Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

J Clin Invest. 2014 Aug;124(8):3501-13. doi: 10.1172/JCI74438. Epub 2014 Jul 8.


Hepatosteatosis is characterized by an aberrant accumulation of triglycerides in the liver; however, the factors that drive obesity-induced fatty liver remain largely unknown. Here, we demonstrated that the secreted cell adhesion protein periostin is markedly upregulated in livers of obese rodents and humans. Notably, overexpression of periostin in the livers of WT mice promoted hepatic steatosis and hypertriglyceridemia. Conversely, both genetic ablation of periostin and administration of a periostin-neutralizing antibody dramatically improved hepatosteatosis and hypertriglyceridemia in obese mice. Overexpression of periostin resulted in reduced expression of peroxisome proliferator-activated receptor α (PPARα), a master regulator of fatty acid oxidation, and activation of the JNK signaling pathway. In mouse primary hepatocytes, inhibition of α6β4 integrin prevented activation of JNK and suppression of PPARα in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented RORα binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Adhesion Molecules / deficiency
  • Cell Adhesion Molecules / genetics
  • Cell Adhesion Molecules / metabolism*
  • Cross-Sectional Studies
  • Down-Regulation
  • Fatty Liver / etiology*
  • Fatty Liver / genetics
  • Fatty Liver / metabolism*
  • Female
  • Hep G2 Cells
  • Humans
  • Hypertriglyceridemia / etiology*
  • Hypertriglyceridemia / genetics
  • Hypertriglyceridemia / metabolism*
  • Integrin alpha6beta4 / metabolism
  • Liver / metabolism
  • MAP Kinase Signaling System
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mice, Obese
  • Models, Biological
  • Nuclear Receptor Subfamily 1, Group F, Member 1 / metabolism
  • Obesity / complications
  • Obesity / genetics
  • Obesity / metabolism
  • PPAR alpha / genetics
  • PPAR alpha / metabolism*
  • Promoter Regions, Genetic
  • RNA, Messenger / genetics
  • RNA, Messenger / metabolism
  • Triglycerides / blood
  • Triglycerides / metabolism
  • Up-Regulation


  • Cell Adhesion Molecules
  • Integrin alpha6beta4
  • Nuclear Receptor Subfamily 1, Group F, Member 1
  • POSTN protein, human
  • PPAR alpha
  • Postn protein, mouse
  • RNA, Messenger
  • RORA protein, human
  • Rora protein, mouse
  • Triglycerides