title: Quercetin stimulates mitochondrial apoptosis dependent on activation of endoplasmic reticulum stress in hepatic stellate cells.
abstract: BACKGROUND
  Activation of hepatic stellate cells (HSCs) is a hallmark of liver fibrosis. Quercetin has benefits for liver fibrosis, but the mechanisms are unknown.
  
  
  OBJECTIVE
  We investigated the quercetin effect on HSC survival and the role of endoplasmic reticulum stress (ERS).
  
  
  METHODS
  Rat HSCs and LO2 hepatocytes were treated with quercetin (0.5-120 μM) for 24 h. Quercetin (10-40 μM) effects on apoptosis for 24 h were analyzed by flow cytometry and TUNEL staining. Quercetin (10-40 μM) effects on the expression of Bcl-2, caspase-9, caspase-3, PARP-1, PERK, IRE1, ATF6, calnexin and CHOP for 24 h were analyzed by Western blot. Quercetin (10-40 μM) effects on mRNA expression of calnexin and CHOP for 24 h were analyzed by Real-time PCR.
  
  
  RESULTS
  Quercetin at concentrations greater than 20 μM significantly inhibited HSC proliferation (IC5027.2 μM), but did not affect hepatocyte growth until 80 μM (IC5068.5 μM). Quercetin stimulated HSC apoptosis and the apoptotic rate reached 40% at a concentration of 40 μM (EC5051.6 μM). Quercetin induced downregulation of Bcl-2 and upregulation of Bax, and increased cytochrome C in the cytoplasm in HSCs. The cleaved forms of caspase-9, caspase-3 and PARP-1 were also increased by quercetin. Furthermore, quercetin elevated mRNA and protein expression of calnexin and CHOP in HSCs but not in hepatocytes. Quercetin also increased phosphorylation of PERK and IRE1 and ATF6 cleavage. However, ERS inhibitor salubrinal significantly abrogated quercetin induction of HSC apoptosis.
  
  
  CONCLUSIONS
  Quercetin activated ERS pathway in HSCs leading to apoptosis. We characterized an ERS-mediated mechanism for quercetin as a promising antifibrotic agent.
authors: a Department of Pharmacy , Nanjing University of Chinese Medicine Hanlin College , Taizhou , China.
authors: Liwei
authors: L
authors: He
authors: b Department of Pharmacology, School of Pharmacy , Nanjing University of Chinese Medicine , Nanjing , China.
authors: Xianbang
authors: X
authors: Hou
authors: a Department of Pharmacy , Nanjing University of Chinese Medicine Hanlin College , Taizhou , China.
authors: Fangtian
authors: F
authors: Fan
authors: c Department of Pharmacy , Yancheng Health Vocational and Technical College , Yancheng , China.
authors: Hongyan
authors: H
authors: Wu
mesh_terms: D000818:Animals; D000975:Antioxidants / Q000494:pharmacology; D017209:Apoptosis / Q000187:drug effects* / Q000502:physiology; D049109:Cell Proliferation / Q000187:drug effects / Q000502:physiology; D002478:Cells, Cultured; D004305:Dose-Response Relationship, Drug; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects* / Q000502:physiology; D055166:Hepatic Stellate Cells / Q000187:drug effects* / Q000378:metabolism; D008928:Mitochondria / Q000187:drug effects* / Q000378:metabolism; D011794:Quercetin / Q000494:pharmacology*; D051381:Rats
chemical_list: D000975:Antioxidants; D011794:Quercetin
keywords: Bcl-2; Hepatic fibrosis; hepatocyte; salubrinal