Glycyrrhizin Alleviates Nonalcoholic Steatohepatitis via Modulating Bile Acids and Meta-Inflammation

• Published in: Drug metabolism and disposition Vol. 46; no. 9; pp. 1310 - 1319
• Main Authors: Yan, Tingting, Wang, Hong, Cao, Lijuan, Wang, Qiong, Takahashi, Shogo, Yagai, Tomoki, Li, Guolin, Krausz, Kristopher W., Wang, Guangji, Gonzalez, Frank J., Hao, Haiping
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2018; American Society for Pharmacology and Experimental Therapeutics, Inc; The American Society for Pharmacology and Experimental Therapeutics
• Subjects: Acids; Animal models; Animals; Anti-Inflammatory Agents - pharmacology; Anti-Inflammatory Agents - therapeutic use; Bile; Bile acids; Bile Acids and Salts - physiology; Choline; Cirrhosis; Deoxycholic acid; Diet; Disruption; Fatty liver; Fibrosis; Glycyrrhizic Acid - pharmacology; Glycyrrhizic Acid - therapeutic use; Glycyrrhizin; Hep G2 Cells; Herbal medicine; Homeostasis; Humans; Inflammasomes; Inflammation; Inflammation - drug therapy; Inflammation - metabolism; Inflammation - pathology; Lipids; Liquorice; Liver; Liver cancer; Liver cirrhosis; Liver diseases; Liver X receptors; Macrophages; Male; Metabolites; Methionine; Mice; Mice, Inbred C57BL; Non-alcoholic Fatty Liver Disease - drug therapy; Non-alcoholic Fatty Liver Disease - metabolism; Non-alcoholic Fatty Liver Disease - pathology; Nutrient deficiency; Oral administration; Pyrin protein; Random Allocation; RAW 264.7 Cells; Restoration; Steatosis; Traditional Chinese medicine; FXR; NAFLD; ALT; FACS; ACTD; TNF; LPS; SREPB; NF-κB; T; GA; SHP; TLR; CA; GW4064; AST; DCA; IL; CASP; GL; MCA; NASH; MCD; TC; MCC950; TG; MCS; DAMP
• ISSN: 0090-9556; 1521-009X; 1521-009X
• DOI: 10.1124/dmd.118.082008

Nonalcoholic steatohepatitis (NASH) is the progressive stage of nonalcoholic fatty liver disease that may ultimately lead to cirrhosis and liver cancer, and there are few therapeutic options for its treatment. Glycyrrhizin (GL), extracted from the traditional Chinese medicine liquorice, has potent hepatoprotective effects in both preclinical animal models and in humans. However, little is currently known about its effects and mechanisms in treating NASH. To explore the effects of GL on NASH, GL or its active metabolite glycyrrhetinic acid (GA) was administered to mice treated with a methionine- and choline-deficient (MCD) diet-induced NASH model, and histologic and biochemical analyses were used to measure the degree of lipid disruption, liver inflammation, and fibrosis. GL significantly improved MCD diet-induced hepatic steatosis, inflammation, and fibrosis and inhibited activation of the NLR family pyrin domain-containing 3 (NLRP3) inflammasome. GL significantly attenuated serum bile acid accumulation in MCD diet-fed mice partially by restoring inflammation-mediated hepatic farnesoid X receptor inhibition. In Raw 264.7 macrophage cells, both GL and GA inhibited deoxycholic acid–induced NLRP3 inflammasome-associated inflammation. Notably, both intraperitoneal injection of GL’s active metabolite GA and oral administration of GL prevented NASH in mice, indicating that GL may attenuate NASH via its active metabolite GA. These results reveal that GL, via restoration of bile acid homeostasis and inhibition of inflammatory injury, can be a therapeutic option for treatment of NASH.