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

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

Author information

1
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan, the Department of Molecular and Cellular Biology, Institute for Frontier Medical Sciences, Kyoto University, Kyoto 606-8507, Japan.
2
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan, ryo3ussy3@cc.kyoto-su.ac.jp.
3
the Department of Anatomy and Regenerative Biology, Graduate School of Medicine, Osaka City University, Asahi-mati, Abeno-ku, Osaka 545-8585, Japan, and.
4
From the Department of Molecular Biosciences, Faculty of Life Sciences, Kyoto Sangyo University, Motoyama, Kamigamo, Kita-ku, Kyoto 603-8555, Japan, CREST, Japan Science and Technology Agency, 4-1-8 Honcho, Kawaguchi, Saitama 332-0012, Japan nagata@cc.kyoto-su.ac.jp.

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

PMID:
25525267
PMCID:
PMC4319029
DOI:
10.1074/jbc.M114.592139
[Indexed for MEDLINE]
Free PMC Article

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