PMID- 37274069
OWN - NLM
STAT- MEDLINE
DCOM- 20230613
LR  - 20230613
IS  - 2219-2840 (Electronic)
IS  - 1007-9327 (Print)
IS  - 1007-9327 (Linking)
VI  - 29
IP  - 18
DP  - 2023 May 14
TI  - Calcitriol attenuates liver fibrosis through hepatitis C virus nonstructural 
      protein 3-transactivated protein 1-mediated TGF beta1/Smad3 and NF-kappaB signaling 
      pathways.
PG  - 2798-2817
LID - 10.3748/wjg.v29.i18.2798 [doi]
AB  - BACKGROUND: Hepatic fibrosis is a serious condition, and the development of 
      hepatic fibrosis can lead to a series of complications. However, the pathogenesis 
      of hepatic fibrosis remains unclear, and effective therapy options are still 
      lacking. Our group identified hepatitis C virus nonstructural protein 
      3-transactivated protein 1 (NS3TP1) by suppressive subtractive hybridization and 
      bioinformatics analysis, but its role in diseases including hepatic fibrosis 
      remains undefined. Therefore, additional studies on the function of NS3TP1 in 
      hepatic fibrosis are urgently needed to provide new targets for treatment. AIM: 
      To elucidate the mechanism of NS3TP1 in hepatic fibrosis and the regulatory 
      effects of calcitriol on NS3TP1. METHODS: Twenty-four male C57BL/6 mice were 
      randomized and separated into three groups, comprising the normal, fibrosis, and 
      calcitriol treatment groups, and liver fibrosis was modeled by carbon 
      tetrachloride (CCl(4)). To evaluate the level of hepatic fibrosis in every group, 
      serological and pathological examinations of the liver were conducted. TGF-beta1 was 
      administered to boost the in vitro cultivation of LX-2 cells. NS3TP1, alpha-smooth 
      muscle actin (alpha-SMA), collagen I, and collagen III in every group were examined 
      using a Western blot and real-time quantitative polymerase chain reaction. The 
      activity of the transforming growth factor beta 1 (TGFbeta1)/Smad3 and NF-kappaB 
      signaling pathways in each group of cells transfected with pcDNA-NS3TP1 or 
      siRNA-NS3TP1 was detected. The statistical analysis of the data was performed 
      using the Student's t test. RESULTS: NS3TP1 promoted the activation, 
      proliferation, and differentiation of hepatic stellate cells (HSCs) and enhanced 
      hepatic fibrosis via the TGFbeta1/Smad3 and NF-kappaB signaling pathways, as evidenced 
      by the presence of alpha-SMA, collagen I, collagen III, p-smad3, and p-p65 in LX-2 
      cells, which were upregulated after NS3TP1 overexpression and downregulated after 
      NS3TP1 interference. The proliferation of HSCs was lowered after NS3TP1 
      interference and elevated after NS3TP1 overexpression, as shown by the luciferase 
      assay. NS3TP1 inhibited the apoptosis of HSCs. Moreover, both Smad3 and p65 could 
      bind to NS3TP1, and p65 increased the promoter activity of NS3TP1, while NS3TP1 
      increased the promoter activity of TGFbeta1 receptor I, as indicated by 
      coimmunoprecipitation and luciferase assay results. Both in vivo and in vitro, 
      treatment with calcitriol dramatically reduced the expression of NS3TP1. 
      Calcitriol therapy-controlled HSCs activation, proliferation, and differentiation 
      and substantially suppressed CCl(4)-induced hepatic fibrosis in mice. 
      Furthermore, calcitriol modulated the activities of the above signaling pathways 
      via downregulation of NS3TP1. CONCLUSION: Our results suggest that calcitriol may 
      be employed as an adjuvant therapy for hepatic fibrosis and that NS3TP1 is a 
      unique, prospective therapeutic target in hepatic fibrosis.
CI  - (c)The Author(s) 2023. Published by Baishideng Publishing Group Inc. All rights 
      reserved.
FAU - Shi, Liu
AU  - Shi L
AD  - Department of Infectious Disease Medicine, The First Hospital Affiliated to Xi'an 
      Jiaotong University, Xi'an 710061, Shaanxi Province, China.
FAU - Zhou, Li
AU  - Zhou L
AD  - China-Japan Friendship Hospital, Department of Infectious Disease China-Japan 
      Friendship Hospital, Beijing 100029, China.
