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Cell Metab. 2014 Jan 7;19(1):84-95. doi: 10.1016/j.cmet.2013.11.018.

Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers.

Author information

1
Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain; Faculty Biology, University of Freiburg, 79104 Freiburg, Germany.
2
Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
3
Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, 1015 Lausanne, Switzerland.
4
Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Electronic address: ewagner@cnio.es.

Abstract

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 PPARγ signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPARγ expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPARγ signaling and NAFLD development. This unique antagonistic regulation of PPARγ by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD.

PMID:
24411941
PMCID:
PMC4023468
DOI:
10.1016/j.cmet.2013.11.018
[Indexed for MEDLINE]
Free PMC Article
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