Regulation of Steatohepatitis and PPARγ Signaling by Distinct AP-1 Dimers

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.