Gentiopicroside Ameliorates the Progression from Hepatic Steatosis to Fibrosis Induced by Chronic Alcohol Intake

Abstract

In current study, we aimed to investigate whether the gentiopicroside (GPS) derived from Gentiana manshurica Kitagawa could block the progression of alcoholic hepatic steatosis to fibrosis induced by chronic ethanol intake. C57BL/6 mice were fed an ethanol-containing Lieber-DeCarli diet for 4 weeks. LX-2 human hepatic stellate cells were treated with GPS 1 h prior to transforming growth factor-β (TGF-β) stimulation, and murine hepatocyte AML12 cells were pretreated by GPS 1 h prior to ethanol treatment. GPS inhibited the expression of type I collagen (collagen I), α-smooth muscle actin (α-SMA) and tissue inhibitor of metal protease 1 in ethanol-fed mouse livers with mild fibrosis. In addition, the imbalanced lipid metabolism induced by chronic ethanol-feeding was ameliorated by GPS pretreatment, characterized by the modulation of lipid accumulation. Consistently, GPS inhibited the expression of collagen I and α-SMA in LX-2 cells stimulated by TGF-β. Inhibition of lipid synthesis and promotion of oxidation by GPS were also confirmed in ethanol-treated AML12 cells. GPS could prevent hepatic steatosis advancing to the inception of a mild fibrosis caused by chronic alcohol exposure, suggesting GPS might be a promising therapy for targeting the early stage of alcoholic liver disease.

Gentiopicroside prevents alcoholic liver damage by improving mitochondrial dysfunction in the rat model

“…Since mechanisms of ALD have not been completely identified and no suitable drug has been reported yet, a group of positive control was not set up in the present work, which was consistent with published reports (Li et al, 2018; Yang et al, 2020). As gentiopicroside is the major active compound of traditional Chinese oral decoction‐Longdan xiegan decoction, gentiopicroside was oral administration once a day in the present work.…”

“…According to pharmacokinetic parameters of gentiopicroside (Liu, Liu, Dai, & Ma, 2018; Lu, Lin, & Tsai, 2014; Wu et al, 2017) and referring to published work, dose of gentiopicroside was set at 20 mg/kg, which equaled to 222 mg per day for 70 kg adults. Although as reported that gentiopicroside at oral 40 mg/kg for mice (equaled 28 mg/kg for rats) showed no toxicity in the liver (Li et al, 2018; Yang et al, 2020), however, there are few reports on the toxicity experiments, which limits the safety evaluation of gentiopicroside. Modern medicine reported that Longdan xiegan decoction was used to treat ALD and showed apparent clinical effect.…”

“…Yang et al reported gentiopicroside could block the progression of alcoholic hepatic steatosis to fibrosis induced by chronic ethanol intake (H.‐X. Yang et al, 2020). Li et al reported gentiopicroside could downregulate P2X7 receptor‐mediated NLRP3 inflammasome by activating LKB1‐AMPK pathway, thereby improving ethanol‐induced acute and chronic alcohol lipid accumulation (Li et al, 2018).…”

“…Previously published works have reported the pharmacological activities of gentiopicroside, including anti‐diabetic nephropathy (Xiao et al, 2020), anti‐depression (Yao et al, 2019), anti‐arthritis (Xie et al, 2019), anti‐cancer (Yang, He, Jin, & Chen, 2018), anti‐inflammatory (Deng, Wang, Zhao, Huang, & Xu, 2018; Xiao et al, 2020; Zhang et al, 2019), and anti‐nociceptive effects (Liu et al, 2016), and so on. Although the hepatoprotective effect of gentiopicroside on hepatopathy has been reported (Han, Xu, Xiong, Zhang, & Wang, 2018; Lian et al, 2010; Mihailovic et al, 2013; Tang et al, 2016; Yang et al, 2017), the published studies on ALD are few (Li et al, 2018; Yang et al, 2020) and the underlying mechanisms are still unclear. The mitochondria are a vital hub that executes appropriate physiological functions, such as generating adenosine triphosphate (ATP), balancing reactive oxygen species (ROS), and regulating apoptosis (Nassir, 2014).…”

Therapeutic Effects of an Inhibitor of Thioredoxin Reductase on Liver Fibrosis by Inhibiting the Transforming Growth Factor-β1/Smads Pathway

“…The chemical structure of BS as an organic selenium molecule with symmetrical diselenide rings was shown in Figure 2A . HSCs and the normal liver cell line AML12 were widely used in liver fibrosis studies in vitro , and AML12 was used as a control ( Li et al, 2019 ; Yang et al, 2020 ). The effect of BS was evaluated in an in vitro system using HSCs.…”