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GIPC-Regulated IGFBP-3 Promotes HSC Migration In Vitro and Portal Hypertension In Vivo Through a β1-Integrin Pathway.

Authors
  • Yaqoob, Usman1
  • Luo, Fanghong2
  • Greuter, Thomas3
  • Jalan Sakrikar, Nidhi1
  • Sehrawat, Tejasav S1
  • Lu, Jianwen1
  • Hu, Xiao1
  • Gao, Jinhang1
  • Kostallari, Enis1
  • Chen, Jingbiao1
  • Arab, Juan Pablo1
  • Martin-Mateos, Rosa4
  • Cao, Sheng5
  • Shah, Vijay H6
  • 1 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota.
  • 2 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Cancer Research Center, Medical College, Xiamen University, Xiamen, China. , (China)
  • 3 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, Switzerland. , (Switzerland)
  • 4 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota; Division of Gastroenterology and Hepatology, Ramón y Cajal University Hospital, Madrid, Spain. , (Spain)
  • 5 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: [email protected]
  • 6 Gastroenterology Research Unit, Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota. Electronic address: [email protected]
Type
Published Article
Journal
Cellular and Molecular Gastroenterology and Hepatology
Publisher
Elsevier
Publication Date
Jan 01, 2020
Volume
10
Issue
3
Pages
545–559
Identifiers
DOI: 10.1016/j.jcmgh.2020.05.005
PMID: 32447051
Source
Medline
Keywords
Language
English
License
Unknown

Abstract

Transforming growth factor (TGF-β)-induced activation of quiescent hepatic stellate cells (HSCs) and their transformation to myofibroblasts is a key event in liver fibrosis and portal hypertension. GIPC (also referred to as synectin) is a downstream signal activation molecule of TGF-β and other receptors. In this study, we sought to identify novel genes targeted by TGF-β and GIPC and elucidate if and how they may contribute to liver fibrosis. We performed sequential messenger RNA sequencing analysis on TGF-β-stimulated HSCs and then on TGF-β-stimulated HSCs in the presence and absence of GIPC also referred to as synectin (GIPC) knockdown. Insulin-like growth factor binding protein-3 (IGFBP-3) transport protein emerged as a top activation target of both TGF-β and GIPC. Quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, targeted chromatin immunoprecipitation, and Western blot analysis were done for further confirmation. IGFBP-3, an insulin growth factor transport protein, emerged as a top activation target of both TGF-β and GIPC, which was confirmed by quantitative polymerase chain reaction, enzyme-linked immunosorbent assay, and Western blot analysis. Targeted chromatin immunoprecipitation showed that GIPC increases the histone 3 lysine 27 (H3K27) acetylation activating mark and concurrently decreases the H3K27 inhibitory trimethylation (H3K27m3) mark, providing an epigenetic correlate to the gene regulation changes. In vivo, global knockout of IGFBP-3 mice resulted in attenuation of HSC activation markers and attenuation of portal pressure in response to chronic liver injury models. Analysis of serum levels from cirrhotic patients also showed an IGFBP-3 increase of more than 2-fold compared with healthy controls. Finally, in vitro mechanism studies showed that IGFBP-3 promotes HSC migration through integrin-dependent phosphorylation of protein kinase B. TGF-β up-regulates IGFBP-3 through GIPC, leading to increased HSC migration in vitro and promotes portal hypertension in vivo. These studies support the role of IGFBP-3 as a potential pathophysiologic target or biomarker in chronic liver disease. Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.

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