BIOCHEMICAL PHARMACOLOGY
·
2026
·
IF 6.5
Yifei Xiao,Jiatian He,Yi Zheng,Xinyu Zhang,Jintao Li,Meng Jin,Min Chen,Yushan Wu,Xiaowen Liu,Haiman Xu,Luomin Lin,Baojian Wu,Lianxia Guo,Dong Dong
Disruption of bile acid (BA) homeostasis and circadian rhythm are interconnected in chronic liver diseases, yet how circadian dysfunction exacerbates cholestasis remains unclear. This study demonstrates that hepatocyte-specific knockout of the core clock gene Bmal1 in female mice markedly aggravates liver injury, inflammation, and fibrosis in an α-naphthylisothiocyanate (ANIT)-induced intrahepatic cholestasis model. The pathological exacerbation is attributed to a profound loss of circadian oscillation and reduced expression of the detoxification enzyme sulfotransferase family 2A member 1 (SULT2A1), resulting in deficient sulfation and hepatic accumulation of cytotoxic bile acids. This hypersusceptibility was further validated in primary hepatocytes under BA overload. Notably, specific in vivo restoration of hepatic Sult2a1 significantly reversed these pathological progressions. Mechanistically, BMAL1 transcriptionally activates Sult2a1 by directly binding to the E-box element within its promoter region. Taken together, our work elucidates the BMAL1-SULT2A1 axis as an essential circadian defense mechanism that maintains hepatic bile acid detoxification homeostasis in female mice, providing a novel theoretical basis for chronotherapeutic strategies in cholestatic liver diseases.
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BRITISH JOURNAL OF PHARMACOLOGY
·
2017
·Vol. 174
·期 23
·4345-4361
·
IF 5.491
Pan Chen,Dongshun Li,Yixin Chen,Jiahong Sun,Kaili Fu,Lihuan Guan,Huizhen Zhang,Yiming Jiang,Xi Li,Xuezhen Zeng,Xiao Chen,Min Huang,Huichang Bi
Background and Purpose The tumour suppressor p53 is traditionally recognized as a surveillance molecule to preserve genome integrity. Recent studies have demonstrated that it contributes to metabolic diseases. Here, we investigated the role of p53 in the regulation of bile acid disposition and cholestasis. Experimental Approach The bile acid disposition-related gene expression profile affected by p53 activation was assessed in mouse primary hepatocytes with p53 depletion and in Trp53 -null mice. Dual luciferase reporter assay was used to detect the transcriptional activities of target genes. Anticholestatic effects of p53 activator doxorubicin were investigated in a 0.5% cholic acid-fed mouse model of cholestasis. Changes in bile acids were evaluated using metabolomics analysis. Key Results Doxorubicin-mediated p53 activation induced Cyp2b10 , Sult2a1 and Abcc2/3/4 expression in mice in vitro and in vivo . ABCC3 and CYP2B6 (human orthologue of Cyp2b10 ) were identified as direct p53 target genes. Doxorubicin attenuated cholic acid-induced cholestasis in mice, as demonstrated by shrunken gall bladder, decreased serum total bile acid and total bilirubin levels and alkaline phosphatase activity. Targeted metabolomics analysis revealed that doxorubicin enhanced the excretion of bile acid metabolites from serum and liver to intestine and faeces. Up-regulation of Cyp2b10 , Sult2a1 and Abcc2/3/4 expression was further confirmed in cholestatic mice. Cholic acid-induced cholestatic injury was aggravated in p53-deficient mice and levels of bile acid in intestine and faeces were decreased. Conclusions and Implications Our findings suggest a novel role of p53 in promoting bile acid disposition and alleviating cholestatic syndrome, which provides a potential therapeutic target for cholestasis.
