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Hu Z, Wei J, Dong K, Li L, Xiong A, Yang L, Wang Z. Enhanced bile acid detection and analysis in liver fibrosis with pseudo-targeted metabolomics. J Pharm Biomed Anal 2025; 257:116668. [PMID: 39879819 DOI: 10.1016/j.jpba.2025.116668] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 12/16/2024] [Accepted: 01/06/2025] [Indexed: 01/31/2025]
Abstract
Bile acids (BAs) are essential signaling molecules that engage in host and gut microbial metabolism, playing a crucial role in maintaining organismal stability. Liquid chromatography-mass spectrometry (LC-MS) is a widely employed technique for metabolite analysis in biological samples due to its high sensitivity, excellent specificity, and low detection limits. This method has emerged as the mainstream approach for the detection and analysis of BAs. Pseudo-targeted analysis combines the advantages of both untargeted and targeted metabolomics methodologies. In this study, we developed a comprehensive and rapid method for detecting and analyzing BAs using LC-MS technology, applied to liver samples from bile duct-ligated (BDL) mice exhibiting liver fibrosis. A self-constructed database containing 488 BAs was established, and raw data from universal metabolome standard (UMS) were acquired using UHPLC-Q/TOF-MS. A total of 172 BA compounds were characterized, including 74 free BAs and 158 BAs were successfully detected using the high-coverage assay established with UHPLC-QQQ-MS. This assay was employed in the BDL liver fibrosis mouse model, where statistical analysis tools identified 20 differential BAs in the livers of affected mice. The development of this rapid method signifies a substantial advancement in the field, illustrating its utility in identifying differential BAs and enhancing our understanding of liver fibrosis. Furthermore, the high-coverage assay's ability to accurately analyze a diverse range of BAs could substantially aid in diagnosing and treating liver diseases.
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Affiliation(s)
- Zhizhi Hu
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Jiaojiao Wei
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Kua Dong
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Linnan Li
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Aizhen Xiong
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
| | - Zhengtao Wang
- State Key Laboratory of Discovery and Utilization of Functional Components in Traditional Chinese Medicine, The MOE Key Laboratory of Standardization of Chinese Medicines, the SATCM Key Laboratory of New Resources and Quality Evaluation of Chinese Medicines and Shanghai Key Laboratory of Compound Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China.
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Beers JL, Hebert MF, Wang J. Transporters and drug secretion into human breast milk. Expert Opin Drug Metab Toxicol 2025; 21:409-428. [PMID: 39893560 DOI: 10.1080/17425255.2025.2461479] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 01/09/2025] [Accepted: 01/29/2025] [Indexed: 02/04/2025]
Abstract
INTRODUCTION Medication use is highly prevalent in breastfeeding persons, posing potential risks for drug exposure to nursing infants. Transporters in the lactating mammary gland carry pharmacological and toxicological significance, as they can mediate the active transfer of drugs and nutrients into breastmilk. AREAS COVERED In this narrative review, we searched and compiled current knowledge on the transport of drugs in the human mammary gland from literature indexed in PubMed (current as of 25 October 2024), and clinical evidence demonstrating active transport of drugs into milk is provided. In vitro and in vivo models of the mammary gland are outlined in brief and known drug transporters at the blood-milk barrier and their potential relevance to drug concentrations in milk are described in detail. EXPERT OPINION Although clinical data show that membrane transporters mediate the transfer of multiple drugs into breast milk, our ability to predict milk concentrations for these drugs is limited. Improving our understanding of the transporter biology and pharmacology in the mammary gland is crucial for developing models to predict drug concentrations in human milk, which will support clinicians and lactating individuals in making rational decisions to balance the benefits of breastfeeding and the risks of drug exposure to infants.
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Affiliation(s)
- Jessica L Beers
- Department of Pharmacy, University of Washington, Seattle, WA, USA
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
| | - Mary F Hebert
- Department of Pharmacy, University of Washington, Seattle, WA, USA
- Department of Obstetrics and Gynecology, University of Washington, Seattle, WA, USA
| | - Joanne Wang
- Department of Pharmaceutics, University of Washington, Seattle, WA, USA
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Liu JJ, Mei HW, Jing YY, Li ZL, Wu SG, Yuan HX, Zhang XB. Yinchenhao decoction alleviates obstructive jaundice liver injury by modulating epidermal growth factor receptor and constitutive androstane receptor signaling. World J Hepatol 2025; 17:101724. [DOI: 10.4254/wjh.v17.i3.101724] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/24/2024] [Revised: 01/18/2025] [Accepted: 03/04/2025] [Indexed: 03/26/2025] Open
Abstract
BACKGROUND Yinchenhao decoction (YCHD) is a traditional Chinese medicine widely used to treat liver damage caused by obstructive jaundice (OJ). Although YCHD has demonstrated protective effects against liver damage, reduced apoptosis, and mitigated oxidative stress in OJ, the precise molecular mechanisms involved remain poorly understood.
AIM To investigate the beneficial effects of YCHD on OJ and elucidate the underlying mechanisms.
METHODS The active constituents of YCHD were identified using liquid chromatography-tandem mass spectrometry, and their potential targets for OJ treatment were predicted through network pharmacology. Gene Ontology and Kyoto Encyclopedia of Genes and Genomes pathway enrichment analyses were performed. An OJ rat model was established by common bile duct ligation. Rats were divided into three groups: Sham surgery (S Group), model (O Group), and YCHD (Y Group). YCHD was administered to Group Y for one week. Bilirubin levels, liver function parameters, and bile acid concentrations in blood and urine were measured by enzyme-linked immunosorbent assay. The bile acid renal clearance rate (Clr) was calculated. Histopathological evaluation of liver and kidney tissues was performed using hematoxylin-eosin staining. Western blotting was utilized to assess the expression of key bile acid metabolism and transport proteins in both liver and kidney tissues. The expression of the constitutive androstane receptor (CAR) and its nuclear localization were evaluated by immunohistochemistry. Molecular docking studies identified the epidermal growth factor receptor (EGFR) as a potential target of YCHD's active components. An OJ cell model was created using human liver (L02) and renal tubular epithelial (HK-2) cells, which were treated with YCHD-containing serum. Western blotting and immunofluorescence assays were employed to evaluate CAR expression and its nuclear localization in relation to EGFR activation.
RESULTS Network analysis identified the EGFR signaling pathway as a key mechanism through which YCHD exerts its effects on OJ. In vivo experiments showed that YCHD improved liver function, reduced OJ-induced pathology in liver and kidney tissues, and decreased serum bile acid content by enhancing bile acid Clr and urine output. YCHD also increased CAR expression and nuclear heterotopy, upregulating proteins involved in bile acid metabolism and transport, including CYP3A4, UGT1A1, MRP3, and MRP4 in the liver, and MRP2 and MRP4 in the kidneys. In vitro, YCHD increased CAR expression and nuclear heterotopy in L02 and HK-2 cells, an effect that was reversed by EGFR agonists.
CONCLUSION YCHD enhances bile acid metabolism in the liver and promotes bile acid excretion in the kidneys, ameliorating liver damage caused by OJ. These effects are likely mediated by the upregulation of CAR and its nuclear translocation.
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Affiliation(s)
- Jun-Jian Liu
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
- Tianjin Key Laboratory, Acute Abdomen Disease Associated Organ Injury and ITCWM Repair, Tianjin 300102, China
| | - Han-Wei Mei
- Department of Gastrointestinal Surgery 3, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 301617, China
| | - Yan-Yan Jing
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Zhong-Lian Li
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
| | - Su-Guo Wu
- Graduate School, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Hong-Xia Yuan
- College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin 301617, China
| | - Xi-Bo Zhang
- Department of Hepatobiliary and Pancreatic Surgery 2, Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300102, China
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Basaly V, Bhattacharya A, Guo GL. Insights of direct and indirect regulation of PXR through phosphorylation in fatty liver disease. Mol Pharmacol 2025; 107:100014. [PMID: 40023513 DOI: 10.1016/j.molpha.2024.100014] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2024] [Accepted: 12/13/2024] [Indexed: 03/04/2025] Open
Abstract
The pregnane X receptor (PXR), a ligand-activated nuclear receptor, regulates the transcription of several genes that encode many enzymes and transporters related to drug metabolism. PXR also performs an important role as a physiological sensor in the modulation of endobiotic metabolism for hormones, bile acids, cholesterol, fatty acids, and glucose. Dysregulation of these PXR-mediated pathways is implicated in the progression of metabolic dysfunction-associated steatohepatitis (MASH), contributing to the complex interplay of factors involved in chronic liver disease development and exacerbation affecting millions worldwide. This review highlights the current knowledge of PXR expression and its role in endobiotic metabolism related to MASH development, which is associated with diverse causes and dire outcomes. This review focuses on elucidating the molecular pathways associated with PXR activation directly or indirectly and PXR interaction with other regulatory factors. Although there is still much to comprehend about the intricate details of these pathways, the conclusion is drawn that PXR exerts a crucial role in the pathological and physiological pathways of hepatic cellular processes, which holds promise as a potential pharmacological target for exploring novel therapeutic approaches for MASH treatment and/or prevention. SIGNIFICANCE STATEMENT: The pregnane X receptor (PXR) plays a fundamental role in regulating gene expression involved in xenobiotic and endobiotic metabolism. Dysregulation of PXR-mediated pathways is related to the development of metabolic dysfunction-associated steatohepatitis. The ligand-independent pathways regulating PXR hepatic functions through phosphorylation shed light on possible indirect molecular mechanisms and pathways that regulate PXR activity and function. Understanding these pathways may provide insight into new pharmaceutical interventions for metabolic dysfunction-associated steatohepatitis development.
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Affiliation(s)
- Veronia Basaly
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Anisha Bhattacharya
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey
| | - Grace L Guo
- Department of Pharmacology and Toxicology, Ernest Mario School of Pharmacy, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Environmental and Occupational Health Sciences Institute, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; Rutgers Center for Lipid Research, Rutgers, The State University of New Jersey, New Brunswick, New Jersey; VA New Jersey Health Care System, Veterans Administration Medical Center, East Orange, New Jersey.
