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

J Biol Chem. 2011 Jun 24;286(25):22195-202. doi: 10.1074/jbc.M110.210237. Epub 2011 Apr 26.

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.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Body Size
  • Dual Specificity Phosphatase 1 / deficiency*
  • Dual Specificity Phosphatase 1 / metabolism
  • Fatty Liver / genetics*
  • Fatty Liver / metabolism*
  • Fatty Liver / pathology
  • Fatty Liver / physiopathology
  • Female
  • Gene Expression Regulation
  • Hepatocytes / metabolism
  • Lipogenesis / genetics
  • Liver / metabolism
  • Mice
  • Mice, Inbred C57BL
  • Mitogen-Activated Protein Kinases / metabolism
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR gamma / metabolism
  • Phosphorylation
  • Proteins / genetics*
  • Triglycerides / metabolism

Substances

  • PPAR gamma
  • Proteins
  • Triglycerides
  • fat-specific protein 27, mouse
  • Mitogen-Activated Protein Kinases
  • Dual Specificity Phosphatase 1