TY - JOUR
T1 - Glycyrrhizin alleviates nonalcoholic steatohepatitis via modulating bile acids and meta-inflammation
AU - Yan, Tingting
AU - Wang, Hong
AU - Cao, Lijuan
AU - Wang, Qiong
AU - Takahashi, Shogo
AU - Yagai, Tomoki
AU - Li, Guolin
AU - Krausz, Kristopher W.
AU - Wang, Guangji
AU - Gonzalez, Frank J.
AU - Hao, Haiping
N1 - Funding Information:
This work was supported by the National Natural Science Foundation of China [Grants 81430091, 81720108032, 81421005, 91429308, and 81603194], the Project for Major New Drug Innovation and Development [Grant 2015ZX09501010], the Overseas Expertise Introduction Project for Discipline Innovation [Grant G20582017001], the China Postdoctoral Science Foundation [Grants 2016M600455 and 2017T100423], and the Intramural Research Program of the National Institutes of Health National Cancer Institute. https://doi.org/10.1124/dmd.118.082008. s This article has supplemental material available at dmd.aspetjournals.org.
Publisher Copyright:
U.S. Government work not protected by U.S. copyright
PY - 2018/9
Y1 - 2018/9
N2 - 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.
AB - 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.
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U2 - 10.1124/dmd.118.082008
DO - 10.1124/dmd.118.082008
M3 - Article
C2 - 29959134
AN - SCOPUS:85051126706
VL - 46
SP - 1310
EP - 1319
JO - Drug Metabolism and Disposition
JF - Drug Metabolism and Disposition
SN - 0090-9556
IS - 9
ER -