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Ma Y, Yang H, Wang X, Huang Y, Li Y, Pan G. Bile acids as signaling molecules in inflammatory bowel disease: Implications for treatment strategies. JOURNAL OF ETHNOPHARMACOLOGY 2025; 337:118968. [PMID: 39427739 DOI: 10.1016/j.jep.2024.118968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/30/2024] [Revised: 09/21/2024] [Accepted: 10/17/2024] [Indexed: 10/22/2024]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Inflammatory bowel disease (IBD) is a globally increasing disease. Despite continuous efforts, the clinical application of treatment drugs has not achieved satisfactory success and faces limitations such as adverse drug reactions. Numerous investigations have found that the pathogenesis of IBD is connected with disturbances in bile acid circulation and metabolism. Traditional Chinese medicine targeting bile acids (BAs) has shown significant therapeutic effects and advantages in treating inflammatory bowel disease. AIM OF THIS REVIEW IThis article reviews the role of bile acids and their receptors in IBD, as well as research progress on IBD therapeutic drugs based on bile acids. It explores bile acid metabolism and its interaction with the intestinal microbiota, summarizes clinical drugs for treating IBD including single herbal medicine, traditional herbal prescriptions, and analyzes the mechanisms of action in treating IBD. MATERIALS AND METHODS IThe electronic databases such as PubMed, Web of Science, and China National Knowledge Infrastructure (CNKI) have been utilized to retrieve relevant literature up to January 2024, using keywords "bile acid", "bile acid receptor", "inflammatory bowel disease", "intestinal microbiota" and "targeted drugs". RESULTS IImbalance in bile acid levels can lead to intestinal inflammation, while IBD can disrupt the balance of microbes, result in alterations in the bile acid pool's composition and amount. This change can damage of intestinal mucosa healing ability. Bile acids are vital for keeping the gut barrier function intact, regulating gene expression, managing metabolic equilibrium, and influencing the properties and roles of the gut's microbial community. Consequently, focusing on bile acids could offer a potential treatment strategy for IBD. CONCLUSION IIBD can induce intestinal homeostasis imbalance and changes in BA pool, leading to fluctuations in levels of relevant metabolic enzymes, transporters, and nuclear receptors. Therefore, by regulating the balance of BA and key signaling molecules of bile acids, we can treat IBD. Traditional Chinese medicine has great potential and promising prospects in treating IBD. We should focus on the characteristics and advantages of Chinese medicine, promote the development and clinical application of innovative Chinese medicine, and ultimately make Chinese medicine targeting bile acids the mainstream treatment for IBD.
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Affiliation(s)
- Yueyue Ma
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Haoze Yang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Xiaoming Wang
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China
| | - Yuhong Huang
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China
| | - Yuhong Li
- Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China; State Key Laboratory of Component-based Chinese Medicine, Tianjin University of Traditional Chinese Medicine, 10 Poyang Lake Road, Jing Hai District, Tianjin, 301617, PR China.
| | - Guixiang Pan
- Second Affiliated Hospital of Tianjin University of Traditional Chinese Medicine, Tianjin, 300250, PR China.
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Liang HF, Yang X, Li HL, Li X, Tian JN, Su HG, Huang M, Fang JH, Bi HC. Activation of pregnane X receptor protects against cholestatic liver injury by inhibiting hepatocyte pyroptosis. Acta Pharmacol Sin 2025; 46:147-158. [PMID: 39112769 PMCID: PMC11696769 DOI: 10.1038/s41401-024-01357-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/22/2024] [Accepted: 07/05/2024] [Indexed: 01/04/2025]
Abstract
Our previous study shows that activation of pregnane X receptor (PXR) exerts hepatoprotection against lithocholic acid (LCA)-induced cholestatic liver injury. In this study we investigated whether PXR activation could inhibit hepatocyte pyroptosis, as well as the underlying mechanisms. Male mice were treated with mouse PXR agonist pregnenolone 16α-carbonitrile (PCN, 50 mg·kg-1·d-1, i.p.) for 7 days, and received LCA (125 mg/kg, i.p., bid) from D4, then sacrificed 12 h after the last LCA injection. We showed that LCA injection resulted in severe cholestatic liver injury characterized by significant increases in gallbladder size, hepatocellular necrosis, and neutrophil infiltration with a mortality rate of 68%; PCN treatment significantly inhibited hepatocyte pyroptosis during LCA-induced cholestatic liver injury, as evidenced by reduced serum lactic dehydrogenase (LDH) levels, TUNEL-positive cells and hepatocyte membrane damage. Furthermore, PXR activation suppressed both the NOD-like receptor protein 3 (NLRP3) inflammasome-induced canonical pyroptosis and the apoptosis protease activating factor-1 (APAF-1) pyroptosome-induced non-canonical pyroptosis. Inhibition of the nuclear factor kappa B (NF-κB) and forkhead box O1 (FOXO1) signaling pathways was also observed following PXR activation. Notably, dual luciferase reporter assay showed that PXR activation inhibited the transcriptional effects of NF-κB on NLRP3, as well as FOXO1 on APAF-1. Our results demonstrate that PXR activation protects against cholestatic liver injury by inhibiting the canonical pyroptosis through the NF-κB-NLRP3 axis and the non-canonical pyroptosis through the FOXO1-APAF-1 axis, providing new evidence for PXR as a prospective anti-cholestatic target.
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Affiliation(s)
- Hang-Fei Liang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xiao Yang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, China.
| | - Hui-Lin Li
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Xuan Li
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jia-Ning Tian
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Hai-Guo Su
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Min Huang
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China
| | - Jian-Hong Fang
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China
| | - Hui-Chang Bi
- NMPA Key Laboratory for Research and Evaluation of Drug Metabolism & Guangdong Provincial Key Laboratory of New Drug Screening & Guangdong-Hongkong-Macao Joint Laboratory for New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, China.
- Guandong Provincial Key Laboratory of New Drug Design and Evaluation, School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, 510006, China.
- The State Key Laboratory of Chemical Oncogenomics, School of Chemical Biology and Biotechnology, Shenzhen Graduate School of Peking University, Shenzhen, 518055, China.
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Zhuang T, Wang X, Wang Z, Gu L, Yue D, Wang Z, Li X, Yang L, Huang W, Ding L. Biological functions and pharmacological behaviors of bile acids in metabolic diseases. J Adv Res 2024:S2090-1232(24)00495-8. [PMID: 39522690 DOI: 10.1016/j.jare.2024.11.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/17/2024] [Revised: 11/02/2024] [Accepted: 11/02/2024] [Indexed: 11/16/2024] Open
Abstract
BACKGROUND Bile acids, synthesized endogenously from cholesterol, play a central role in metabolic regulation within the enterohepatic circulatory system. Traditionally known as emulsifying agents that facilitate the intestinal absorption of vitamins and lipids, recent research reveals their function as multifaceted signal modulators involved in various physiological processes. These molecules are now recognized as key regulators of chronic metabolic diseases and immune dysfunction. Despite progress in understanding their roles, their structural diversity and the specific functions of individual bile acids remain underexplored. AIM OF REVIEW This study categorizes the bile acids based on their chemical structures and their roles as signaling molecules in physiological processes. It consolidates current knowledge and provides a comprehensive overview of the current research. The review also includes natural and semisynthetic variants that have demonstrated potential in regulating metabolic processes in animal models or clinical contexts. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acids circulate primarily within the enterohepatic circulation, where they help maintain a healthy digestive system. Disruptions in their balance are linked to metabolic disorders, hepatobiliary diseases and intestinal inflammation. Through receptor-mediated pathways, bile acids influence the progression of metabolic diseases by regulating glucose and lipid metabolism, immune function, and energy expenditure. This review aims to provide a comprehensive, systematic foundation to for understanding their physiological roles and supporting future therapeutic developments for metabolic and inflammatory diseases.
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Affiliation(s)
- Tongxi Zhuang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Zixuan Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Lihua Gu
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Dawei Yue
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Xiaohua Li
- Department of Endocrinology, Seventh People's Hospital of Shanghai University of Traditional Chinese Medicine, Shanghai 200163, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Wendong Huang
- Arthur Riggs Diabetes & Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Fiorucci S, Urbani G, Di Giorgio C, Biagioli M, Distrutti E. Current Landscape and Evolving Therapies for Primary Biliary Cholangitis. Cells 2024; 13:1580. [PMID: 39329760 PMCID: PMC11429758 DOI: 10.3390/cells13181580] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Revised: 09/18/2024] [Accepted: 09/19/2024] [Indexed: 09/28/2024] Open
Abstract
Primary Biliary Cholangitis (PBC) is a chronic autoimmune liver disorder characterized by progressive cholestatic that, if untreated, can progress to liver fibrosis, cirrhosis and liver decompensation requiring liver transplant. Although the pathogenesis of the disease is multifactorial, there is a consensus that individuals with a genetic predisposition develop the disease in the presence of specific environmental triggers. A dysbiosis of intestinal microbiota is increasingly considered among the potential pathogenic factors. Cholangiocytes, the epithelial cells lining the bile ducts, are the main target of a dysregulated immune response, and cholangiocytes senescence has been recognized as a driving mechanism, leading to impaired bile duct function, in disease progression. Bile acids are also recognized as playing an important role, both in disease development and therapy. Thus, while bile acid-based therapies, specifically ursodeoxycholic acid and obeticholic acid, have been the cornerstone of therapy in PBC, novel therapeutic approaches have been developed in recent years. In this review, we will examine published and ongoing clinical trials in PBC, including the recently approved peroxisome-proliferator-activated receptor (PPAR) agonist, elafibranor and seladelpar. These novel second-line therapies are expected to improve therapy in PBC and the development of personalized approaches.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Cristina Di Giorgio
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, 06123 Perugia, Italy; (G.U.); (C.D.G.); (M.B.)
