title: Loss of mitogen-activated protein kinase phosphatase-1 protects from hepatic steatosis by repression of cell death-inducing DNA fragmentation factor A (DFFA)-like effector C (CIDEC)/fat-specific protein 27.
abstract: The integration of metabolic signals required for the regulation of hepatic lipid homeostasis is complex. Previously, we showed that mice lacking expression of the mitogen-activated protein kinase (MAPK) phosphatase-1 (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 γ (PPARγ) target genes. We identified the fat-specific protein 27 (Fsp27), which promotes PPARγ-mediated hepatic steatosis, as repressed in livers of both db/db and high fat diet-fed mice lacking MKP-1. Hepatocytes from MKP-1-deficient mice exhibited reduced PPARγ-induced lipid droplet formation. Mechanistically, loss of MKP-1 inhibited PPARγ function by increasing MAPK-dependent phosphorylation on PPARγ 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 PPARγ. Hence, MKP-1 plays an important role in MAPK-mediated control of hepatic lipid homeostasis.
authors.affiliation: Department of Pharmacology and Program in Integrative Cell Signaling and Neurobiology of Metabolism, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
authors.forename: Rachel J Roth
authors.initials: RJ
authors.lastname: Flach
authors.forename: Hui
authors.initials: H
authors.lastname: Qin
authors.forename: Lei
authors.initials: L
authors.lastname: Zhang
authors.forename: Anton M
authors.initials: AM
authors.lastname: Bennett
mesh_terms: D000818:Animals; D049628:Body Size; D054638:Dual Specificity Phosphatase 1 / Q000172:deficiency* / Q000378:metabolism; D005234:Fatty Liver / Q000235:genetics* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D005786:Gene Expression Regulation; D022781:Hepatocytes / Q000378:metabolism; D050155:Lipogenesis / Q000235:genetics; D008099:Liver / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009765:Obesity / Q000235:genetics / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D010766:Phosphorylation; D011506:Proteins / Q000235:genetics*; D014280:Triglycerides / Q000378:metabolism
chemical_list: D047495:PPAR gamma; D011506:Proteins; D014280:Triglycerides; C525805:fat-specific protein 27, mouse; D020928:Mitogen-Activated Protein Kinases; D054638:Dual Specificity Phosphatase 1