研究领域:
分子生物学
·
肝病学
·
药理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
EUROPEAN JOURNAL OF PHARMACOLOGY
·
2018
·
IF 3.04
Yulong Kong,Xiaoguang Gao,Changyuan Wang,Chenqing Ning,Kexin Liu,Zhihao Liu,Huijun Sun,Xiaodong Ma,Pengyuan Sun,Qiang Meng
Accumulation of toxic bile acids in liver could cause cholestasis and liver injury. The purpose of the current study is to evaluate the hepatoprotective effect of yangonin , a product isolated from an edible botanical Kava against lithocholic acid (LCA)-induced cholestasis, and further to elucidate the involvement of farnesoid X receptor (FXR) in the anticholestatic effect using in vivo and in vitro experiments. The cholestatic liver injury model was established by intraperitoneal injections of LCA in C57BL/6 mice. Serum biomarkers and H&E staining were used to identify the amelioration of cholestasis after yangonin treatment. Mice hepatocytes culture, gene silencing experiment, real-time PCR and Western blot assay were used to elucidate the mechanisms underlying yangonin hepatoprotection . The results indicated that yangonin promoted bile acid efflux and reduced hepatic uptake via an induction in FXR-target genes Bsep , Mrp2 expression and an inhibition in Ntcp , all of which are responsible for bile acid transport. Furthermore, yangonin reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in gene expression of Sult2a1, which are involved in bile acid synthesis and metabolism. In addition, yangonin suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α and IL-1β. In vitro evidences showed that the changes in transporters and enzymes induced by yangonin were abrogated when FXR was silenced. In conclusions, yangonin produces protective effect against LCA-induced hepatotoxity and cholestasis due to FXR-mediated regulation. Yangonin may be an effective approach for the prevention against cholestatic liver diseases.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
Frontiers in Cell and Developmental Biology
·
2021
·
IF 6.684
Peijie Wu,Ling Qiao,Han Yu,Hui Ming,Chao Liu,Wenjun Wu,Baixue Li
Cholestasis is a kind of stressful syndrome along with liver toxicity, which has been demonstrated to be related to fibrosis, cirrhosis, even cholangiocellular or hepatocellular carcinomas. Cholestasis usually caused by the dysregulated metabolism of bile acids that possess high cellular toxicity and synthesized by cholesterol in the liver to undergo enterohepatic circulation. In cholestasis, the accumulation of bile acids in the liver causes biliary and hepatocyte injury, oxidative stress, and inflammation. The farnesoid X receptor (FXR) is regarded as a bile acid–activated receptor that regulates a network of genes involved in bile acid metabolism, providing a new therapeutic target to treat cholestatic diseases. Arbutin is a glycosylated hydroquinone isolated from medicinal plants in the genus Arctostaphylos , which has a variety of potentially pharmacological properties, such as anti-inflammatory, antihyperlipidemic, antiviral, antihyperglycemic, and antioxidant activity. However, the mechanistic contributions of arbutin to alleviate liver injury of cholestasis, especially its role on bile acid homeostasis via nuclear receptors, have not been fully elucidated. In this study, we demonstrate that arbutin has a protective effect on α -naphthylisothiocyanate–induced cholestasis via upregulation of the levels of FXR and downstream enzymes associated with bile acid homeostasis such as Bsep, Ntcp, and Sult2a1, as well as Ugt1a1. Furthermore, the regulation of these functional proteins related to bile acid homeostasis by arbutin could be alleviated by FXR silencing in L-02 cells. In conclusion, a protective effect could be supported by arbutin to alleviate ANIT-induced cholestatic liver toxicity, which was partly through the FXR pathway, suggesting arbutin may be a potential chemical molecule for the cholestatic disease.
研究领域:
药理学
·
肝病学
·
分子生物学
·
毒理学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
BIOCHEMICAL PHARMACOLOGY
·
2017
·
IF 4.581
Xiaoguang Gao,Ting Fu,Changyuan Wang,Chenqing Ning,Yulong Kong,Zhihao Liu,Huijun Sun,Xiaodong Ma,Kexin Liu,Qiang Meng
Recently obeticholic acid (OCA) which is a farnesoid X receptor (FXR) agonist was approved by FDA to treat cholestatic liver diseases, which provided us a novel therapeutic strategy against cholestasis . Herein, we used a novel computational strategy with two-dimensional virtual screening for FXR agonists. For the first time, we found that auraptene (AUR), a natural product, can activate FXR to exert hepatoprotective effect against cholestatic liver injury in vivo and in vitro . Importantly, AUR was found to significantly decrease the mortality of cholestatic mice. Dynamic change analysis of bile acids and gene analysis revealed that AUR promoted bile acid efflux from liver into intestine via an induction in FXR-target genes Bsep and Mrp2 expression, and reduced hepatic uptake through an inhibition in Ntcp . Furthermore, AUR reduced bile acid synthesis through repressing FXR-target genes Cyp7a1 and Cyp8b1, and increased bile acid metabolism through an induction in Sult2a1 . In addition, AUR promoted liver repair through an induction in liver regeneration-related gene, and suppressed liver inflammation through repressing inflammation-related gene NF-κB, TNF-α, IL-1β and IL-6. However, the changes in these genes and protein, as well as ameliorative liver histology induced by AUR were abrogated by FXR antagonist guggulsterone in vivo and FXR siRNA in vitro . These findings suggest that AUR may be an effective approach for the prevention against cholestatic liver diseases.
研究领域:
药理学
·
肝病学
·
分子生物学
✓ 已验证
产品关联
DOI
PubMed
高影响因子
危险品化学品经营许可证（带存储）