Journal
CELL METABOLISM
Volume 19, Issue 1, Pages 84-95Publisher
CELL PRESS
DOI: 10.1016/j.cmet.2013.11.018
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Funding
- Ecole Polytechnique Federale de Lausanne
- EU Ideas program [AdG-231138]
- Swiss National Science Foundation [31003A-140780]
- NIH [R01AG043930]
- Banco Bilbao Vizcaya Argentaria Foundation (F-BBVA)
- Spanish Ministry of Economy [BFU2012-40230]
- ERC-Advanced grant [ERC-FCK/2008/37]
- Juan de la Cierva postdoctoral fellowship
- Boehringer Ingelheim Fonds (BIF)
- EMBO [ASTF 198-2012]
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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 PPAR gamma signaling. Moreover, established NAFLD and the associated liver damage can be efficiently reversed by hepatocyte-specific Fra-1 expression. In contrast, c-Fos promotes PPAR gamma expression, while c-Jun exerts opposing, dimer-dependent functions. Interestingly, JunD was found to be essential for PPAR gamma signaling and NAFLD development. This unique antagonistic regulation of PPAR gamma by distinct AP-1 dimers occurs at the transcriptional level and establishes AP-1 as a link between obesity, hepatic lipid metabolism, and NAFLD.
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