Ameliorative effect of atorvastatin on hepatic fibrosis and its mechanism

doi:10.3969/j.issn.1674-8115.2021.12.011

Abstract

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 CCl₄injection group, and immunostaining suggested high expression of collagen ⅠA in the CCl₄injection 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

CLC Number:

R575.2

Nan WANG, Ye LU, Feng-jie HAO, Jun-qing WANG. Ameliorative effect of atorvastatin on hepatic fibrosis and its mechanism[J]. JOURNAL OF SHANGHAI JIAOTONG UNIVERSITY (MEDICAL SCIENCE), 2021, 41(12): 1619-1626.

Figures/Tables 8

TrendMD

References 23

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No.	Author	Year	Location	Type	Time period	Patients numbers	Etiology	Outcomes of interest	Stain users	Nonusers
1	Chang	2017	Chinese Taipei	Propensity matched cohort	2000‒2013	1 350	HBV， HCV， ALD	Decompensated cirrhosis； Mortality	14%； 9%	28%； 18%
2	Huang	2016	Chinese Taipei	Propensity matched cohort	1997‒2009	13 086	HBV	Decompensated cirrhosis； Developing cirrhosis	2.6%； 0.9%	6.1%； 1.9%
3	Simon	2016	USA	Retrospective cohort	2001‒2014	9 135	HCV	Developing cirrhosis	14.0%	21.4%
4	Hsiang	2015	Chinese Hongkong	Propensity matched cohort	2000‒2012	53 513	HBV	Mortality	6.5%	14.3%
5	Mohanty	2016	USA	Propensity matched cohort	1996‒2009	2 747	HCV	Decompensated cirrhosis； Mortality	2.1%； 6.3%	3.9%； 11.1%
6	Simon	2015	USA	Retrospective cohort	2000‒2004	543	HCV	Developing cirrhosis	10%	28%
7	Yang	2015	Chinese Taipei	Propensity matched cohort	1999‒2010	84 213	HCV	Developing cirrhosis	6.0%	21.9%
8	Kumar	2014	USA	Retrospective cohort	1988‒2011	243	Mixed	Decompensated cirrhosis	30.0%	40.5%
9	Abraldes	2016	Spain	RCT	2010‒2013	147	Mixed	Mortality	9%	22%

No.	Author	Year	Location	Type	Time period	Patients numbers	Etiology	Outcomes of interest	Stain users	Nonusers
1	Chang	2017	Chinese Taipei	Propensity matched cohort	2000‒2013	1 350	HBV， HCV， ALD	Decompensated cirrhosis； Mortality	14%； 9%	28%； 18%
2	Huang	2016	Chinese Taipei	Propensity matched cohort	1997‒2009	13 086	HBV	Decompensated cirrhosis； Developing cirrhosis	2.6%； 0.9%	6.1%； 1.9%
3	Simon	2016	USA	Retrospective cohort	2001‒2014	9 135	HCV	Developing cirrhosis	14.0%	21.4%
4	Hsiang	2015	Chinese Hongkong	Propensity matched cohort	2000‒2012	53 513	HBV	Mortality	6.5%	14.3%
5	Mohanty	2016	USA	Propensity matched cohort	1996‒2009	2 747	HCV	Decompensated cirrhosis； Mortality	2.1%； 6.3%	3.9%； 11.1%
6	Simon	2015	USA	Retrospective cohort	2000‒2004	543	HCV	Developing cirrhosis	10%	28%
7	Yang	2015	Chinese Taipei	Propensity matched cohort	1999‒2010	84 213	HCV	Developing cirrhosis	6.0%	21.9%
8	Kumar	2014	USA	Retrospective cohort	1988‒2011	243	Mixed	Decompensated cirrhosis	30.0%	40.5%
9	Abraldes	2016	Spain	RCT	2010‒2013	147	Mixed	Mortality	9%	22%

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