Periostin promotes liver fibrogenesis by activating lysyl oxidase in hepatic stellate cells

• Type of Material: Article
• Authors: Pradeep Kumar, Emory University; Tekla Smith, Emory University; Reben Raeman, University of Pittsburgh; Daniel M Chopyk, Emory University; Hannah Brink, Georgia Institute of Technology; Yunshan Liu, Emory University; Todd Sulchek, Georgia Institute of Technology; Frank Anania, Emory University
• Language: English
• Date: 2018-08-17
• Publisher: American Society for Biochemistry and Molecular Biology
• Publication Version: Final Published Version
• Copyright Statement: © 2018 by The American Society for Biochemistry and Molecular Biology, Inc.
• Final Published Version (URL): http://dx.doi.org/10.1074/jbc.RA117.001601
• Title of Journal or Parent Work: Journal of Biological Chemistry
• ISSN: 0021-9258
• Volume: 293
• Issue: 33
• Start Page: 12781
• End Page: 12792
• Grant/Funding Information: This work was supported by NIDDK, National Institutes of Health, Grants RO1 DK062092, DK111678, and DK113147 (all to F. A. A.).; A portion of this work was also supported by funds from Emory University.
• Keywords: SMAD2; collagen; fibrogenesis; POSTN; hepatic stellate cell (HSC); lysyl oxidase (LOX); Life Sciences & Biomedicine; transforming growth factor beta (TGF-beta); EXPRESSION; COLLAGEN; Science & Technology; inflammation; extracellular matrix protein; SERUM PERIOSTIN; HEPATOCYTES; fibrosis; KIDNEY-DISEASE; MICE; EPITHELIAL-MESENCHYMAL TRANSITION; fibronectin; MATRICELLULAR PROTEIN; CANCER CELLS; 3; PULMONARY-FIBROSIS; Biochemistry & Molecular Biology
• Research Categories: Chemistry, Biochemistry; Health Sciences, Pathology

Abstract

Liver fibrosis arises from dysregulated wound healing due to persistent inflammatory hepatic injury. Periostin is a nonstructural extracellular matrix protein that promotes organ fibrosis in adults. Here, we sought to identify the molecular mechanisms in periostin-mediated hepatic fibrosis. Hepatic fibrosis in periostin/ mice was attenuated as evidenced by significantly reduced collagen fibril density and liver stiffness compared with those in WT controls. A single dose of carbon tetrachloride caused similar acute liver injury in periostin/ and WT littermates, and we did not detect significant differences in transaminases and major fibrosis-related hepatic gene expression between these two genotypes. Activated hepatic stellate cells (HSCs) are the major periostin-producing liver cell type. We found that in primary rat HSCs in vitro, periostin significantly increases the expression levels and activities of lysyl oxidase (LOX) and lysyl oxidase–like (LOXL) isoforms 1–3. Periostin also induced expression of intra- and extracellular collagen type 1 and fibronectin in HSCs. Interestingly, periostin stimulated phosphorylation of SMAD2/3, which was sustained despite short hairpin RNA–mediated knockdown of transforming growth factor (TGF) receptor I and II, indicating that periostin-mediated SMAD2/3 phosphorylation is independent of TGF receptors. Moreover, periostin induced the phosphorylation of focal adhesion kinase (FAK) and AKT in HSCs. Notably, siRNA-mediated FAK knockdown failed to block periostin-induced SMAD2/3 phosphorylation. These results suggest that periostin promotes enhanced matrix stiffness in chronic liver disease by activating LOX and LOXL, independently of TGF receptors. Hence, targeting periostin may be of therapeutic benefit in combating hepatic fibrosis.