State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.).
State Key Laboratory of Natural Medicines, Key Laboratory of Drug Metabolism and Pharmacokinetics, China Pharmaceutical University, Nanjing, Jiangsu, China (Ti. Y., H.W., L.C., G.W., H.H.); and Laboratory of Metabolism, Center for Cancer Research, National Institutes of Health National Cancer Institute, Bethesda, Maryland (Ti. Y., Q.W., S.T., To.Y., G.L., K.W.K., F.J.G.)
Drug Metab Dispos. 2018 Sep;46(9):1310-1319. doi: 10.1124/dmd.118.082008. Epub 2018 Jun 29.
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.
非酒精性脂肪性肝炎（NASH）是一种非酒精性脂肪性肝病的进展阶段，它可能最终导致肝硬化和肝癌，目前针对其治疗的方法选择有限。从中国传统草药甘草中提取的甘草酸（GL）在临床前动物模型和人类中均具有强大的肝脏保护作用。然而，目前对于 GL 治疗 NASH 的作用和机制知之甚少。为了探索 GL 对 NASH 的影响，将 GL 或其活性代谢物甘草次酸（GA）给予用蛋氨酸和胆碱缺乏（MCD）饮食诱导的 NASH 模型治疗的小鼠，并通过组织学和生化分析来测量脂质破坏、肝脏炎症和纤维化的程度。GL 显著改善了 MCD 饮食诱导的肝脂肪变性、炎症和纤维化，并抑制了 NOD 样受体家族 pyrin 结构域包含 3 （NLRP3）炎性体的激活。GL 通过恢复炎症介导的法尼醇 X 受体抑制，显著减轻了 MCD 饮食喂养小鼠的血清胆汁酸积累。在 Raw 264.7 巨噬细胞中，GL 和 GA 均抑制了脱氧胆酸诱导的 NLRP3 炎性体相关炎症。值得注意的是，GL 的活性代谢物 GA 的腹腔内注射和 GL 的口服给药均可预防小鼠的 NASH，表明 GL 可能通过其活性代谢物 GA 来减轻 NASH。这些结果表明，GL 通过恢复胆汁酸稳态和抑制炎症损伤，可能成为治疗 NASH 的一种治疗选择。
