Deletion of the collagen-specific molecular chaperone Hsp47 causes endoplasmic reticulum stress-mediated apoptosis of hepatic stellate cells

J Biol Chem. 2015 Feb 6;290(6):3639-46. doi: 10.1074/jbc.M114.592139. Epub 2014 Dec 18.

Abstract

Chronic liver injury, often caused by alcoholism and viral hepatitis, causes liver fibrosis via the induction of collagen production. In liver fibrosis, hepatic stellate cells (HSCs) are activated and transform into myofibroblasts, which actively produce and secrete collagen into the extracellular matrix. Hsp47 (heat shock protein 47) is a collagen-specific molecular chaperone that is essential for the maturation and secretion of collagen. Here, we used the Cre-LoxP system to disrupt the Hsp47 gene in isolated HSCs from Hsp47 floxed mice. Immature type I procollagen accumulated and partially aggregated in Hsp47-KO HSCs. This accumulation was augmented when autophagy was inhibited, which induced expression of the endoplasmic reticulum (ER) stress-inducible proteins BiP (immunoglobulin heavy chain-binding protein) and Grp94 (94-kDa glucose-regulated protein). The inhibition of autophagy in Hsp47-KO HSCs also induced CHOP (CCAAT/enhancer-binding protein homologous protein), which is an ER stress-induced transcription factor responsible for apoptosis. These data suggest that apoptosis is induced through ER stress by procollagen accumulation in Hsp47-KO HSCs when autophagy is inhibited. Thus, Hsp47 could be a promising therapeutic target in liver fibrosis.

Keywords: Apoptosis; Autophagy; Collagen; Endoplasmic Reticulum Stress (ER Stress); Hepatic Stellate Cell (HSC); Hsp47.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis*
  • Autophagy
  • Cells, Cultured
  • Endoplasmic Reticulum Stress*
  • Gene Deletion*
  • HSP47 Heat-Shock Proteins / genetics
  • HSP47 Heat-Shock Proteins / metabolism*
  • Heat-Shock Proteins / genetics
  • Heat-Shock Proteins / metabolism
  • Hepatic Stellate Cells / metabolism*
  • Membrane Glycoproteins / genetics
  • Membrane Glycoproteins / metabolism
  • Mice
  • Procollagen / metabolism

Substances

  • HSP47 Heat-Shock Proteins
  • Heat-Shock Proteins
  • Membrane Glycoproteins
  • Procollagen
  • Serpinh1 protein, mouse
  • endoplasmin
  • molecular chaperone GRP78