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06123 Perugia, Italy;
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10
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Huang K, Wang C, Mei B, Li J, Ren T, Zhan H, Zhang Y, Zhang B, Lv X, Zhang Q, Guan Y, Zhang X, Wang G, Pan W, Xu P, Wang H, Zhang J. Bile acids attenuate hepatic inflammation during ischemia/reperfusion injury. JHEP Rep 2024; 6:101101. [PMID: 39091991 PMCID: PMC11292370 DOI: 10.1016/j.jhepr.2024.101101] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2023] [Revised: 04/10/2024] [Accepted: 04/16/2024] [Indexed: 08/04/2024] Open
Abstract
Background & Aims Persistent cholestasis has been associated with poor prognosis after orthotopic liver transplantation. In this study, we aimed to investigate how the accumulation of tauro-beta-muricholic acid (TβMCA), resulting from the reprogramming of bile acid (BA) metabolism during liver ischemia/reperfusion (IR) stress, attenuates liver inflammation. Methods Ingenuity Pathway Analysis was performed using transcriptome data from a murine hepatic IR model. Three different models of hepatic IR (liver warm IR, bile duct separation-IR, common bile duct ligation-IR) were employed. We generated adeno-associated virus-transfected mice and CD11b-DTR mice to assess the role of BAs in regulating the myeloid S1PR2-GSDMD axis. Hepatic BA levels were analyzed using targeted metabolomics. Finally, the correlation between the reprogramming of BA metabolism and hepatic S1PR2 levels was validated through RNA-seq of human liver transplant biopsies. Results We found that BA metabolism underwent reprogramming in murine hepatocytes under IR stress, leading to increased synthesis of TβMCA, catalyzed by the enzyme CYP2C70. The levels of hepatic TβMCA were negatively correlated with the severity of hepatic inflammation, as indicated by the serum IL-1β levels. Inhibition of hepatic CYP2C70 resulted in reduced TβMCA production, which subsequently increased serum IL-1β levels and exacerbated IR injury. Moreover, our findings suggested that TβMCA could inhibit canonical inflammasome activation in macrophages and attenuate inflammatory responses in a myeloid-specific S1PR2-GSDMD-dependent manner. Additionally, Gly-βMCA, a derivative of TβMCA, could effectively attenuate inflammatory injury in vivo and inhibit human macrophage pyroptosis in vitro. Conclusions IR stress orchestrates hepatic BA metabolism to generate TβMCA, which attenuates hepatic inflammatory injury by inhibiting the myeloid S1PR2-GSDMD axis. Bile acids have immunomodulatory functions in liver reperfusion injury that may guide therapeutic strategies. Impact and implications Our research reveals that liver ischemia-reperfusion stress triggers reprogramming of bile acid metabolism. This functions as an adaptive mechanism to mitigate inflammatory injury by regulating the S1PR2-GSDMD axis, thereby controlling the release of IL-1β from macrophages. Our results highlight the crucial role of bile acids in regulating hepatocyte-immune cell crosstalk, which demonstrates an immunomodulatory function in liver reperfusion injury that may guide therapeutic strategies targeting bile acids and their receptors.
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Affiliation(s)
- Kunpeng Huang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan 430022, China
| | - Changyan Wang
- Department of Medical Genetics, Basic School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Bosheng Mei
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Jinglei Li
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Tianxing Ren
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hanjing Zhan
- Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Yunwei Zhang
- Department of Emergency, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Department of Surgery, University of Virginia, Charlottesville, Virginia 22903, USA
| | - Bowen Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xinyu Lv
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Qi Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Yong Guan
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Xiaofei Zhang
- Center for Translational Medicine, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Guoliang Wang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Wenming Pan
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Peng Xu
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
| | - Hui Wang
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan 430022, China
- Department of Medical Genetics, Basic School of Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Jinxiang Zhang
- Department of Emergency Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430022, China
- Key Laboratory of Anesthesiology and Resuscitation, Huazhong University of Science and Technology, Ministry of Education, Wuhan 430022, China
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11
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Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
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12
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Huillet M, Lasserre F, Gratacap MP, Engelmann B, Bruse J, Polizzi A, Fougeray T, Martin CMP, Rives C, Fougerat A, Naylies C, Lippi Y, Garcia G, Rousseau-Bacquie E, Canlet C, Debrauwer L, Rolle-Kampczyk U, von Bergen M, Payrastre B, Boutet-Robinet E, Gamet-Payrastre L, Guillou H, Loiseau N, Ellero-Simatos S. Pharmacological activation of constitutive androstane receptor induces female-specific modulation of hepatic metabolism. JHEP Rep 2024; 6:100930. [PMID: 38149074 PMCID: PMC10749885 DOI: 10.1016/j.jhepr.2023.100930] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/17/2023] [Revised: 09/25/2023] [Accepted: 09/27/2023] [Indexed: 12/28/2023] Open
Abstract
Background & Aims The constitutive androstane receptor (CAR) is a nuclear receptor that binds diverse xenobiotics and whose activation leads to the modulation of the expression of target genes involved in xenobiotic detoxification and energy metabolism. Although CAR hepatic activity is considered to be higher in women than in men, its sex-dependent response to an acute pharmacological activation has seldom been investigated. Methods The hepatic transcriptome, plasma markers, and hepatic metabolome, were analysed in Car+/+ and Car-/- male and female mice treated either with the CAR-specific agonist 1,4-bis[2-(3,5-dichloropyridyloxy)]benzene (TCPOBOP) or with vehicle. Results Although 90% of TCPOBOP-sensitive genes were modulated in a sex-independent manner, the remaining 10% showed almost exclusive female liver specificity. These female-specific CAR-sensitive genes were mainly involved in xenobiotic metabolism, inflammation, and extracellular matrix organisation. CAR activation also induced higher hepatic oxidative stress and hepatocyte cytolysis in females than in males. Hepatic expression of flavin monooxygenase 3 (Fmo3) was almost abolished and was associated with a decrease in hepatic trimethylamine-N-oxide (TMAO) concentration in TCPOBOP-treated females. In line with a potential role in the control of TMAO homeostasis, CAR activation decreased platelet hyper-responsiveness in female mice supplemented with dietary choline. Conclusions More than 10% of CAR-sensitive genes are sex-specific and influence hepatic and systemic responses such as platelet aggregation. CAR activation may be an important mechanism of sexually-dimorphic drug-induced liver injury. Impact and implications CAR is activated by many drugs and pollutants. Its pharmacological activation had a stronger impact on hepatic gene expression and metabolism in females than in males, and had a specific impact on liver toxicity and trimethylamine metabolism. Sexual dimorphism should be considered when testing and/or prescribing xenobiotics known to activate CAR.
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Affiliation(s)
- Marine Huillet
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Frédéric Lasserre
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Marie-Pierre Gratacap
- INSERM, UMR-1297 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), CHU-Rangueil, Toulouse, France
| | - Beatrice Engelmann
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Justine Bruse
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Arnaud Polizzi
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Tiffany Fougeray
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Céline Marie Pauline Martin
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Clémence Rives
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Anne Fougerat
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Claire Naylies
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Yannick Lippi
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Géraldine Garcia
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Elodie Rousseau-Bacquie
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Cécile Canlet
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Laurent Debrauwer
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Ulrike Rolle-Kampczyk
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Martin von Bergen
- Department of Molecular Systems Biology, Helmholtz Centre for Environmental Research, Leipzig, Germany
| | - Bernard Payrastre
- INSERM, UMR-1297 and Université Toulouse III, Institut de Maladies Métaboliques et Cardiovasculaires (I2MC), CHU-Rangueil, Toulouse, France
- Laboratoire d’Hématologie, CHU de Toulouse, Toulouse, France
| | - Elisa Boutet-Robinet
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Laurence Gamet-Payrastre
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Hervé Guillou
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Nicolas Loiseau
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
| | - Sandrine Ellero-Simatos
- Toxalim (Research Centre in Food Toxicology), INRAE, ENVT, INP-Purpan, UPS, Université de Toulouse, Toulouse, France
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13
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Lan H, Zhang Y, Fan M, Wu B, Wang C. Pregnane X receptor as a therapeutic target for cholestatic liver injury. Drug Metab Rev 2023; 55:371-387. [PMID: 37593784 DOI: 10.1080/03602532.2023.2248680] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/11/2023] [Accepted: 08/02/2023] [Indexed: 08/19/2023]
Abstract
Cholestatic liver injury (CLI) is caused by toxic bile acids (BAs) accumulation in the liver and can lead to inflammation and liver fibrosis. The mechanisms underlying CLI development remain unclear, and this disease has no effective cure. However, regulating BA synthesis and homeostasis represents a promising therapeutic strategy for CLI treatment. Pregnane X receptor (PXR) plays an essential role in the metabolism of endobiotics and xenobiotics via the transcription of metabolic enzymes and transporters, which can ultimately modulate BA homeostasis and exert anticholestatic effects. Furthermore, recent studies have demonstrated that PXR exhibits antifibrotic and anti-inflammatory properties, providing novel insights into treating CLI. Meanwhile, several drugs have been identified as PXR agonists that improve CLI. Nevertheless, the precise role of PXR in CLI still needs to be fully understood. This review summarizes how PXR improves CLI by ameliorating cholestasis, inhibiting inflammation, and reducing fibrosis and discusses the progress of promising PXR agonists for treating CLI.
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Affiliation(s)
- Huan Lan
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Ying Zhang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Minqi Fan
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Bingxin Wu
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
| | - Caiyan Wang
- International Institute for Translational Chinese Medicine, Guangzhou University of Chinese Medicine, Guangzhou, P.R. China
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14
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Grama A, Mititelu A, Sîrbe C, Benţa G, Pop TL. Immune-mediated cholangiopathies in children: the need to better understand the pathophysiology for finding the future possible treatment targets. Front Immunol 2023; 14:1206025. [PMID: 37928553 PMCID: PMC10623351 DOI: 10.3389/fimmu.2023.1206025] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2023] [Accepted: 09/28/2023] [Indexed: 11/07/2023] Open
Abstract
Cholangiopathies are defined as focal or extensive damage of the bile ducts. According to the pathogenetic mechanism, it may be immune-mediated or due to genetic, infectious, toxic, vascular, and obstructive causes. Their chronic evolution is characterized by inflammation, obstruction of bile flow, cholangiocyte proliferation, and progression toward fibrosis and cirrhosis. Immune-mediated cholangiopathies comprise primary sclerosing cholangitis (PSC), autoimmune cholangitis and IgG4-associated cholangitis in adults and biliary atresia (BA), neonatal sclerosing cholangitis (NSC) in children. The main purpose of this narrative review was to highlight the similarities and differences among immune-mediated cholangiopathies, especially those frequent in children in which cholangiocyte senescence plays a key role (BA, NSC, and PSC). These three entities have many similarities in terms of clinical and histopathological manifestations, and the distinction between them can be hard to achieve. In BA, bile duct destruction occurs due to aggression of the biliary cells due to viral infections or toxins during the intrauterine period or immediately after birth. The consequence is the activation of the immune system leading to severe inflammation and fibrosis of the extrahepatic biliary tract, lumen stenosis, and impairment of the biliary flow. PSC is characterized by inflammation and fibrosis of intra- and extrahepatic bile ducts, leading to secondary biliary cirrhosis. It is a multifactorial disease that occurs because of genetic predisposition [human leukocyte antigen (HLA) and non-HLA haplotypes], autoimmunity (cellular immune response, autoantibodies, association with inflammatory bowel disease), environmental factors (infections or toxic bile), and host factors (intestinal microbiota). NSC seems to be a distinct subgroup of childhood PSC that appears due to the interaction between genetic predisposition (HLA B8 and DR3) and the disruption of the immune system, validated by elevated IgG levels or specific antibodies [antinuclear antibody (ANA), anti-smooth muscle antibody (ASMA)]. Currently, the exact mechanism of immune cholangiopathy is not fully understood, and further data are required to identify individuals at high risk of developing these conditions. A better understanding of the immune mechanisms and pathophysiology of BA, NSC, and PSC will open new perspectives for future treatments and better methods of preventing severe evolution.
