Astragaloside IV Improves High-Fat Diet-Induced Hepatic Steatosis in Nonalcoholic Fatty Liver Disease Rats by Regulating Inflammatory Factors Level via TLR4/NF-κB Signaling Pathway.

Ying-Li Liu,Jing Zhang,Yan-Rong Wang,Bang-Mao Wang,Qiu-Zan Zhang,Li-Na Fu,Jing-Shu Han

doi:10.3389/fphar.2020.605064

Abstract

Objective: Astragaloside IV (AS-IV) is the primary bioactive component purified from Astragalus membranaceus which is one of the traditional Chinese medicines. Research studies found that AS-IV has significant pharmacological effects on focal cerebral ischemia/reperfusion, cardiovascular disease, pulmonary disease, liver cirrhosis, and diabetic nephropathy, but little is known about the effects of AS-IV on nonalcoholic fatty liver disease (NAFLD). In this study, we investigated whether AS-IV has beneficial effects on NAFLD in rats and its potential mechanisms. Methods: Male SD rats were fed with high-fat diet (HFD) for 12 weeks to establish NAFLD rat model, and then, the rats were divided into five groups. The control group rats were fed with normal diet for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The model group rats were fed with HFD for 12 weeks and then were given normal saline (1.0 ml kg−1 day−1) by intragastric administration for 4 weeks. The AS-IV-L, AS-IV-M, and AS-IV-H groups were treated with 20, 40, and 80 mg kg−1 day−1 of AS-IV by intragastric administration for 4 weeks and given HFD diet. Then, we detected serum transaminase (ALT, AST), blood lipid (TG, TC), inflammatory cytokines (IL-6, IL-8 and TNF-α), liver histology(NAFLD activity score), TLR4/MyD88 signaling pathway in liver tissue. Results: We found AS-IV significantly reduced serum levels of AST, ALT, TG, TNF-α, IL-6, and IL-8 in NAFLD rats and downregulate the expression of TLR4 mRNA, MyD88 mRNA, NF-κB mRNA, and proteins in liver tissue. Moreover, AS-IV could significantly reduce the NAFLD activity score of NAFLD rat liver. Conclusion: In this study, we demonstrated that AS-IV have a protective effect on NAFLD by inhibiting TNF-α, IL-6 and IL-8 levels and down-regulating TLR4, MyD88 and NF-κB expression in rat liver tissues.

Highlights

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide
After treated with high-dose AS-IV for 4 weeks, the serum TG level was significantly deceased in NAFLD rats (p < 0.01), but the low-dose and middle-dose AS-IV have no obvious effect on reducing the serum TG level
We found that TLR4 mRNA, MyD88 mRNA, NF-κB mRNA, and their proteins were significantly upregulated in the NAFLD rat model rats induced by high-fat diet

Summary

Introduction

Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide. NAFLD includes three subtypes: nonalcoholic fatty liver (NAFL), nonalcoholic steatohepatitis (NASH), and related liver cirrhosis. Studies had indicated that TLR4 signaling pathway was one of the key factors in the pathogenesis of different chronic liver diseases including NAFLD (Soares et al, 2010; Roh and Seki, 2013) and was associated with the progression of NASH (Zhang et al, 2013; Kapil et al, 2016). Singh et al (2011) revealed that the expression of TLR4 mRNA and its protein in normal liver tissues was lower than that in NASH patients This suggested the importance of immunological inhibition and immune tolerance in the normal liver. The expression of TLR4 and its downstream mediators were upregulated after treated with palmitate and lipopolysaccharide (LPS) It indicated that TLR4 had vital function on pathogenesis of NASH and was one of the important factors related to LPS sensitivity and fatty acid damage

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