Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα
Yan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, Xiaoying Li
Yan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, Xiaoying Li
View: Text | PDF
Research Article Hepatology

Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα

Abstract

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.

Authors

Yan Lu, Xing Liu, Yang Jiao, Xuelian Xiong, E Wang, Xiaolin Wang, Zhijian Zhang, Huijie Zhang, Lingling Pan, Youfei Guan, Dongsheng Cai, Guang Ning, Xiaoying Li

×

Figure 8

Neutralization of periostin improved hepatosteatosis in db/db mice.

Options: View larger image (or click on image) Download as PowerPoint
Neutralization of periostin improved hepatosteatosis in db/db mice. (A–D...
(A–D) Liver weight (A), hepatic (B) and serum (C) TG content, and β-hydroxybutyrate level (D) in db/db mice treated with control IgG or anti-periostin Ab for 2 weeks. n = 6–8. (E) qRT-PCR analysis of fatty acid oxidation–related genes in livers from db/db mice treated with control IgG or anti-periostin Ab. (F) BW of db/db mice treated with control IgG or anti-periostin Ab. (G) Working model. Periostin is a nutritionally regulated cytokine secreted by the liver. In obese subjects, overproduced periostin binds to α6β4 integrins, activates the JNK signaling pathway, downregulates PPARα, and consequently leads to hepatosteatosis and hypertriglyceridemia. Our data suggest that periostin may have autocrine or paracrine roles in the liver. Whether hepatic periostin can exert endocrine effects upon distant targets remains to be defined. *P < 0.05, **P < 0.01, ***P < 0.001.