TY - JOUR
T1 - Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα
AU - Lu, Yan
AU - Liu, Xing
AU - Jiao, Yang
AU - Xiong, Xuelian
AU - Wang, E.
AU - Wang, Xiaolin
AU - Zhang, Zhijian
AU - Zhang, Huijie
AU - Pan, Lingling
AU - Guan, Youfei
AU - Cai, Dongsheng
AU - Ning, Guang
AU - Li, Xiaoying
PY - 2014/8/1
Y1 - 2014/8/1
N2 - 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.
AB - 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.
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U2 - 10.1172/JCI74438
DO - 10.1172/JCI74438
M3 - Article
C2 - 25003192
AN - SCOPUS:84905492812
SN - 0021-9738
VL - 124
SP - 3501
EP - 3513
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 8
ER -