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 5

Periostin inhibits PPARα expression through c-Jun–mediated suppression of RORα transcriptional activity.

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Periostin inhibits PPARα expression through c-Jun–mediated suppression o...
(A) Luciferase reporters carrying a series of truncated mouse Ppara promoter. The promoter region from –1,242 to +1 bp was cloned and transfected into HepG2 cells. The transcription start site was set as +1 bp. (B) WT and mutant (Mut) Ppara promoters (–216 to +1 bp) were transfected into HepG2 cells, and luciferase reporter assays were measured. Potential binding sites for ATF/CREB, SP1, and RORα were mutated as indicated. (C) WT and RORα binding site mutant Ppara promoters (–216 to +1 bp) were cotransfected with RORα, c-Jun, or empty vectors into HepG2 cells. Cells were treated with CS (5 μM) or DMSO vehicle control for 12 hours before harvest. (D) RORα interacted with c-Jun. c-Jun was pulled down by RORα by IP in HEK293T cells transfected with Flag-tagged RORα and HA-tagged c-Jun. (E) Interaction of endogenous RORα and c-Jun. Cell lysates were extracted from HepG2 cells and subjected to IP using c-Jun or IgG Ab and IB using RORα Ab. (F) ChIP analysis showing binding of RORα and acetylated histone H3 (Ac-H3) to the Ppara promoter. MPHs were preincubated with IgG or Abs targeting α6β4 integrins for 2 hours, then treated with PBS or periostin for another 2 hours. The exon 1 region of Ppara was used as a negative control. **P < 0.01, ***P < 0.001.