FAU - Han, Ming
AU  - Han M
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Zhang, Yu
AU  - Zhang Y
AD  - The Division of Liver Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Zhang, Yang
AU  - Zhang Y
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Yuan, Xiao-Xue
AU  - Yuan XX
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Lu, Hong-Ping
AU  - Lu HP
AD  - Institute of Liver Diseases, Beijing Pan-Asia Tongze Institute of Biomedicine 
      Co., Ltd, Beijing 100015, China.
FAU - Wang, Yun
AU  - Wang Y
AD  - The Division of Liver Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Yang, Xue-Liang
AU  - Yang XL
AD  - Department of Rehabilitation Medicine, The First Affiliated Hospital of Xi'an 
      Jiaotong University, Xi'an 710061, Shaanxi Province, China.
FAU - Liu, Chen
AU  - Liu C
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Wang, Jun
AU  - Wang J
AD  - Beijing Key Laboratory of Emerging Infectious Diseases, Peking University Ditan 
      Teaching Hospital, Beijing 100015, China.
FAU - Liang, Pu
AU  - Liang P
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Liu, Shun-Ai
AU  - Liu SA
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Liu, Xiao-Jing
AU  - Liu XJ
AD  - Department of Infectious Disease Medicine, The First Hospital Affiliated to Xi'an 
      Jiaotong University, Xi'an 710061, Shaanxi Province, China.
FAU - Cheng, Jun
AU  - Cheng J
AD  - Institute of Infectious Diseases, Beijing Ditan Hospital, Capital Medical 
      University, Beijing 100015, China.
FAU - Lin, Shu-Mei
AU  - Lin SM
AD  - Department of Infectious Disease Medicine, The First Hospital Affiliated to Xi'an 
      Jiaotong University, Xi'an 710061, Shaanxi Province, China. lsmxjtu@126.com.
LA  - eng
PT  - Journal Article
PL  - United States
TA  - World J Gastroenterol
JT  - World journal of gastroenterology
JID - 100883448
RN  - FXC9231JVH (Calcitriol)
RN  - CL2T97X0V0 (Carbon Tetrachloride)
RN  - 0 (Collagen Type I)
RN  - 0 (NF-kappa B)
RN  - 0 (Transforming Growth Factor beta1)
RN  - 0 (Viral Nonstructural Proteins)
RN  - 0 (Smad3 Protein)
SB  - IM
MH  - Animals
MH  - Male
MH  - Mice
MH  - *Calcitriol/pharmacology/therapeutic use
MH  - Carbon Tetrachloride/toxicity
MH  - Collagen Type I/metabolism
MH  - Hepacivirus/metabolism
MH  - Hepatic Stellate Cells/metabolism
MH  - Liver Cirrhosis/chemically induced/drug therapy/prevention & control
MH  - Mice, Inbred C57BL
MH  - *NF-kappa B/metabolism
MH  - Signal Transduction
MH  - *Transforming Growth Factor beta1/metabolism
MH  - *Viral Nonstructural Proteins/metabolism
MH  - *Smad3 Protein/metabolism
PMC - PMC10237113
OTO - NOTNLM
OT  - Calcitriol
OT  - Hepatic stellate cells
OT  - Liver fibrosis
OT  - Mouse model
OT  - NF-kappaB
OT  - Nonstructural protein 3-transactivated protein 1
OT  - Signaling pathway
OT  - TGFbeta1/Smad3
COIS- Conflict-of-interest statement: The authors declare that they have no competing 
      interests.
EDAT- 2023/06/05 13:04
MHDA- 2023/06/07 06:42
PMCR- 2023/05/14
CRDT- 2023/06/05 11:56
PHST- 2022/12/13 00:00 [received]
PHST- 2023/03/08 00:00 [revised]
PHST- 2023/04/10 00:00 [accepted]
PHST- 2023/06/07 06:42 [medline]
PHST- 2023/06/05 13:04 [pubmed]
PHST- 2023/06/05 11:56 [entrez]
PHST- 2023/05/14 00:00 [pmc-release]
AID - 10.3748/wjg.v29.i18.2798 [doi]
PST - ppublish
SO  - World J Gastroenterol. 2023 May 14;29(18):2798-2817. doi: 
      10.3748/wjg.v29.i18.2798.