Calreticulin regulates hepatic stellate cell activation through modulating TGF-beta-induced Smad signaling.

Autor: Chen CC; Department of Psychiatry, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; School of Medicine, Chang Gung University, Taoyuan, Taiwan., Hsu LW; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Chen KD; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Chiu KW; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Division of Hepato-Gastroenterology, Department of Internal Medicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Kung CP; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Li SR; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Chen CL; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan., Huang KT; Liver Transplantation Center, Department of General Surgery, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan; Institute for Translational Research in Biomedicine, Kaohsiung Chang Gung Memorial Hospital, Kaohsiung, Taiwan. Electronic address: huangkt@cgmh.org.tw.
Jazyk: angličtina
Zdroj: Cell calcium [Cell Calcium] 2024 Jul; Vol. 121, pp. 102895. Date of Electronic Publication: 2024 Apr 30.
DOI: 10.1016/j.ceca.2024.102895
Abstrakt: Liver fibrosis is characterized by excessive deposition of extracellular matrix (ECM) as a wound healing process. Activated hepatic stellate cells (HpSCs) are the major producer of the ECM and play a central role in liver fibrogenesis. It has been widely accepted that elimination of activated HpSCs or reversion to a quiescent state can be a feasible strategy for resolving the disease, further highlighting the urgent need for novel therapeutic targets. Calreticulin (CRT) is a molecular chaperone that normally resides in the endoplasmic reticulum (ER), important in protein folding and trafficking through the secretory pathway. CRT also plays a critical role in calcium (Ca 2+ ) homeostasis, with its Ca 2+ storage capacity. In the current study, we aimed to demonstrate its function in directing HpSC activation. In a mouse liver injury model, CRT was up-regulated in HpSCs. In cellular experiments, we further showed that this activation was through modulating the canonical TGF-β signaling. As down-regulation of CRT in HpSCs elevated intracellular Ca 2+ levels through a form of Ca 2+ influx, named store-operated Ca 2+ entry (SOCE), we examined whether moderating SOCE affected TGF-β signaling. Interestingly, blocking SOCE had little effect on TGF-β-induced gene expression. In contrast, inhibition of ER Ca 2+ release using the inositol trisphosphate receptor inhibitor 2-APB increased TGF-β signaling. Treatment with 2-APB did not alter SOCE but decreased intracellular Ca 2+ at the basal level. Indeed, adjusting Ca 2+ concentrations by EGTA or BAPTA-AM chelation further enhanced TGF-β-induced signaling. Our results suggest a crucial role of CRT in the liver fibrogenic process through modulating Ca 2+ concentrations and TGF-β signaling in HpSCs, which may provide new information and help advance the current discoveries for liver fibrosis.
Competing Interests: Declaration of competing interest The authors declare no conflict of interest.
(Copyright © 2024 Elsevier Ltd. All rights reserved.)
Databáze: MEDLINE
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