Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα
Yan Lu, … , Guang Ning, Xiaoying Li
Yan Lu, … , Guang Ning, Xiaoying Li
Published July 8, 2014
Citation Information: J Clin Invest. 2014;124(8):3501-3513. https://doi.org/10.1172/JCI74438.
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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

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Figure 4

Periostin activates the JNK signaling pathway to promote hepatosteatosis.

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Periostin activates the JNK signaling pathway to promote hepatosteatosis...
(A) Phosphorylated and total JNK, c-Jun, p38, AKT, and ERK in the liver of C57BL/6 mice injected with GFP or Postn adenovirus. Total JNK, c-Jun, p38, AKT, and ERK were used as loading controls. (B and C) Phosphorylated and total JNK and c-Jun in HepG2 cells (B) and MPHs (C) incubated with PBS or periostin protein for 1 hour. (D) Phosphorylated and total JNK in MPHs incubated with PBS or periostin protein. Cells were preincubated with Abs against the indicated integrins or IgG as a control for 2 hours, and then treated with PBS or periostin protein for another 1 hour. (E) Cellular TG content in MPHs incubated with PBS or periostin protein. Cells were preincubated with Abs against integrins or IgG control for 2 hours, then treated with PBS or periostin protein for another 36 hours. (F) Ppara mRNA levels in MPHs incubated with PBS or periostin protein. Cells were preincubated with Abs against integrins or IgG control for 2 hours, then treated with PBS or periostin protein for another 24 hours. (G) Cellular TG content in MPHs isolated from WT and Jnk1 KO mice. Cells were treated with periostin protein (50 ng/ml) or PBS for 36 hours (n = 4). (H and I) mRNA levels of Ppara (H) and its target genes (I) in MPHs. *P < 0.05, **P < 0.01, ***P < 0.001.