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Affiliation(s)
- Alina Grama
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Alexandra Mititelu
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Claudia Sîrbe
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Gabriel Benţa
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
| | - Tudor Lucian Pop
- 2Pediatric Discipline, Department of Mother and Child, Iuliu Hatieganu University of Medicine and Pharmacy, Cluj-Napoca, Romania
- 2Pediatric Clinic and Center of Expertise in Pediatric Liver Rare Disorders, Emergency Clinical Hospital for Children, Cluj-Napoca, Romania
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Fan S, Yan Y, Xia Y, Zhou Z, Luo L, Zhu M, Han Y, Yao D, Zhang L, Fang M, Peng L, Yu J, Liu Y, Gao X, Guan H, Li H, Wang C, Wu X, Zhu H, Cao Y, Huang C. Pregnane X receptor agonist nomilin extends lifespan and healthspan in preclinical models through detoxification functions. Nat Commun 2023; 14:3368. [PMID: 37291126 PMCID: PMC10250385 DOI: 10.1038/s41467-023-39118-9] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Accepted: 05/31/2023] [Indexed: 06/10/2023] Open
Abstract
Citrus fruit has long been considered a healthy food, but its role and detailed mechanism in lifespan extension are not clear. Here, by using the nematode C. elegans, we identified that nomilin, a bitter-taste limoloid that is enriched in citrus, significantly extended the animals' lifespan, healthspan, and toxin resistance. Further analyses indicate that this ageing inhibiting activity depended on the insulin-like pathway DAF-2/DAF-16 and nuclear hormone receptors NHR-8/DAF-12. Moreover, the human pregnane X receptor (hPXR) was identified as the mammalian counterpart of NHR-8/DAF-12 and X-ray crystallography showed that nomilin directly binds with hPXR. The hPXR mutations that prevented nomilin binding blocked the activity of nomilin both in mammalian cells and in C. elegans. Finally, dietary nomilin supplementation improved healthspan and lifespan in D-galactose- and doxorubicin-induced senescent mice as well as in male senescence accelerated mice prone 8 (SAMP8) mice, and induced a longevity gene signature similar to that of most longevity interventions in the liver of bile-duct-ligation male mice. Taken together, we identified that nomilin may extend lifespan and healthspan in animals via the activation of PXR mediated detoxification functions.
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Affiliation(s)
- Shengjie Fan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Yingxuan Yan
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Xia
- Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Shanghai, 200125, China
| | - Zhenyu Zhou
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lingling Luo
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Mengnan Zhu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- CAS Center for Excellence in Molecular Cell Science; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yongli Han
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Deqiang Yao
- iHuman Institute, ShanghaiTech University, Shanghai, 201210, China
| | - Lijun Zhang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Minglv Fang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Lina Peng
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China
- CAS Center for Excellence in Molecular Cell Science; Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, Shanghai; University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jing Yu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Ying Liu
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaoyan Gao
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huida Guan
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Hongli Li
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Changhong Wang
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Xiaojun Wu
- Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Huanhu Zhu
- School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China.
| | - Yu Cao
- Department of Orthopaedics, Shanghai Key Laboratory of Orthopaedic Implant, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China.
- Institute of Precision Medicine, the Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, 115 Jinzun Road, Shanghai, 200125, China.
| | - Cheng Huang
- School of Pharmacy, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China.
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Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2023; 21:236-247. [PMID: 36253479 DOI: 10.1038/s41579-022-00805-x] [Citation(s) in RCA: 356] [Impact Index Per Article: 178.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/08/2022]
Abstract
Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.
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Affiliation(s)
- Stephanie L Collins
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - Jonathan G Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Public Health Sciences, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Health Liver Center, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jordan E Bisanz
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - C Denise Okafor
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
- Department of Chemistry, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
- Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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17
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Wang J, Lu P, Xie W. Atypical functions of xenobiotic receptors in lipid and glucose metabolism. MEDICAL REVIEW (2021) 2022; 2:611-624. [PMID: 36785576 PMCID: PMC9912049 DOI: 10.1515/mr-2022-0032] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/30/2022] [Accepted: 11/08/2022] [Indexed: 12/02/2022]
Abstract
Xenobiotic receptors are traditionally defined as xenobiotic chemical-sensing receptors, the activation of which transcriptionally regulates the expression of enzymes and transporters involved in the metabolism and disposition of xenobiotics. Emerging evidence suggests that "xenobiotic receptors" also have diverse endobiotic functions, including their effects on lipid metabolism and energy metabolism. Dyslipidemia is a major risk factor for cardiovascular disease, diabetes, obesity, metabolic syndrome, stroke, nonalcoholic fatty liver disease (NAFLD), and nonalcoholic steatohepatitis (NASH). Understanding the molecular mechanism by which transcriptional factors, including the xenobiotic receptors, regulate lipid homeostasis will help to develop preventive and therapeutic approaches. This review describes recent advances in our understanding the atypical roles of three xenobiotic receptors: aryl hydrocarbon receptor (AhR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR), in metabolic disorders, with a particular focus on their effects on lipid and glucose metabolism. Collectively, the literatures suggest the potential values of AhR, PXR and CAR as therapeutic targets for the treatment of NAFLD, NASH, obesity and diabetes, and cardiovascular diseases.
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Affiliation(s)
- Jingyuan Wang
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peipei Lu
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wen Xie
- Center for Pharmacogenetics and Department of Pharmaceutical Sciences, University of Pittsburgh, Pittsburgh, PA, USA
- Department of Pharmacology and Chemical Biology, University of Pittsburgh, Pittsburgh, PA, USA
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18
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Bertolini A, Fiorotto R, Strazzabosco M. Bile acids and their receptors: modulators and therapeutic targets in liver inflammation. Semin Immunopathol 2022; 44:547-564. [PMID: 35415765 PMCID: PMC9256560 DOI: 10.1007/s00281-022-00935-7] [Citation(s) in RCA: 41] [Impact Index Per Article: 13.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022]
Abstract
Bile acids participate in the intestinal emulsion, digestion, and absorption of lipids and fat-soluble vitamins. When present in high concentrations, as in cholestatic liver diseases, bile acids can damage cells and cause inflammation. After the discovery of bile acids receptors about two decades ago, bile acids are considered signaling molecules. Besides regulating bile acid, xenobiotic, and nutrient metabolism, bile acids and their receptors have shown immunomodulatory properties and have been proposed as therapeutic targets for inflammatory diseases of the liver. This review focuses on bile acid-related signaling pathways that affect inflammation in the liver and provides an overview of the preclinical and clinical applications of modulators of these pathways for the treatment of cholestatic and autoimmune liver diseases.
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Affiliation(s)
- Anna Bertolini
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA
- Department of Pediatrics, Section of Molecular Metabolism and Nutrition, University Medical Center Groningen, Groningen, The Netherlands
| | - Romina Fiorotto
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA
| | - Mario Strazzabosco
- Section of Digestive Diseases, Yale Liver Center, Yale School of Medicine, PO Box 208019, New Haven, CT, 06520-8019, USA.
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19
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Stern S, Kurian R, Wang H. Clinical Relevance of the Constitutive Androstane Receptor. Drug Metab Dispos 2022; 50:1010-1018. [PMID: 35236665 PMCID: PMC11022901 DOI: 10.1124/dmd.121.000483] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Accepted: 02/10/2022] [Indexed: 11/22/2022] Open
Abstract
Constitutive androstane receptor (CAR) (NR1I3), a xenobiotic receptor, has long been considered a master mediator of drug disposition and detoxification. Accumulating evidence indicates that CAR also participates in various physiologic and pathophysiological pathways regulating the homeostasis of glucose, lipid, and bile acids, and contributing to cell proliferation, tissue regeneration and repair, as well as cancer development. The expression and activity of CAR can be regulated by various factors, including small molecular modulators, CAR interaction with other transcription factors, and naturally occurring genetic variants. Given that the influence of CAR has extended beyond the realm of drug metabolism and disposition and has expanded into a potential modulator of human diseases, growing efforts have centered on understanding its clinical relevance and impact on human pathophysiology. This review highlights the current information available regarding the contribution of CAR to various metabolic disorders and cancers and ponders the possible challenges that might arise from pursuing CAR as a potential therapeutic target for these diseases. SIGNIFICANCE STATEMENT: The growing importance of the constitutive androstane receptor (CAR) in glucose and lipid metabolism as well as its potential implication in cell proliferation emphasizes a need to keenly understand the biological function and clinical impact of CAR. This minireview captures the clinical relevance of CAR by highlighting its role in metabolic disorders and cancer development.
