Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

Meng, Qiang; Chen, Han Y. H.; Wang, Changyuan; Liu, Qi; Sun, Huijun; Sun, Pengyuan; Huo, Xiaokui; Liu, Zhihao; Yao, Jihong; Liu, Kexin

doi:10.1016/j.taap.2015.01.020

Cited by 70 publications

(38 citation statements)

References 38 publications

(42 reference statements)

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“…4 and 5). In our previous study, AB23A treatment was found to reduce Ntcp, Cyp7a1 and Cyp8b1 expression, while increasing Bsep and Mrp2 expression in alpha-naphthylisothiocyanate (ANIT)-induced hepatotoxity model (16). The effects of AB23A on the expression of genes involved in bile acid homeostasis in EE-induced cholestatic liver injury are similar to the effects of AB23A in ANIT-induced hepatotoxity and cholestasis in mice.…”

Section: Discussionmentioning

confidence: 63%

“…Most importantly, EE was proved to orchestrate adaptive response by activating FXR, indicating that as the key regulatory transcription factor for bile acid, FXR may become the focus of targeted therapies in cholestasis (34). We have shown that AB23A is an exogenous activator of FXR in the previous studies (15,16). In the present study, we used FXR antagonist GS in mice to verify that AB23A activate FXR to regulate expression level of genes in bile acid homeostasis.…”

Section: Discussionmentioning

confidence: 74%

“…Many pharmacological studies have revealed that AB23A has several pharmacological activities, such as antihepatitis virus, anti-proliferative activity of cancer cell lines and antibacterial effects (12)(13)(14). Recently, we have demonstrated that AB23A has promotive effect on liver regeneration and protective effect through FXR activation in mice (15,16). Therefore, an intriguing and important question arises whether AB23A has hepatoprotective effect on cholestatic liver injury such as EE-induced hepatic toxicity and cholestasis.…”

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

et al. 2015

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Section: Discussionmentioning

confidence: 63%

Section: Discussionmentioning

confidence: 74%

Section: Introductionmentioning

confidence: 99%

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Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

et al. 2015

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“…Due to treatment duration differences, we could determine the exact effect of INH-LPS in relation to bile acids as follows: in response to LPS-induced inflammation and released inflammatory cytokines, expression of the key regulatory transcriptional factor, the FXR gene, was repressed, causing increased production of bile acids. In the meantime, inflammation induced the rapid reduction in bile acid transporters, which caused the elevation and entrapment of bile acids in hepatocytes (42)(43)(44)(45). This massive accumulation of bile acids in hepatocytes might initiate a negative-feedback mechanism that results in the observed gene expression reduction.…”

Section: Discussionmentioning

confidence: 99%

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Hassan

Guo

Yousef

et al. 2016

Antimicrob Agents Chemother

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Isoniazid (INH), since its introduction in the year 1952, still serves as a frontline drug in tuberculosis treatment (1). Despite the fact that INH has been widely used as a first-line antitubercular agent (2, 3), its therapeutic value is usually accompanied by severe hepatotoxicity and lethal hepatic injury (4, 5). Although the pathophysiology of INH-induced liver injury might vary, the toxicity features of the drug, including hepatocellular steatosis, necrosis, and inflammatory infiltration, are nearly consistent (6, 7).Even though extensive studies expounding INH toxicity have been carried out, the exact mechanism of INH hepatotoxicity remains controversial. Among numerous established theories, an inflammatory stress theory has recently been widely used to explain the idiosyncrasy. One hypothesis is that inflammatory stress increases sensitivity to drug-induced liver injury (DILI) (8, 9). In this theory, an incidence of systemic inflammation might reduce the xenobiotic toxicity threshold, which could be easily accomplished by coadministration with an inflammatory agent (10), thus promoting drug toxicity. Lipopolysaccharide (LPS) is an outer cell wall membrane constituent of Gram-negative bacteria that has been comprehensively studied as an inflammatory agent with a major role in bacterial infections (11,12). Previous studies have suggested that LPS might intensify DILI (13-15), and, hence, a possible cornerstone role for LPS in INH-induced hepatotoxicity might be assumed.Oxidative stress, generated from the accumulation of reactive oxygen species (ROS), may be potentiated by different factors, including drugs and inflammation (16,17). In addition, oxidative stress plays a major role in several types of hepatic injury (18). Furthermore, with cytochrome P450 2E1 (CYP2E1) playing a major role in drug metabolism and the pathophysiology of DILI (19) and being considered a principal element in human susceptibility to chemical toxins (20), it plays a central part in oxidative stress, production of ROS, and hepatotoxic injury. Moreover, a previous report proposed that hepatic CYP2E1 plays a fundamental role in the propagation of INH-induced hepatotoxicity, mainly throughout ROS generation (21). Nevertheless, a full understanding of CYP2E1 as a major hepatotoxin-forming, catalyzing enzyme and its influence on INH-induced liver damage has not been completely achieved.Studies of the hepatotoxic mechanisms of INH were previously conducted using different animal models; however, results were accompanied by the absence of certain features of INH toxicity, i.e., delayed onset or inconsistency in severity compared to that in hu-

