene signature. Collectively, our data suggest that the GPS2-PPARα partnership in hepatocytes coordinates the progression of NAFLD in mice and in humans and thus might be of therapeutic interest.

Highlights

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes
Gps[2] liver-specific Gps2 KO (LKO) triglyceride in the very low-density lipoproteins (VLDL) fraction presented more than 50% reduction compared to WT mice, along with the total serum triglyceride level (Supplementary Fig. 1e)
Lipoprotein triglyceride metabolism is tightly regulated via hepatic production and hydroxylation, but we found that serum (LPL) and hepatic lipoprotein lipase (HL) activities (Supplementary Fig. 1f) were similar between the two groups, suggesting decreased hepatic VLDL production rather than increased lipase activity

Summary

Introduction

Obesity triggers the development of non-alcoholic fatty liver disease (NAFLD), which involves alterations of regulatory transcription networks and epigenomes in hepatocytes. The specific KO phenotypes of different subunits of what is thought to be the same corepressor complex suggests multiple target TFs to be affected, resulting in the modulation of in part opposing metabolic liver pathways, such as fatty acid oxidation versus lipogenesis. These data raise the intriguing possibility that metabolic liver pathways that protect against NAFLD/NASH are controlled by a different corepressor subunit or sub-complex, the identity of which remains to be explored

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Results

Conclusion