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Affiliation(s)
- Sydney Stern
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland
| | - Ritika Kurian
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland
| | - Hongbing Wang
- Department of Pharmaceutical Sciences, University of Maryland School of Pharmacy, Baltimore, Maryland
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20
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Keely SJ, Urso A, Ilyaskin AV, Korbmacher C, Bunnett NW, Poole DP, Carbone SE. Contributions of bile acids to gastrointestinal physiology as receptor agonists and modifiers of ion channels. Am J Physiol Gastrointest Liver Physiol 2022; 322:G201-G222. [PMID: 34755536 PMCID: PMC8782647 DOI: 10.1152/ajpgi.00125.2021] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2021] [Revised: 10/28/2021] [Accepted: 11/08/2021] [Indexed: 02/03/2023]
Abstract
Bile acids (BAs) are known to be important regulators of intestinal motility and epithelial fluid and electrolyte transport. Over the past two decades, significant advances in identifying and characterizing the receptors, transporters, and ion channels targeted by BAs have led to exciting new insights into the molecular mechanisms involved in these processes. Our appreciation of BAs, their receptors, and BA-modulated ion channels as potential targets for the development of new approaches to treat intestinal motility and transport disorders is increasing. In the current review, we aim to summarize recent advances in our knowledge of the different BA receptors and BA-modulated ion channels present in the gastrointestinal system. We discuss how they regulate motility and epithelial transport, their roles in pathogenesis, and their therapeutic potential in a range of gastrointestinal diseases.
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Affiliation(s)
- Stephen J Keely
- Royal College of Surgeons in Ireland, Education and Research Centre, Beaumont Hospital, Dublin, Ireland
| | - Andreacarola Urso
- Department of Surgery, Vagelos College of Physicians and Surgeons, Columbia University, New York, New York
- Department of Pharmacology, Columbia University, New York, New York
| | - Alexandr V Ilyaskin
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Christoph Korbmacher
- Institute of Cellular and Molecular Physiology, Friedrich-Alexander University Erlangen-Nürnberg, Bavaria, Germany
| | - Nigel W Bunnett
- Department of Molecular Pathobiology, Neuroscience Institute, New York University, New York, New York
- Department of Neuroscience and Physiology, Neuroscience Institute, New York University, New York, New York
| | - Daniel P Poole
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
| | - Simona E Carbone
- Drug Discovery Biology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
- Australian Research Council, Centre of Excellence in Convergent Bio-Nano Science and Technology, Monash Institute of Pharmaceutical Sciences, Monash University, Parkville, Victoria, Australia
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21
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Şehirli AÖ, Kökeş A, Velioğlu-Öğünç A, Tetik Ş, Özkan N, Çetinel Ş, Sayıner S, Dülger G. The Effects of Spironolactone in Preventing Bile Duct Ligation-induced Hepatitis in A Rat Model. IRANIAN JOURNAL OF PHARMACEUTICAL RESEARCH : IJPR 2021; 20:35-44. [PMID: 34567144 PMCID: PMC8457727 DOI: 10.22037/ijpr.2020.112488.13786] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/18/2022]
Abstract
Cholestasis is associated with the accumulation of bile acids and bilirubin in the hepatocytes and leads to liver injury. Pregnane X Receptor (PXR) coordinates protective hepatic responses to toxic stimuli, and this receptor was reported to stimulate bile secretion by increasing MRP2 expression. Since PXR activators were reported to be anti-inflammatory in the liver, PXR was proposed as a drug target for the treatment of chronic inflammatory liver diseases. We investigated the potential protective effect of spironolactone (SPL), an enzyme inducer, in hepatotoxicity induced by bile duct ligation in rats. Wistar Albino (250-300 g) rats were divided into the control group and the bile duct ligated (BDL) group. BDL group was divided into three subgroups; following BDL, for 3 days, the first group received propylene glycol (vehicle of SPL) (blinded), the second subgroup received spironolactone (SPL) (200 mg/kg oral), and the third subgroup received SPL for 3 days, starting 3 days after the bile duct ligation, in order to investigate if it has a healing effect after hepatitis had developed. The control group was sham-operated and received saline. At the end of the experiment, blood and tissue samples were collected. Serum TNF-α, NF-ĸB, bilirubin, IL-6 levels, ALT, AST, ALP activities and tissue MPO activity and oxidant damage increased after the bile duct ligation was significantly decreased following SPL administration. PXR and MRP2 activity showed an increase in the hepatocytes as a result of the treatment. In conclusion, it was observed that SPL administration significantly decreases liver inflammation and damage related to BDL.
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Affiliation(s)
- Ahmet Özer Şehirli
- Department of Pharmacology, Faculty of Dentistry, Near East University, 99138 Nicosia, North Cyprus, Mersin 10, Turkey
| | - Azime Kökeş
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34722 Istanbul, Turkey
| | - Ayliz Velioğlu-Öğünç
- Vocational School of Health-Related Professions, Marmara University, 34722 Istanbul, Turkey
| | - Şermin Tetik
- Department of Biochemistry, Faculty of Pharmacy, Marmara University, 34722 Istanbul, Turkey
| | - Naziye Özkan
- Department of Histology and Embryology, School of Medicine, Marmara University, 34722 Istanbul, Turkey
| | - Şule Çetinel
- Department of Histology and Embryology, School of Medicine, Marmara University, 34722 Istanbul, Turkey
| | - Serkan Sayıner
- Department of Biochemistry, Faculty of Veterinary Medicine, Near East University, 99138 Nicosia, North Cyprus, Mersin 10, Turkey
| | - Gül Dülger
- Department of Pharmacology, Faculty of Pharmacy, Marmara University, 34722 Istanbul, Turkey
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22
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Orozco-Aguilar J, Simon F, Cabello-Verrugio C. Redox-Dependent Effects in the Physiopathological Role of Bile Acids. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:4847941. [PMID: 34527174 PMCID: PMC8437588 DOI: 10.1155/2021/4847941] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/06/2021] [Accepted: 08/17/2021] [Indexed: 12/17/2022]
Abstract
Bile acids (BA) are recognized by their role in nutrient absorption. However, there is growing evidence that BA also have endocrine and metabolic functions. Besides, the steroidal-derived structure gives BA a toxic potential over the biological membrane. Thus, cholestatic disorders, characterized by elevated BA on the liver and serum, are a significant cause of liver transplant and extrahepatic complications, such as skeletal muscle, central nervous system (CNS), heart, and placenta. Further, the BA have an essential role in cellular damage, mediating processes such as membrane disruption, mitochondrial dysfunction, and the generation of reactive oxygen species (ROS) and oxidative stress. The purpose of this review is to describe the BA and their role on hepatic and extrahepatic complications in cholestatic diseases, focusing on the association between BA and the generation of oxidative stress that mediates tissue damage.
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Affiliation(s)
- Josué Orozco-Aguilar
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
| | - Felipe Simon
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Millennium Nucleus of Ion Channel-Associated Diseases (MiNICAD), Universidad de Chile, Santiago 8370146, Chile
- Laboratory of Integrative Physiopathology, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Department of Biological Sciences, Faculty of Life Sciences, Universidad Andres Bello, Santiago 8370146, Chile
- Millennium Institute on Immunology and Immunotherapy, Santiago 8370146, Chile
- Center for the Development of Nanoscience and Nanotechnology (CEDENNA), Universidad de Santiago de Chile, Santiago 8350709, Chile
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23
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Sultana H, Komai M, Shirakawa H. The Role of Vitamin K in Cholestatic Liver Disease. Nutrients 2021; 13:nu13082515. [PMID: 34444675 PMCID: PMC8400302 DOI: 10.3390/nu13082515] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Revised: 07/14/2021] [Accepted: 07/21/2021] [Indexed: 12/13/2022] Open
Abstract
Vitamin K (VK) is a ligand of the pregnane X receptor (PXR), which plays a critical role in the detoxification of xenobiotics and metabolism of bile acids. VK1 may reduce the risk of death in patients with chronic liver failure. VK deficiency is associated with intrahepatic cholestasis, and is already being used as a drug for cholestasis-induced liver fibrosis in China. In Japan, to treat osteoporosis in patients with primary biliary cholangitis, VK2 formulations are prescribed, along with vitamin D3. Animal studies have revealed that after bile duct ligation-induced cholestasis, PXR knockout mice manifested more hepatic damage than wild-type mice. Ligand-mediated activation of PXR improves biochemical parameters. Rifampicin is a well-known human PXR ligand that has been used to treat intractable pruritus in severe cholestasis. In addition to its anti-cholestatic properties, PXR has anti-fibrotic and anti-inflammatory effects. However, because of the scarcity of animal studies, the mechanism of the effect of VK on cholestasis-related liver disease has not yet been revealed. Moreover, the application of VK in cholestasis-related diseases is controversial. Considering this background, the present review focuses on the effect of VK in cholestasis-related diseases, emphasizing its function as a modulator of PXR.
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Affiliation(s)
- Halima Sultana
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Michio Komai
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
| | - Hitoshi Shirakawa
- Laboratory of Nutrition, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan; (H.S.); (M.K.)
- International Education and Research Center for Food Agricultural Immunology, Graduate School of Agricultural Science, Tohoku University, 468-1 Aramaki Aza Aoba, Aoba-ku, Sendai 980-8572, Japan
- Correspondence: ; Tel.: +81-22-757-4402
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24
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Effects of rifampicin on hepatic antioxidant enzymes in PXR and CAR double humanized mice. Mol Cell Toxicol 2021. [DOI: 10.1007/s13273-021-00134-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022]
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25
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Wu S, Lu H, Wang W, Song L, Liu M, Cao Y, Qi X, Sun J, Gong L. Prevention of D-GalN/LPS-induced ALI by 18β-glycyrrhetinic acid through PXR-mediated inhibition of autophagy degradation. Cell Death Dis 2021; 12:480. [PMID: 33986260 PMCID: PMC8119493 DOI: 10.1038/s41419-021-03768-8] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Revised: 04/20/2021] [Accepted: 04/22/2021] [Indexed: 12/26/2022]
Abstract
Acute liver injury (ALI) has multiple causes and results in liver dysfunction. Severe or persistent liver injury eventually leads to liver failure and even death. Pregnane X receptor (PXR)-null mice present more severe liver damage and lower rates of autophagy. 18β-glycyrrhetinic acid (GA) has been proposed as a promising hepatoprotective agent. We hypothesized that GA significantly alleivates D-GalN/LPS-induced ALI, which involved in PXR-mediated autophagy and lysosome biogenesis. We found that GA can significantly decrease hepatocyte apoptosis and increase the hepatic autophagy marker LC3-B. Ad-mCherry-GFP-LC3 tandem fluorescence, RNA-seq and real-time PCR indicated that GA may stabilize autophagosomes and lysosomes and inhibit autophagosome-lysosome fusion. Simultaneously, GA markedly activates PXR, even reversing the D-GalN/LPS-induced reduction of PXR and its downstream genes. In contrast, GA has a weak protective effect in pharmacological inhibition of PXR and PXR-null mice, which significantly affected apoptosis- and autophagy-related genes. PXR knockout interferes with the stability of autophagosomes and lysosomes, preventing GA reducing the expression of lysosomal genes such as Cst B and TPP1, and suppressing autophagy flow. Therefore, we believe that GA increases autophagy by inhibiting autophagosome-lysosome fusion and blocked autophagy flux via activation of PXR. In conclusion, our results show that GA activates PXR to regulate autophagy and lysosome biogenesis, represented by inhibiting autophagosome-lysosome fusion and stabilization of lysosome. These results identify a new mechanism by which GA-dependent PXR activation reduces D-GalN/LPS-induced acute liver injury.
