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
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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 3

Periostin regulates liver lipid metabolism via PPARα.

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Periostin regulates liver lipid metabolism via PPARα. (A) Serum β-hydrox...
(A) Serum β-hydroxybutyrate levels in mice transduced with GFP or Postn adenoviruses (n = 6–7). (B and C) mRNA expression of hepatic Ppara (B) and protein expression of hepatic PPARα (C) in mice. (D) mRNA levels of hepatic Cpt1a, Mcad, and Acox1 in mice. (E) β-hydroxybutyrate levels in the medium of HepG2 cells. Cells were treated with periostin protein (50 ng/ml) or PBS vehicle control for 36 hours. (F) mRNA levels of Ppara, Cpt1a, Mcad, and Acox1 in HepG2 cells as in E. (G) Representative PPARα protein levels in HepG2 cells. (H) β-hydroxybutyrate levels in the medium of MPHs. Cells were treated with periostin protein (50 ng/ml) or PBS for 36 hours. (I) mRNA levels of Ppara, Cpt1a, Mcad, and Acox1 in MPHs as in H. (J) Representative PPARα protein levels in MPHs. (K) 3H-palmitate oxidation rate in MPHs treated with periostin protein or PBS. MPHs were preincubated in maintenance medium for 24 hours in the presence of WY14643 (20 μM) or DMSO followed by incubation with 125 mM 3H palmitic acid and 1 mM carnitine in PBS for 2 hours. 3H2O was then measured. n = 4. (L) Cellular TG content in MPHs isolated from WT or Ppara KO mice. Cells were treated with recombinant periostin protein (50 ng/ml) or PBS for 36 hours (n = 4–5). (M) mRNA levels of Cpt1a, Mcad, and Acox1 in MPHs. *P < 0.05, **P < 0.01, ***P < 0.001.