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

SC Hasenfuss, L Bakiri, MK Thomsen, EG Williams… - Cell Metabolism, 2014 - cell.com
SC Hasenfuss, L Bakiri, MK Thomsen, EG Williams, J Auwerx, EF Wagner
Cell Metabolism, 2014cell.com
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 …
Summary
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.
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