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Affiliation(s)
- Shouyan Wu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Henglei Lu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wenjie Wang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
- Department of Pharmacology, Fudan University, Shanghai, 201203, China
| | - Luyao Song
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Meng Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Yuhan Cao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xinming Qi
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Jianhua Sun
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
| | - Likun Gong
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
- Zhongshan Branch, the Institute of Drug Discovery and Development, Chinese Academy of Sciences, Zhongshan, China.
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26
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Thibaut MM, Sboarina M, Roumain M, Pötgens SA, Neyrinck AM, Destrée F, Gillard J, Leclercq IA, Dachy G, Demoulin JB, Tailleux A, Lestavel S, Rastelli M, Everard A, Cani PD, Porporato PE, Loumaye A, Thissen JP, Muccioli GG, Delzenne NM, Bindels LB. Inflammation-induced cholestasis in cancer cachexia. J Cachexia Sarcopenia Muscle 2021; 12:70-90. [PMID: 33350058 PMCID: PMC7890151 DOI: 10.1002/jcsm.12652] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2020] [Revised: 09/22/2020] [Accepted: 11/02/2020] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Cancer cachexia is a debilitating metabolic syndrome contributing to cancer death. Organs other than the muscle may contribute to the pathogenesis of cancer cachexia. This work explores new mechanisms underlying hepatic alterations in cancer cachexia. METHODS We used transcriptomics to reveal the hepatic gene expression profile in the colon carcinoma 26 cachectic mouse model. We performed bile acid, tissue mRNA, histological, biochemical, and western blot analyses. Two interventional studies were performed using a neutralizing interleukin 6 antibody and a bile acid sequestrant, cholestyramine. Our findings were evaluated in a cohort of 94 colorectal cancer patients with or without cachexia (43/51). RESULTS In colon carcinoma 26 cachectic mice, we discovered alterations in five inflammatory pathways as well as in other pathways, including bile acid metabolism, fatty acid metabolism, and xenobiotic metabolism (normalized enrichment scores of -1.97, -2.16, and -1.34, respectively; all Padj < 0.05). The hepatobiliary transport system was deeply impaired in cachectic mice, leading to increased systemic and hepatic bile acid levels (+1512 ± 511.6 pmol/mg, P = 0.01) and increased hepatic inflammatory cytokines and neutrophil recruitment to the liver of cachectic mice (+43.36 ± 16.01 neutrophils per square millimetre, P = 0.001). Adaptive mechanisms were set up to counteract this bile acid accumulation by repressing bile acid synthesis and by enhancing alternative routes of basolateral bile acid efflux. Targeting bile acids using cholestyramine reduced hepatic inflammation, without affecting the hepatobiliary transporters (e.g. tumour necrosis factor α signalling via NFκB and inflammatory response pathways, normalized enrichment scores of -1.44 and -1.36, all Padj < 0.05). Reducing interleukin 6 levels counteracted the change in expression of genes involved in the hepatobiliary transport, bile acid synthesis, and inflammation. Serum bile acid levels were increased in cachectic vs. non-cachectic cancer patients (e.g. total bile acids, +5.409 ± 1.834 μM, P = 0.026) and were strongly correlated to systemic inflammation (taurochenodeoxycholic acid and C-reactive protein: ρ = 0.36, Padj = 0.017). CONCLUSIONS We show alterations in bile acid metabolism and hepatobiliary secretion in cancer cachexia. In this context, we demonstrate the contribution of systemic inflammation to the impairment of the hepatobiliary transport system and the role played by bile acids in the hepatic inflammation. This work paves the way to a better understanding of the role of the liver in cancer cachexia.
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Affiliation(s)
- Morgane M Thibaut
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Martina Sboarina
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Martin Roumain
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Sarah A Pötgens
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Audrey M Neyrinck
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Florence Destrée
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Justine Gillard
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Isabelle A Leclercq
- Laboratory of Hepato-Gastroenterology, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Guillaume Dachy
- Experimental Medicine Unit, de Duve Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Jean-Baptiste Demoulin
- Experimental Medicine Unit, de Duve Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Anne Tailleux
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Sophie Lestavel
- Université de Lille, Inserm, CHU Lille, Institut Pasteur de Lille, U1011-EGID, Lille, France
| | - Marialetizia Rastelli
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Amandine Everard
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Patrice D Cani
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium.,Walloon Excellence in Life Sciences and BIOtechnology (WELBIO), Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Paolo E Porporato
- Department of Molecular Biotechnology and Health Science, Molecular Biotechnology Center, University of Turin, Turin, Italy
| | - Audrey Loumaye
- Endocrinology, Diabetology and Nutrition Department, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Jean-Paul Thissen
- Endocrinology, Diabetology and Nutrition Department, Institut de Recherche Expérimentale et Clinique, UCLouvain, Université catholique de Louvain, Cliniques Universitaires Saint-Luc, Brussels, Belgium
| | - Giulio G Muccioli
- Bioanalysis and Pharmacology of Bioactive Lipids Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Nathalie M Delzenne
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
| | - Laure B Bindels
- Metabolism and Nutrition Research Group, Louvain Drug Research Institute, UCLouvain, Université catholique de Louvain, Brussels, Belgium
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27
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Isaeva MK, Belova VA, Korostin DO, Degtyareva AV. Genetic aspects of biliary atresia etiology. BULLETIN OF RUSSIAN STATE MEDICAL UNIVERSITY 2020. [DOI: 10.24075/brsmu.2020.069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Biliary atresia (BA) is a cholestatic disorder of infancy that is fatal if untreated. Despite years of study the etiology of BA remains unknown. Three etiopathogenic mechanisms may be involved, such as immune dysregulation, environmental factors and genetic susceptibility. Genetic predisposition is being actively studied. Candidate genes associated with BA in certain populations, genes affecting the cholangiocyte cilia function, as well as genes involved in stress responses have been identified. However, the long-term follow-up of twins with BA suggests that genotype is not of paramount importance for the disease development. Both epigenetic patterns and postzygotic somatic mutations may contribute to etiology of the disease. Recently, some evidence is being accumulated on the possible genetic predisposition to certain outcome of Kasai portoenterostomy performed in patients with BA. However, the presence of a number of factors contributing to the development of the disease makes it difficult to identify the genetic markers.
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Affiliation(s)
- MKh Isaeva
- Academician V. I. Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia
| | - VA Belova
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - DO Korostin
- Pirogov Russian National Research Medical University, Moscow, Russia
| | - AV Degtyareva
- Academician V. I. Kulakov Research Center for Obstetrics, Gynecology and Perinatology, Moscow, Russia; I. M. Sechenov First Moscow State Medical University, Moscow, Russia
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Küblbeck J, Niskanen J, Honkakoski P. Metabolism-Disrupting Chemicals and the Constitutive Androstane Receptor CAR. Cells 2020; 9:E2306. [PMID: 33076503 PMCID: PMC7602645 DOI: 10.3390/cells9102306] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2020] [Revised: 10/13/2020] [Accepted: 10/13/2020] [Indexed: 02/07/2023] Open
Abstract
During the last two decades, the constitutive androstane receptor (CAR; NR1I3) has emerged as a master activator of drug- and xenobiotic-metabolizing enzymes and transporters that govern the clearance of both exogenous and endogenous small molecules. Recent studies indicate that CAR participates, together with other nuclear receptors (NRs) and transcription factors, in regulation of hepatic glucose and lipid metabolism, hepatocyte communication, proliferation and toxicity, and liver tumor development in rodents. Endocrine-disrupting chemicals (EDCs) constitute a wide range of persistent organic compounds that have been associated with aberrations of hormone-dependent physiological processes. Their adverse health effects include metabolic alterations such as diabetes, obesity, and fatty liver disease in animal models and humans exposed to EDCs. As numerous xenobiotics can activate CAR, its role in EDC-elicited adverse metabolic effects has gained much interest. Here, we review the key features and mechanisms of CAR as a xenobiotic-sensing receptor, species differences and selectivity of CAR ligands, contribution of CAR to regulation hepatic metabolism, and evidence for CAR-dependent EDC action therein.
