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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.

SUBMITTER: Hasenfuss SC

PROVIDER: S-EPMC4023468 | biostudies-literature | 2014 Jan

REPOSITORIES: biostudies-literature

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

Hasenfuss Sebastian C SC Bakiri Latifa L Thomsen Martin K MK Williams Evan G EG Auwerx Johan J Wagner Erwin F EF

Cell metabolism 20140101 1

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 expressio ...[more]

PMID: 24411941

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