Martin Kristian Thomsen

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

Research output: Contribution to journal/Conference contribution in journal/Contribution to newspaperJournal articleResearchpeer-review

  • Sebastian C Hasenfuss, 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.
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  • Latifa Bakiri, Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
  • ,
  • Martin K Thomsen
  • Evan G Williams, Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, 1015 Lausanne, Switzerland.
  • ,
  • Johan Auwerx, Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, 1015 Lausanne, Switzerland.
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  • Erwin F Wagner, Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Electronic address: ewagner@cnio.es.

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.

Original languageEnglish
JournalCell Metabolism
Volume19
Issue1
Pages (from-to)84-95
Number of pages12
ISSN1550-4131
DOIs
Publication statusPublished - 7 Jan 2014
Externally publishedYes

    Research areas

  • Adenoviridae, Animals, Cell Line, Tumor, Fatty Liver, Gene Expression Regulation, Hepatocytes, Humans, Lipid Metabolism, Liver, Mice, Non-alcoholic Fatty Liver Disease, PPAR gamma, Protein Multimerization, Proto-Oncogene Proteins c-fos, Proto-Oncogene Proteins c-jun, Signal Transduction, Transcription Factor AP-1, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't

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