Glycyrrhetinic Acid Protects α-Naphthylisothiocyanate- Induced Cholestasis Through Regulating Transporters, Inflammation and Apoptosis.

Miao Yan,Zhenyan Hou,Bikui Zhang,Hongmei Gu,Yan Yang,Yue Gao,Hui Gong,Lin Guo

doi:10.3389/fphar.2021.701240

Abstract

Glycyrrhetinic acid (GA), the active metabolic product of Glycyrrhizin (GL) that is the main ingredient of licorice, was reported to protect against α-naphthylisothiocyanate (ANIT)- induced cholestasis. However, its protective mechanism remains unclear. In our work, the cholestatic liver injury in mice was caused by ANIT and GA was used for the treatment. We assessed cholestatic liver injury specific indexes, histopathological changes, bile acid transporters, inflammation and apoptosis. The results of liver biochemical index and histopathological examination showed that GA markedly attenuated ANIT-induced liver injury. Mechanism research suggested that GA could activate the expression of farnesoid x receptor (FXR) and its downstream bile acids transporters Na+/taurocholate co-transporting polypeptide (NTCP), bile salt export pump (BSEP) and multidrug resistance-associated protein 2 (MRP2), as well as the nuclear factor erythroid 2-related factor 2 (Nrf2) and its downstream proteins MRP3, MRP4. These transporters play a vital role in mediating bile acid homeostasis in hepatocytes. Moreover, GA could significantly inhibit the ANIT-induced activation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) inflammatory pathway and the increase of tumor necrosis factor-α (TNF-α) concentration in serum. Also, GA protected against ANIT-induced mitochondrial apoptosis by regulating the expression of Bcl-2, Bax, cleaved caspase 3 and cleaved caspase 9. In conclusion, GA alleviates the hepatotoxicity caused by ANIT by regulating bile acids transporters, inflammation and apoptosis, which suggests that GA may be a potential therapeutic agent for cholestasis.

Highlights

Cholestasis is a clinical syndrome characterized by impaired bile flow and retention of bile acids in the liver and body, resulting from mechanical or functional obstruction of the hepatobiliary system
hematoxylin and eosin (HE) staining of liver sections showed compared with the control group, multiple focal hepatocyte necrosis, nucleolysis and a small amount of neutrophil infiltration in the against α-naphthylisothiocyanate (ANIT) group
Compared with the control group, no difference in GPx and SOD activities was seen after ANIT or combined Glycyrrhetinic acid (GA) treatment in Figure 3B, indicating that alleviation of ANIT-induced cholestasis by GA was not mediated via activation of antioxidant enzymes

Summary

Introduction

Cholestasis is a clinical syndrome characterized by impaired bile flow and retention of bile acids in the liver and body, resulting from mechanical or functional obstruction of the hepatobiliary system. Cholestasis will result in hepatic fibrosis, cirrhosis, or liver failure (Jansen et al, 2017). GA Protection Against Cholestasis acid (UDCA), obeticholic acid and ademetionine are recognized as effective medicines. Their efficacy and safety are not satisfactory (Wagner and Fickert, 2020).

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