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Affiliation(s)
- Jenni Küblbeck
- A.I. Virtanen Institute for Molecular Sciences, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
| | - Jonna Niskanen
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
| | - Paavo Honkakoski
- School of Pharmacy, University of Eastern Finland, P.O. Box 1627, FI-70210 Kuopio, Finland;
- Division of Pharmacotherapy and Experimental Therapeutics, Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Campus Box 7569, Chapel Hill, NC 27599-7569, USA
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29
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Hui Y, Wang X, Yu Z, Fan X, Cui B, Zhao T, Mao L, Feng H, Lin L, Yu Q, Zhang J, Wang B, Chen X, Zhao X, Sun C. Scoparone as a therapeutic drug in liver diseases: Pharmacology, pharmacokinetics and molecular mechanisms of action. Pharmacol Res 2020; 160:105170. [DOI: 10.1016/j.phrs.2020.105170] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 08/13/2020] [Accepted: 08/19/2020] [Indexed: 02/06/2023]
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30
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Yang M, Pan H, Chen H, Liu W, Lu L, He X, Yi H, Tang S. Association between NR1I2 polymorphisms and susceptibility to anti-tuberculosis drug-induced hepatotoxicity in an Eastern Chinese Han population: A case-control study. INFECTION GENETICS AND EVOLUTION 2020; 83:104349. [DOI: 10.1016/j.meegid.2020.104349] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/09/2020] [Revised: 04/23/2020] [Accepted: 04/29/2020] [Indexed: 12/19/2022]
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31
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Lucchinetti E, Lou PH, Wawrzyniak P, Wawrzyniak M, Scharl M, Holtzhauer GA, Krämer SD, Hersberger M, Rogler G, Zaugg M. Novel Strategies to Prevent Total Parenteral Nutrition-Induced Gut and Liver Inflammation, and Adverse Metabolic Outcomes. Mol Nutr Food Res 2020; 65:e1901270. [PMID: 32359213 DOI: 10.1002/mnfr.201901270] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2019] [Revised: 04/09/2020] [Indexed: 12/15/2022]
Abstract
Total parenteral nutrition (TPN) is a life-saving therapy administered to millions of patients. However, it is associated with significant adverse effects, namely liver injury, risk of infections, and metabolic derangements. In this review, the underlying causes of TPN-associated adverse effects, specifically gut atrophy, dysbiosis of the intestinal microbiome, leakage of the epithelial barrier with bacterial invasion, and inflammation are first described. The role of the bile acid receptors farnesoid X receptor and Takeda G protein-coupled receptor, of pleiotropic hormones, and growth factors is highlighted, and the mechanisms of insulin resistance, namely the lack of insulinotropic and insulinomimetic signaling of gut-originating incretins as well as the potentially toxicity of phytosterols and pro-inflammatory fatty acids mainly released from soybean oil-based lipid emulsions, are discussed. Finally, novel approaches in the design of next generation lipid delivery systems are proposed. Propositions include modifying the physicochemical properties of lipid emulsions, the use of lipid emulsions generated from sustainable oils with favorable ratios of anti-inflammatory n-3 to pro-inflammatory n-6 fatty acids, beneficial adjuncts to TPN, and concomitant pharmacotherapies to mitigate TPN-associated adverse effects.
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Affiliation(s)
- Eliana Lucchinetti
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Phing-How Lou
- Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
| | - Paulina Wawrzyniak
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Marcin Wawrzyniak
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Gregory A Holtzhauer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Stefanie D Krämer
- Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, ETH Zurich, Zurich, 8093, Switzerland
| | - Martin Hersberger
- Division of Clinical Chemistry and Biochemistry, Children's Hospital Zurich, Zurich, 8032, Switzerland
| | - Gerhard Rogler
- Department of Gastroenterology and Hepatology, University Hospital Zurich, Zurich, 8091, Switzerland
| | - Michael Zaugg
- Department of Anesthesiology and Pain Medicine and Cardiovascular Research Centre, University of Alberta, Edmonton, T6G 2R3, Canada.,Department of Pharmacology, University of Alberta, Edmonton, T6G 2R3, Canada
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32
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Tardelli M, Bruschi FV, Fuchs CD, Claudel T, Auer N, Kunczer V, Baumgartner M, A.H.O. Ronda O, Verkade HJ, Stojakovic T, Scharnagl H, Habib A, Zimmermann R, Lotersztajn S, Trauner M. Monoacylglycerol Lipase Inhibition Protects From Liver Injury in Mouse Models of Sclerosing Cholangitis. Hepatology 2020; 71:1750-1765. [PMID: 31505038 PMCID: PMC7317927 DOI: 10.1002/hep.30929] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 08/29/2019] [Indexed: 12/19/2022]
Abstract
BACKGROUND AND AIMS Monoacylglycerol lipase (MGL) is the last enzymatic step in triglyceride degradation, hydrolyzing monoglycerides into glycerol and fatty acids (FAs) and converting 2-arachidonoylglycerol into arachidonic acid, thus providing ligands for nuclear receptors as key regulators of hepatic bile acid (BA)/lipid metabolism and inflammation. We aimed to explore the role of MGL in the development of cholestatic liver and bile duct injury in mouse models of sclerosing cholangitis, a disease so far lacking effective pharmacological therapy. APPROACH AND RESULTS To this aim we analyzed the effects of 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC) feeding to induce sclerosing cholangitis in wild-type (WT) and knockout (MGL-/- ) mice and tested pharmacological inhibition with JZL184 in the multidrug resistance protein 2 knockout (Mdr2-/- ) mouse model of sclerosing cholangitis. Cholestatic liver injury and fibrosis were assessed by serum biochemistry, liver histology, gene expression, and western blot characterization of BA and FA synthesis/transport. Moreover, intestinal FAs and fecal microbiome were analyzed. Transfection and silencing were performed in Caco2 cells. MGL-/- mice were protected from DDC-induced biliary fibrosis and inflammation with reduced serum liver enzymes and increased FA/BA metabolism and β-oxidation. Notably, pharmacological (JZL184) inhibition of MGL ameliorated cholestatic injury in DDC-fed WT mice and protected Mdr2-/- mice from spontaneous liver injury, with improved liver enzymes, inflammation, and biliary fibrosis. In vitro experiments confirmed that silencing of MGL decreases prostaglandin E2 accumulation in the intestine and up-regulates peroxisome proliferator-activated receptors alpha and gamma activity, thus reducing inflammation. CONCLUSIONS Collectively, our study unravels MGL as a metabolic target, demonstrating that MGL inhibition may be considered as potential therapy for sclerosing cholangitis.
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Affiliation(s)
- Matteo Tardelli
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Francesca V. Bruschi
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Claudia D. Fuchs
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thierry Claudel
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Nicole Auer
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Victoria Kunczer
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Maximilian Baumgartner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Onne A.H.O. Ronda
- Center for Liver, Digestive and Metabolic DiseasesDepartments of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Henk Jan Verkade
- Center for Liver, Digestive and Metabolic DiseasesDepartments of PediatricsUniversity Medical Center GroningenUniversity of GroningenGroningenthe Netherlands
| | - Tatjana Stojakovic
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsUniversity Hospital GrazGrazAustria
| | - Hubert Scharnagl
- Clinical Institute of Medical and Chemical Laboratory DiagnosticsMedical University of GrazGrazAustria
| | - Aida Habib
- Université de ParisCentre de Recherche sur l'InflammationINSERMUMR1149CNRSERL 8252ParisFrance
- Department of Biochemistry and Molecular GeneticsAmerican University of BeirutBeirutLebanon
| | | | - Sophie Lotersztajn
- Université de ParisCentre de Recherche sur l'InflammationINSERMUMR1149CNRSERL 8252ParisFrance
| | - Michael Trauner
- Hans Popper Laboratory of Molecular HepatologyDivision of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
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33
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Zhao L, Chen F, Zhang Y, Yue L, Guo H, Ye G, Shi F, Lv C, Jing B, Tang H, Yin Z, Fu H, Lin J, Li Y, Wang X. Involvement of P450s and nuclear receptors in the hepatoprotective effect of quercetin on liver injury by bacterial lipopolysaccharide. Immunopharmacol Immunotoxicol 2020; 42:211-220. [PMID: 32253952 DOI: 10.1080/08923973.2020.1742154] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/24/2022]
Abstract
Objective: Quercetin (Que), a flavonoid, possesses anti-inflammatory and antioxidant properties. It has been shown to protect against liver injury induced by various factors. This study was designed to investigate the underlying mechanism of its protective effect against lipopolysaccharide (LPS)- induced liver damage.Methods: Mice were pretreated with Que for 7 consecutive days and then exposed to LPS. To study the hepatoprotective effect of Que, oxidative stress parameters, inflammatory cytokine levels in liver and serum liver function indexes were examined. Protein and mRNA expression of nuclear orphan receptors and cytochrome P450 enzymes were measured by Western Blotting and qPCR, respectively.Results: Que significantly reduced circulating ALT, AST, ALP, and ameliorated LPS-induced histological alterations. In addition, Que obviously decreased markers of oxidative stress and pro-inflammatory cytokines. Furthermore, Que carried out the hepatoprotective effect via regulation of the expression of nuclear orphan receptors (CAR, PXR) and cytochrome P450 enzymes (CYP1A2, CYP2E1, CYP2D22, CYP3A11).Conclusions: Our findings suggested that Que pretreatment could ameliorate LPS-induced liver injury.
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Affiliation(s)
- Ling Zhao
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Fang Chen
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Yuanli Zhang
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Ling Yue
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Hongrui Guo
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Gang Ye
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Fei Shi
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Cheng Lv
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Bo Jing
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Huaqiao Tang
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Zhongqiong Yin
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Hualin Fu
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Jvchun Lin
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Yinglun Li
- Institute of Animal Veterinary, Sichuan Agricultural University, Chengdu, P. R. China
| | - Xun Wang
- Institute of Animal Genetics and Breeding, College of Animal Science and Technology, Sichuan Agricultural University, Chengdu, P. R. China
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Pham B, Arons AB, Vincent JG, Fernandez EJ, Shen T. Regulatory Mechanics of Constitutive Androstane Receptors: Basal and Ligand-Directed Actions. J Chem Inf Model 2019; 59:5174-5182. [PMID: 31714771 DOI: 10.1021/acs.jcim.9b00695] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Constitutive androstane receptor (CAR) is a nuclear hormone receptor that primarily functions in sensing and metabolizing xenobiotics. The basal activity of this receptor is relatively high, and CAR is deemed active in the absence of ligand. The (over)activation can promote drug toxicity and tumor growth. Thus, therapeutic treatments seek inverse agonists to inhibit or modulate CAR activities. To advance our understanding of the regulatory mechanisms of CAR, we used computational and experimental approaches to elucidate three aspects of CAR activation and inactivation: (1) ligand-dependent actions, (2) ligand-orthologue specificity, and (3) constitutive activity. For ligand-dependent actions, we examined the ligand-bound simulations and identified two sets of ligand-induced contacts promoting CAR activation via coactivator binding (H11-H12 contact) or inactivation via corepressor binding (H4-H11 contact). For orthologue specificity, we addressed a puzzling fact that murine CAR (mCAR) and human CAR (hCAR) respond differently to the same ligand (CITCO), despite their high sequence homology. We found that the helix H7 of hCAR is responsible for a stronger binding of the ligand CITCO compared to mCAR, hence a stronger CITCO-induced activation. For basal activity, we reported computer-generated unliganded CAR structures and critical mutagenesis (mCAR's V209A and N333D) results of a cell-based transcription assay. Our results reveal that the basal conformation of CAR shares prominent features with the agonist-bound form, and helix HX has an important contribution to the constitutive activity. These findings altogether can be useful for the understanding of constitutively active receptors and the design of drug molecules targeting them.
