title: Regulation of steatohepatitis and PPARγ signaling by distinct AP-1 dimers.
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.
authors.affiliation: 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.
authors.forename: Sebastian C
authors.initials: SC
authors.lastname: Hasenfuss
authors.affiliation: Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Latifa
authors.initials: L
authors.lastname: Bakiri
authors.affiliation: Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain.
authors.forename: Martin K
authors.initials: MK
authors.lastname: Thomsen
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, 1015 Lausanne, Switzerland.
authors.forename: Evan G
authors.initials: EG
authors.lastname: Williams
authors.affiliation: Laboratory of Integrative and Systems Physiology, School of Life Sciences, École Polytechnique Fédérale, 1015 Lausanne, Switzerland.
authors.forename: Johan
authors.initials: J
authors.lastname: Auwerx
authors.affiliation: Genes, Development, and Disease Group, F-BBVA Cancer Cell Biology Programme, National Cancer Research Centre (CNIO), 28029 Madrid, Spain. Electronic address: ewagner@cnio.es.
authors.forename: Erwin F
authors.initials: EF
authors.lastname: Wagner
mesh_terms: D000256:Adenoviridae / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D005234:Fatty Liver / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism / Q000473:pathology; D006801:Humans; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism / Q000473:pathology; D051379:Mice; D065626:Non-alcoholic Fatty Liver Disease; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism*; D055503:Protein Multimerization; D016760:Proto-Oncogene Proteins c-fos / Q000235:genetics / Q000378:metabolism; D016755:Proto-Oncogene Proteins c-jun / Q000378:metabolism; D015398:Signal Transduction; D018808:Transcription Factor AP-1 / Q000378:metabolism*; D000099169:Fos-Related Antigen 1
chemical_list: D047495:PPAR gamma; D016760:Proto-Oncogene Proteins c-fos; D016755:Proto-Oncogene Proteins c-jun; D018808:Transcription Factor AP-1; D000099169:Fos-Related Antigen 1; C528955:junD protein, mouse