Reference : Regulation of steatohepatitis and PPARgamma signaling by distinct AP-1 dimers.
Scientific journals : Article
Life sciences : Genetics & genetic processes
Regulation of steatohepatitis and PPARgamma signaling by distinct AP-1 dimers.
Hasenfuss, Sebastian C. [> >]
Bakiri, Latifa [> >]
Thomsen, Martin K. [> >]
Williams, Evan mailto [University of Luxembourg > Luxembourg Centre for Systems Biomedicine (LCSB) >]
Auwerx, Johan [> >]
Wagner, Erwin F. [> >]
Cell metabolism
Yes (verified by ORBilu)
United States
[en] Adenoviridae/metabolism ; Animals ; Cell Line, Tumor ; Fatty Liver/genetics/metabolism/pathology ; Gene Expression Regulation ; Hepatocytes/metabolism/pathology ; Humans ; Lipid Metabolism/genetics ; Liver/metabolism/pathology ; Mice ; Non-alcoholic Fatty Liver Disease ; PPAR gamma/genetics/metabolism ; Protein Multimerization ; Proto-Oncogene Proteins c-fos/genetics/metabolism ; Proto-Oncogene Proteins c-jun/metabolism ; Signal Transduction ; Transcription Factor AP-1/metabolism
[en] Nonalcoholic fatty liver disease (NAFLD) affects up to 30% of the adult population in Western societies, yet the underlying molecular pathways remain poorly understood. Here, we identify the dimeric Activator Protein 1 as a regulator of NAFLD. Fos-related antigen 1 (Fra-1) and Fos-related antigen 2 (Fra-2) prevent dietary NAFLD by inhibiting prosteatotic PPARgamma signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARgamma expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARgamma signaling and NAFLD development. This unique antagonistic regulation of PPARgamma by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD.
Copyright (c) 2014 Elsevier Inc. All rights reserved.

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