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“…Recent studies have suggested that FXR has a complementary role in the regulation of genes in the synthesis and transport of BAs [36,37]. Cholestasis-related transporters and enzymes have adaptive responses through the activation of FXR, indicating that FXR may become the focus of targeted therapies in cholestasis as the key regulatory transcription factor for BA [38]. FXR can suppress the expression of Cyp7a1, the rate-limiting enzyme in BA synthesis [39].…”

Section: Discussionmentioning

confidence: 99%

Exploration of Hepatoprotective Effect of Gentiopicroside on Alpha-Naphthylisothiocyanate-Induced Cholestatic Liver Injury in Rats by Comprehensive Proteomic and Metabolomic Signatures

Han

Xiong

et al. 2018

Cell Physiol Biochem

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Background/Aims: Cholestasis is the major cause of the accumulation of bile acids and results in liver damage, fibrosis, and failure. A growing number of studies have shown that gentiopicroside is a promising prospect that may protect the liver. However, its therapeutic mechanism has not yet been clarified. This study aimed to explore the effect and mechanism of gentiopicroside in cholestasis induced by alpha-naphthylisothiocyanate. Methods: We performed isobaric tags for relative and absolute quantification-based quantitative proteomics and metabolomics using liquid chromatography quadruple time-of-fight mass spectrometry and identified the expression of 73 metabolites and 84 proteins associated with cholestasis-related dysfunctions in the metabolism of bile acids, fatty acids, and glycerophospholipids. Results: Integrated analyses of proteomic and metabonomic studies showed altered pathways in cholestasis-induced liver injury involving increased activity of farnesoid X receptor/retinoid X receptor, bile acid biosynthesis, and peroxisome proliferator-activated receptor-α/retinoid X receptor-α. Gentiopicroside could reverse these metabolite, protein, and blood biochemical indices, as well as alleviate liver damage. The progressive changes in the proteins and genes may be correlated with cholestasis and were confirmed by western blot and quantitative realtime polymerase chain reaction. Conclusion: Gentiopicroside could be used to protect the liver in the presence of cholestasis.

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Alisol B 23-acetate protects against ANIT-induced hepatotoxity and cholestasis, due to FXR-mediated regulation of transporters and enzymes involved in bile acid homeostasis

Cited by 70 publications

References 38 publications

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

Protective Effects of Alisol B 23-Acetate Via Farnesoid X Receptor-Mediated Regulation of Transporters and Enzymes in Estrogen-Induced Cholestatic Liver Injury in Mice

Role of Inflammatory and Oxidative Stress, Cytochrome P450 2E1, and Bile Acid Disturbance in Rat Liver Injury Induced by Isoniazid and Lipopolysaccharide Cotreatment

Exploration of Hepatoprotective Effect of Gentiopicroside on Alpha-Naphthylisothiocyanate-Induced Cholestatic Liver Injury in Rats by Comprehensive Proteomic and Metabolomic Signatures

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