Loss of Map Kinase Phosphatase-1 Protects from Hepatic Steatosis by Repression of Cidec/fat-specific Protein 27

The integration of metabolic signals required for the regulation of hepatic lipid homeostasis is complex. Previously, we showed that mice lacking expression of the mitogenactivated protein kinase (MAPK) phosphatase1 (MKP-1) have increased fatty acid oxidation and are protected from the development of hepatic steatosis. Here, we show that leptin receptor-deficient (db/db) mice lacking MKP-1 are also resistant to the development of hepatic steatosis. Microarray analyses of livers from db/db mice lacking MKP-1 showed suppression of peroxisome proliferator-activated receptor (PPAR ) target genes. We identified the fatspecific protein 27 (Fsp27), which promotes PPAR -mediated hepatic steatosis, as repressed in livers of both db/db and high fat diet-fed mice lacking MKP-1. Hepatocytes from MKP-1deficient mice exhibited reduced PPAR induced lipid droplet formation. Mechanistically, loss of MKP-1 inhibited PPAR function by increasing MAPKdependent phosphorylation on PPAR at its inhibitory residue of serine 112. These results demonstrate that in addition to inhibiting hepatic fatty acid oxidation, MKP-1 promotes hepatic lipogenic gene expression through PPAR . Hence, MKP-1 plays an important role in MAPK-mediated control of hepatic lipid homeostasis.