The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy

Rosa S. Kim, Daisuke Hasegawa, Nicolas Goossens, Takuma Tsuchida, Varinder Athwal, Xiaochen Sun, Christopher L. Robinson, Dipankar Bhattacharya, Hsin I. Chou, David Y. Zhang, Bryan C. Fuchs, Youngmin Lee, Yujin Hoshida, Scott L. Friedman

Research output: Contribution to journalArticle

24 Citations (Scopus)

Abstract

Autophagy and the unfolded protein response (UPR) both promote activation of hepatic stellate cells (HSC), however the link between the two stimuli remains unclear. Here we have explored the role of X-box binding protein 1 (XBP1), one of three UPR effector pathways and sought to establish the interdependence between autophagy and the UPR during HSC activation. XBP1 induction accompanied both culture-based HSC activation and ER stress induced by tunicamycin. Ectopic overexpression of XBP1 induced collagen 1-alpha expression in HSCs, which was inhibited by knockdown of ATG7, a critical autophagy mediator. Genome-wide transcriptomic profiling indicated an upregulation of collagen synthesis pathways, but not of the transforming growth factor (TGF)-b pathway, a canonical fibrogenic driver, suggesting that XBP1 activates a specific subset of fibrogenesis pathways independent of TGF-β1. XBP1 target gene signatures were significantly induced in rodent liver fibrosis models (n = 3-5) and in human samples of non-alcoholic fatty liver disease (NAFLD) (n = 72-135). Thus, XBP1-mediated UPR contributes to fibrogenic HSC activation and is functionally linked to cellular autophagy.

Original languageEnglish (US)
Article number39342
JournalScientific reports
Volume6
DOIs
StatePublished - Dec 20 2016
Externally publishedYes

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Unfolded Protein Response
Hepatic Stellate Cells
Autophagy
Transforming Growth Factors
Collagen
Tunicamycin
Liver Cirrhosis
X-Box Binding Protein 1
Rodentia
Up-Regulation
Genome
Genes

ASJC Scopus subject areas

  • General

Cite this

Kim, R. S., Hasegawa, D., Goossens, N., Tsuchida, T., Athwal, V., Sun, X., ... Friedman, S. L. (2016). The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy. Scientific reports, 6, [39342]. https://doi.org/10.1038/srep39342

The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy. / Kim, Rosa S.; Hasegawa, Daisuke; Goossens, Nicolas; Tsuchida, Takuma; Athwal, Varinder; Sun, Xiaochen; Robinson, Christopher L.; Bhattacharya, Dipankar; Chou, Hsin I.; Zhang, David Y.; Fuchs, Bryan C.; Lee, Youngmin; Hoshida, Yujin; Friedman, Scott L.

In: Scientific reports, Vol. 6, 39342, 20.12.2016.

Research output: Contribution to journalArticle

Kim, RS, Hasegawa, D, Goossens, N, Tsuchida, T, Athwal, V, Sun, X, Robinson, CL, Bhattacharya, D, Chou, HI, Zhang, DY, Fuchs, BC, Lee, Y, Hoshida, Y & Friedman, SL 2016, 'The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy', Scientific reports, vol. 6, 39342. https://doi.org/10.1038/srep39342
Kim, Rosa S. ; Hasegawa, Daisuke ; Goossens, Nicolas ; Tsuchida, Takuma ; Athwal, Varinder ; Sun, Xiaochen ; Robinson, Christopher L. ; Bhattacharya, Dipankar ; Chou, Hsin I. ; Zhang, David Y. ; Fuchs, Bryan C. ; Lee, Youngmin ; Hoshida, Yujin ; Friedman, Scott L. / The XBP1 Arm of the Unfolded Protein Response Induces Fibrogenic Activity in Hepatic Stellate Cells Through Autophagy. In: Scientific reports. 2016 ; Vol. 6.
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