FXR controls CHOP expression in steatohepatitis

Claudia D Fuchs; Thierry Claudel; Hubert Scharnagl; Tatjana Stojakovic; Michael Trauner

doi:10.1002/1873-3468.12845

FXR controls CHOP expression in steatohepatitis

FEBS Lett. 2017 Oct;591(20):3360-3368. doi: 10.1002/1873-3468.12845. Epub 2017 Oct 11.

Authors

Claudia D Fuchs¹, Thierry Claudel¹, Hubert Scharnagl², Tatjana Stojakovic², Michael Trauner¹

Affiliations

¹ Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Austria.
² Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, Austria.

Abstract

The farnesoid X receptor (FXR) and C/EBP homologous protein (CHOP) have critical functions in hepatic lipid metabolism. Here, we aimed to explore a potential relationship between FXR and CHOP. We fed wild-type (WT) and FXR KO mice a MCD diet (model of steatohepatitis) and found that Chop mRNA expression is upregulated in WT but not FXR KO mice. The absence of FXR aggravates hepatic inflammation after MCD feeding. In HepG2 cells, we found that Chop expression is regulated in a FXR/Retinoid X receptor (RXR)-dependent manner. We identified a FXR/RXR-binding site in the human CHOP promoter, demonstrating a highly conserved regulatory pathway. Our study shows that FXR/RXR regulates Chop expression in a mouse model of steatohepatitis, providing novel insights into pathogenesis of this disorder.

Keywords: inflammation; nonalcoholic fatty liver disease (NAFLD); nonalcoholic steatohepatitis (NASH); nuclear receptor.

MeSH terms

Animals
Binding Sites
Chenodeoxycholic Acid / pharmacology
Diet, High-Fat
Disease Models, Animal
Gene Expression Regulation
Glucose / pharmacology
Hep G2 Cells
Humans
Lipid Metabolism / drug effects
Liver / drug effects
Liver / metabolism*
Liver / pathology
Mice
Mice, Inbred C57BL
Mice, Knockout
Non-alcoholic Fatty Liver Disease / etiology
Non-alcoholic Fatty Liver Disease / genetics*
Non-alcoholic Fatty Liver Disease / metabolism
Non-alcoholic Fatty Liver Disease / pathology
Promoter Regions, Genetic
Protein Binding
RNA, Messenger / genetics
RNA, Messenger / metabolism
Receptors, Cytoplasmic and Nuclear / genetics*
Receptors, Cytoplasmic and Nuclear / metabolism
Retinoid X Receptors / genetics*
Retinoid X Receptors / metabolism
Signal Transduction
Transcription Factor CHOP / genetics*
Transcription Factor CHOP / metabolism
Tretinoin / pharmacology

Substances

Ddit3 protein, mouse
RNA, Messenger
Receptors, Cytoplasmic and Nuclear
Retinoid X Receptors
farnesoid X-activated receptor
Chenodeoxycholic Acid
Transcription Factor CHOP
Tretinoin
Glucose