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Hepatic apoptosis can modulate liver fibrosis through TIMP1 pathway

Authors
  • Wang, Kewei1
  • Lin, Bingliang2
  • Brems, John J.3
  • Gamelli, Richard L.3
  • 1 University of Illinois College of Medicine at Peoria, Departments of Surgery, One Illini Drive, Peoria, IL, 61605, USA , Peoria (United States)
  • 2 Third Affiliated Hospital of Sun Yat-sen University, Department of Infectious Diseases, Guangzhou, China , Guangzhou (China)
  • 3 Loyola University Medical Center, Department of Surgery, Maywood, IL, 60153, USA , Maywood (United States)
Type
Published Article
Journal
APOPTOSIS
Publisher
Springer-Verlag
Publication Date
Mar 02, 2013
Volume
18
Issue
5
Pages
566–577
Identifiers
DOI: 10.1007/s10495-013-0827-5
Source
Springer Nature
Keywords
License
Yellow

Abstract

Apoptotic injury participates in hepatic fibrosis, but the molecular mechanisms are not well understood. The present study aimed to investigate the role of inducible TIMP1 in the pathogenesis of hepatic apoptosis-fibrosis. Apoptosis was induced with GCDC, LPS, and alcohol in precision-cut liver slices or bile duct ligation (BDL) in rats, as reflected by caspase-3 activity, TUNEL assay, and apoptosis-related gene profiles. The hepatic fibrosis was detected with Picrosirius staining, hydroxyproline determination, and expression profiling of fibrosis-related genes. Levels of TIMP1 were upregulated by the hepatic apoptosis, but downregulated by caspase inhibitor. The inducible TIMP1 was apoptosis-dependent. Once TIMP1 was inhibited with treatment of TIMP1-siRNA, the fibrotic response was reduced as demonstrated by hydroxyproline assay. In addition, the expression of fibrosis-related genes aSMA, CTGF, and TGFb2r were down-regulated subsequent to the treatment of TIMP1-siRNA. TIMP1 could mediate the expression of fibrosis-related genes. TIMP1 was transcriptionally regulated by nuclear factor c-Jun as demonstrated by EMSA and ChIP assay. The treatment of c-Jun siRNA could significantly decrease the expression of TIMP1 induced by alcohol, GCDC, or LPS treatment. Hepatic apoptosis induces the expression of TIMP1. Inducible TIMP1 can modulate the expression of fibrosis-related genes in liver. TIMP1 pathway is a potential target for therapeutic intervention of fibrotic liver diseases.

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