title: 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.forename: Yan
authors.initials: Y
authors.lastname: Lu
authors.forename: Xing
authors.initials: X
authors.lastname: Liu
authors.forename: Yang
authors.initials: Y
authors.lastname: Jiao
authors.forename: Xuelian
authors.initials: X
authors.lastname: Xiong
authors.forename: E
authors.initials: E
authors.lastname: Wang
authors.forename: Xiaolin
authors.initials: X
authors.lastname: Wang
authors.forename: Zhijian
authors.initials: Z
authors.lastname: Zhang
authors.forename: Huijie
authors.initials: H
authors.lastname: Zhang
authors.forename: Lingling
authors.initials: L
authors.lastname: Pan
authors.forename: Youfei
authors.initials: Y
authors.lastname: Guan
authors.forename: Dongsheng
authors.initials: D
authors.lastname: Cai
authors.forename: Guang
authors.initials: G
authors.lastname: Ning
authors.forename: Xiaoying
authors.initials: X
authors.lastname: Li
mesh_terms: D000818:Animals; D015815:Cell Adhesion Molecules / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D003430:Cross-Sectional Studies; D015536:Down-Regulation; D005234:Fatty Liver / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D005260:Female; D056945:Hep G2 Cells; D006801:Humans; D015228:Hypertriglyceridemia / Q000209:etiology* / Q000235:genetics / Q000378:metabolism*; D039161:Integrin alpha6beta4 / Q000378:metabolism; D008099:Liver / Q000378:metabolism; D020935:MAP Kinase Signaling System; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008820:Mice, Obese; D008954:Models, Biological; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000378:metabolism; D009765:Obesity / Q000150:complications / Q000235:genetics / Q000378:metabolism; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D014280:Triglycerides / Q000097:blood / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015815:Cell Adhesion Molecules; D039161:Integrin alpha6beta4; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C512835:POSTN protein, human; D047493:PPAR alpha; C082838:Postn protein, mouse; D012333:RNA, Messenger; C539738:RORA protein, human; C539739:Rora protein, mouse; D014280:Triglycerides