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

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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.

Original languageEnglish (US)
Pages (from-to)3501-3513
Number of pages13
JournalJournal of Clinical Investigation
Volume124
Issue number8
DOIs
StatePublished - Aug 1 2014

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Peroxisome Proliferator-Activated Receptors
Hypertriglyceridemia
Fatty Liver
Down-Regulation
Liver
Obesity
Obese Mice
MAP Kinase Signaling System
Neutralizing Antibodies
Cell Adhesion
Integrins
Hepatocytes
Rodentia
Triglycerides
Fatty Acids
Proteins

ASJC Scopus subject areas

  • Medicine(all)

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Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα. / Lu, Yan; Liu, Xing; Jiao, Yang; Xiong, Xuelian; Wang, E.; Wang, Xiaolin; Zhang, Zhijian; Zhang, Huijie; Pan, Lingling; Guan, Youfei; Cai, Dongsheng; Ning, Guang; Li, Xiaoying.

In: Journal of Clinical Investigation, Vol. 124, No. 8, 01.08.2014, p. 3501-3513.

Research output: Contribution to journalArticle

Lu, Y, Liu, X, Jiao, Y, Xiong, X, Wang, E, Wang, X, Zhang, Z, Zhang, H, Pan, L, Guan, Y, Cai, D, Ning, G & Li, X 2014, 'Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα', Journal of Clinical Investigation, vol. 124, no. 8, pp. 3501-3513. https://doi.org/10.1172/JCI74438
Lu, Yan ; Liu, Xing ; Jiao, Yang ; Xiong, Xuelian ; Wang, E. ; Wang, Xiaolin ; Zhang, Zhijian ; Zhang, Huijie ; Pan, Lingling ; Guan, Youfei ; Cai, Dongsheng ; Ning, Guang ; Li, Xiaoying. / Periostin promotes liver steatosis and hypertriglyceridemia through downregulation of PPARα. In: Journal of Clinical Investigation. 2014 ; Vol. 124, No. 8. pp. 3501-3513.
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