Journal of Shanghai Jiao Tong University (Medical Science) >

2021 , Vol. 41 >Issue 12: 1619 - 1626

DOI: https://doi.org/10.3969/j.issn.1674-8115.2021.12.011

Basic research

Ameliorative effect of atorvastatin on hepatic fibrosis and its mechanism

  • Nan WANG ,
  • Ye LU ,
  • Feng-jie HAO ,
  • Jun-qing WANG
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  • Department of General Surgery, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
WANG Jun-qing, E-mail: wangjunqingmd@hotmail.com. #Co-corresponding author.
HAO Feng-jie, E-mail: fengjie_haochn@163.com

Received date: 2021-06-29

  Online published: 2021-01-28

Supported by

Shanghai Municipal Education Commission—Gaofeng Clinical Medicine Grant Support(20191901);Shanghai Pujiang Talent Project(18PJD029);Interdisciplinary Research Foundation for Medicine and Engineering from Shanghai Jiao Tong University(YG2021QN21)

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Abstract

Objective

·To investigate the role of atorvastatin and its mechanisms in patients and animal models of hepatic fibrosis.

Methods

·The literatures in PubMed were searched for statins for different chronic liver diseases from January 2010 to June 2020. Meta analysis was performed based on the occurrence of liver fibrosis, liver failure and overall patient mortality. Sixteen male C57BL/6 mice were randomly divided into control group, atorvastatin group, CCl4 injection group, and CCl4 injection combined with atorvastatin group with 4 mice in each group. The mice in the CCl4 injection group were administered intraperitoneally twice a week with 20% volume fraction of CCl4 at a dose of 1 mL/kg; the control group was administered intraperitoneally by using the same dose of corn oil; the mice in the atorvastatin group were gavaged once daily with a dose of 15 mg/kg of atorvastatin; the mice in the CCl4 injection combined with atorvastatin group were treated with a combination of CCl4 and atorvastatin. After 4 weeks, the animals were euthanized, and serum glutamic pyruvic transaminase (GPT) and glutamic oxaloacetic transaminase (GOT) were detected; the degree of intrahepatic fibrosis in the mice was detected by Sirius red staining; immunofluorescence staining was used to detect the expression of collagen ⅠA; the mRNA expressions of α-smooth muscle actin (α-SMA), collagen Ⅰ, collagen Ⅲ, interleukin (IL)-1b, IL-6, and transforming growth factor-β (TGF-β) were detected by real-time fluorescence quantitative PCR; the expressions of α-SMA protein and phosphorylated Smad4 (pSmad4) protein were detected by Western blotting.

Results

·Finally 9 papers were selected for meta analysis, and the results showed that statins reduced the incidence of liver fibrosis, liver failure and overall mortality in patients with liver disease. In the animal experiments, the weight of mice in both the CCl4 injection group and the CCl4 injection combined with atorvastatin group decreased significantly compared with that in the control group (P=0.000); while the weight of mice in the CCl4 injection combined with atorvastatin group decreased to a lesser extent compared with that in the CCl4 injection group (P=0.040). Compared with the control group, GPT and GOT concentrations were significantly increased in both the CCl4 injection group and CCl4 injection combined with atorvastatin group (P=0.000), while liver enzymes in the CCl4 injection combined with atorvastatin group showed a smaller increase in GPT and GOT compared with that in the CCl4 injection group (P=0.020). Sirius red staining showed excessive deposition of intrahepatic fibers in the CCl4 injection group, and immunostaining suggested high expression of collagen ⅠA in the CCl4 injection group. The results of fluorescence quantitative PCR and Western blotting suggested that α-SMA protein expression increased, and mRNA expressions of α-SMA, collagen Ⅰ, and collagen Ⅲ were upregulated in the CCl4 injection group compared with the control group(P<0.05), whereas the expressions of these markers were downregulated in the CCl4 injection combined with atorvastatin group compared with the CCl4 injection group (P<0.05). The mRNA expressions of IL-1b and IL-6 were slightly upregulated and the expression of TGF-β was significantly upregulated in the CCl4 injection group compared with the control group (P<0.05). In contrast, the mRNA expressions of IL-1b and IL-6 were significantly up-regulated and the expression of TGF-β decreased in the CCl4 injection combined with atorvastatin group compared with the CCl4 injection group (P<0.05). The expression of pSmad4 protein increased in the CCl4 injection group compared with the control group, while the expression of pSmad4 protein was lower in the CCl4 injection combined with atorvastatin group compared with the CCl4 injection group.

Conclusion

·Atorvastatin may attenuate the occurrence and development of liver fibrosis via manipulating TGF-β signaling pathway.

Key words： atorvastatin; liver fibrosis; inflammation; transforming growth factor-β; signaling pathway

Cite this article

Nan WANG , Ye LU , Feng-jie HAO , Jun-qing WANG . Ameliorative effect of atorvastatin on hepatic fibrosis and its mechanism[J]. Journal of Shanghai Jiao Tong University (Medical Science), 2021 , 41(12) : 1619 -1626 . DOI: 10.3969/j.issn.1674-8115.2021.12.011

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