18β-Glycyrrhetinic acid protects against alpha-naphthylisothiocyanate-induced cholestasis through activation of the Sirt1/FXR signaling pathway

Abstract

Cholestasis is a common feature of liver injury, which manifests as bile acid excretion and/or enterohepatic circulation disorders. However, very few effective therapies exist for cholestasis. Recently, 18β-Glycyrrhetinic acid (18b-GA), a major metabolic component of glycyrrhizin, which is the main ingredient of licorice, was reported to protect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis. However, its protective mechanism remains unclear. We hypothesized that 18b-GA may stimulate the signaling pathway of bile acid (BA) transportation in hepatocytes, resulting its hepatoprotective effect. According to the results, 18b-GA markedly attenuated ANIT-induced liver injury as indicated the hepatic plasma chemistry index and histopathology examination. In addition, the expression levels of nuclear factors, including Sirt1, FXR and Nrf2, and their target efflux transporters in the liver, which mainly mediate bile acid homeostasis in hepatocytes, significantly increased. Furthermore, we first revealed that 18b-GA treatment significantly activated FXR, and which can be significantly reduced by EX-527 (a potent and selective Sirt1 inhibitor), indicating that 18b-GA activates FXR through Sirt1. Taken together, 18b-GA confers hepatoprotection against ANIT-induced cholestasis by activating FXR through Sirt1, which promotes gene expression of the efflux transporter, and consequently attenuates dysregulation of bile acid homeostasis in hepatocyte compartments.

The Protective Effects of 18β-Glycyrrhetinic Acid on Imiquimod-Induced Psoriasis in Mice via Suppression of mTOR/STAT3 Signaling

“…18 β -Glycyrrhetinic acid (GA, structure shown in Figure 1 ), an aglycone and active metabolite of glycyrrhizic acid, has been shown to have a series of pharmacological effects such as antioxidative [ 12 , 13 ], antitumor [ 14 – 16 ], and anti-inflammatory [ 17 , 18 ] activities. Moreover, in recent years, this compound has also been reported to show some protective effect in skin disorders [ 19 – 21 ].…”

Natural products for the prevention and treatment of cholestasis: A review

“…In addition, 18β‐glycyrrhetic acid at 60 mg/kg markedly attenuated ANIT‐induced cholestatic liver injury by restoring hepatic function and histopathology. The mechanism by which this effect occurred was through activation of FXR through Sirt1, further promoting efflux transporter function and consequently attenuating the disturbance in bile acid homeostasis (Wu et al, ).…”

Hepatoprotective properties of glycyrrhizic acid

“…С другой стороны, на фоне воспаления снижается активность фермента CYP3A4, играющего важную роль в детоксикации желчных кислот (хенодезоксихолевой, дезоксихолевой, литохолевой) в печени [66]. Было доказано снижение уровня экспрессии этой изоформы цитохрома Р450 именно при НАЖБП [67].…”

“…В дополнение к восстановлению гомеостаза липидов и желчных кислот, ГК может также непосредственно ингибировать индуцированную гидрофобными желчными кислотами активацию воспаления через NLRP3-инфламмасоммы, уменьшая опосредуемые ими провоспалительные эффекты [69]. В-четвертых, как ГК, так и УДХК являются индукторами CYP3A4, а значит возможен их синергизм при устранении негативных последствий воспаления в печени и холестаза [67,70]. Подтверждением этой гипотезы могут служить результаты доклинических исследований фиксированной комбинации ГК и УДХК, впервые зарегистрированной в Российской Федерации.…”

“…Возможный механизм антихолестатического действия ГК [67] BSEP -экспортирующая помпа желчных кислот. Mrp2 -белок множественной лекарственной устойчивости 2 (АТФ-связывающий переносчик желчных кислот); Mrp3 -белок множественной лекарственной устойчивости 3 (базально-латеральный переносчик желчных кислот); Mrp4-белок множественной лекарственной устойчивости 4 (АТФ-связывающий переносчик желчных кислот); FRXR -фарнезоид Х-рецептор-чувствительный элемент; Nrf2-ядерный фактор эритроид 2-родственный фактор 2.…”