Periostin promotes liver steatosis and hypertriglyceridernia through dovvnregulation of PPARα

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 a (PPAR alpha), a master regulator of fatty acid oxidation, and activation of the INK signaling pathway. In mouse primary hepatocytes, inhibition of alpha 6 beta 4 integrin prevented activation of JNK and suppression of PPARa in response to periostin. Periostin-dependent activation of JNK resulted in activation of c-Jun, which prevented ROR alpha binding and transactional activation at the Ppara promoter. Together, these results identify a periostin-dependent pathway that mediates obesity-induced hepatosteatosis.