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Affiliation(s)
- Bill Pham
- Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States
| | - Avery Bancroft Arons
- Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States
| | - Jeremy G Vincent
- Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States
| | - Elias J Fernandez
- Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States
| | - Tongye Shen
- Department of Biochemistry & Cellular and Molecular Biology , University of Tennessee , Knoxville , Tennessee 37996 , United States
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Lian W, Liu X, Chen W. TNFα Induces Multidrug Resistance-Associated Protein 4 Expression through p38-E2F1-Nrf2 Signaling in Obstructive Cholestasis. Yonsei Med J 2019; 60:1045-1053. [PMID: 31637886 PMCID: PMC6813138 DOI: 10.3349/ymj.2019.60.11.1045] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/22/2019] [Revised: 07/24/2019] [Accepted: 08/14/2019] [Indexed: 12/15/2022] Open
Abstract
PURPOSE To explore the molecular mechanism of the upregulation of multidrug resistance-associated protein 4 (MRP4) in cholestasis. MATERIALS AND METHODS The mRNA and protein levels of MRP4 in liver samples from cholestatic patients were determined by quantitative real-time PCR and Western blot. In human hepatoma HepG2 cells, electrophoretic mobility shift assay (EMSA) was used to determine the affinity of nuclear factor-E2-related factor (Nrf2) binding to MRP4 promoter. Dual-luciferase reporter assay was used to detect the binding of tumor necrosis factor α (TNFα) to the promotor of E2F1. The bile duct ligation mouse models were established using male C57BL/6 mice. RESULTS The mRNA and protein levels of MRP4 were significantly increased in cholestatic patients. TNFα treatment induced the expression of MRP4 and Nrf2 and enhanced cell nuclear extract binding activity to MRP4 promoter, as demonstrated by EMSA. Nrf2 knockdown reduced MRP4 mRNA levels in both HepG2 and Hep-3B cells. In addition, TNFα increased Rb phosphorylation and expression of MRP4 and Nrf2 and activated E2F1 and phosphorylated p38 in HepG2 and Hep-3B cells. These effects were markedly inhibited by pretreatment with E2F1 siRNA. Dual-luciferase reporter assay validated that TNFα induces the transcription of E2F1. Furthermore, the expression of MRP4, Nrf2, E2F1, and p-p38 proteins was improved with treatment of TNFα in a mouse model of cholestasis. E2F1 siRNA lentivirus or SB 203580 (p38 inhibitor) inhibited these positive effects. CONCLUSION Our findings indicated that TNFα induces hepatic MRP4 expression through activation of the p38-E2F1-Nrf2 signaling pathway in human obstructive cholestasis.
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Affiliation(s)
- Wei Lian
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Xiaocong Liu
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China
| | - Wensheng Chen
- Department of Gastroenterology, Southwest Hospital, Army Medical University (Third Military Medical University), Chongqing, China.
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36
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Dempsey JL, Wang D, Siginir G, Fei Q, Raftery D, Gu H, Yue Cui J. Pharmacological Activation of PXR and CAR Downregulates Distinct Bile Acid-Metabolizing Intestinal Bacteria and Alters Bile Acid Homeostasis. Toxicol Sci 2019; 168:40-60. [PMID: 30407581 PMCID: PMC6821357 DOI: 10.1093/toxsci/kfy271] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The gut microbiome regulates important host metabolic pathways including xenobiotic metabolism and intermediary metabolism, such as the conversion of primary bile acids (BAs) into secondary BAs. The nuclear receptors pregnane X receptor (PXR) and constitutive androstane receptor (CAR) are well-known regulators for xenobiotic biotransformation in liver. However, little is known regarding the potential effects of PXR and CAR on the composition and function of the gut microbiome. To test our hypothesis that activation of PXR and CAR regulates gut microbiota and secondary BA synthesis, 9-week-old male conventional and germ-free mice were orally gavaged with corn oil, PXR agonist PCN (75 mg/kg), or CAR agonist TCPOBOP (3 mg/kg) once daily for 4 days. PCN and TCPOBOP decreased two taxa in the Bifidobacterium genus, which corresponded with decreased gene abundance of the BA-deconjugating enzyme bile salt hydrolase. In liver and small intestinal content of germ-free mice, there was a TCPOBOP-mediated increase in total, primary, and conjugated BAs corresponding with increased Cyp7a1 mRNA. Bifidobacterium, Dorea, Peptociccaceae, Anaeroplasma, and Ruminococcus positively correlated with T-UDCA in LIC, but negatively correlated with T-CDCA in serum. In conclusion, PXR and CAR activation downregulates BA-metabolizing bacteria in the intestine and modulates BA homeostasis in a gut microbiota-dependent manner.
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Affiliation(s)
- Joseph L Dempsey
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
| | - Dongfang Wang
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
- Chongqing Blood Center, Chongqing 400015, P.R. China
| | - Gunseli Siginir
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
| | - Qiang Fei
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
- Department of Chemistry, Jilin University, Changchun, Jilin Province 130061, P.R. China
| | - Daniel Raftery
- Department of Anesthesiology and Pain Medicine, University of Washington, Seattle, Washington 98109
| | - Haiwei Gu
- Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona 85004
| | - Julia Yue Cui
- Department of Environmental and Occupational Health Sciences, University of Washington, Seattle, Washington 98105
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Abstract
Nuclear receptors (NRs) are ligand-dependent transcription factors that are involved in various biological processes including metabolism, reproduction, and development. Upon activation by their ligands, NRs bind to their specific DNA elements, exerting their biological functions by regulating their target gene expression. Bile acids are detergent-like molecules that are synthesized in the liver. They not only function as a facilitator for the digestion of lipids and fat-soluble vitamins but also serve as signaling molecules for several nuclear receptors to regulate diverse biological processes including lipid, glucose, and energy metabolism, detoxification and drug metabolism, liver regeneration, and cancer. The nuclear receptors including farnesoid X receptor (FXR), pregnane X receptor (PXR), constitutive androstane receptor (CAR), vitamin D receptor (VDR), and small heterodimer partner (SHP) constitute an integral part of the bile acid signaling. This chapter reviews the role of the NRs in bile acid homeostasis, highlighting the regulatory functions of the NRs in lipid and glucose metabolism in addition to bile acid metabolism.
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38
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Kim KH, Choi JM, Li F, Dong B, Wooton-Kee CR, Arizpe A, Anakk S, Jung SY, Hartig SM, Moore DD. Constitutive Androstane Receptor Differentially Regulates Bile Acid Homeostasis in Mouse Models of Intrahepatic Cholestasis. Hepatol Commun 2018; 3:147-159. [PMID: 30620001 PMCID: PMC6312660 DOI: 10.1002/hep4.1274] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/07/2018] [Accepted: 10/03/2018] [Indexed: 12/14/2022] Open
Abstract
Bile acid (BA) homeostasis is tightly regulated by multiple transcription factors, including farnesoid X receptor (FXR) and small heterodimer partner (SHP). We previously reported that loss of the FXR/SHP axis causes severe intrahepatic cholestasis, similar to human progressive familial intrahepatic cholestasis type 5 (PFIC5). In this study, we found that constitutive androstane receptor (CAR) is endogenously activated in Fxr:Shp double knockout (DKO) mice. To test the hypothesis that CAR activation protects DKO mice from further liver damage, we generated Fxr;Shp;Car triple knockout (TKO) mice. In TKO mice, residual adenosine triphosphate (ATP) binding cassette, subfamily B member 11 (ABCB11; alias bile salt export pump [BSEP]) function and fecal BA excretion are completely impaired, resulting in severe hepatic and biliary damage due to excess BA overload. In addition, we discovered that pharmacologic CAR activation has different effects on intrahepatic cholestasis of different etiologies. In DKO mice, CAR agonist 1,4‐bis[2‐(3,5‐dichloropyridyloxy)]benzene (TCPOBOP; here on TC) treatment attenuated cholestatic liver injury, as expected. However, in the PFIC2 model Bsep knockout (BKO) mice, TC treatment exhibited opposite effects that reflect increased BA accumulation and liver injury. These contrasting results may be linked to differential regulation of systemic cholesterol homeostasis in DKO and BKO livers. TC treatment selectively up‐regulated hepatic cholesterol levels in BKO mice, supporting de novo BA synthesis. Conclusion: CAR activation in DKO mice is generally protective against cholestatic liver injury in these mice, which model PFIC5, but not in the PFIC2 model BKO mice. Our results emphasize the importance of the genetic and physiologic background when implementing targeted therapies to treat intrahepatic cholestasis.
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Affiliation(s)
- Kang Ho Kim
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX
| | - Jong Min Choi
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX
| | - Feng Li
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX.,Center for Drug Discovery Baylor College of Medicine Houston TX
| | - Bingning Dong
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX
| | | | - Armando Arizpe
- School of Natural Science University of Texas Austin Austin TX
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology University of Illinois at Urbana-Champaign Urbana IL
| | - Sung Yun Jung
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX.,Verna and Marrs McLean Department of Biochemistry and Molecular Biology Baylor College of Medicine Houston TX
| | - Sean M Hartig
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX.,Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine Baylor College of Medicine Houston TX
| | - David D Moore
- Department of Molecular and Cellular Biology Baylor College of Medicine Houston TX
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Ðanić M, Stanimirov B, Pavlović N, Goločorbin-Kon S, Al-Salami H, Stankov K, Mikov M. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome. Front Pharmacol 2018; 9:1382. [PMID: 30559664 PMCID: PMC6287190 DOI: 10.3389/fphar.2018.01382] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022] Open
Abstract
Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.
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Affiliation(s)
- Maja Ðanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
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Nuclear Receptor Metabolism of Bile Acids and Xenobiotics: A Coordinated Detoxification System with Impact on Health and Diseases. Int J Mol Sci 2018; 19:ijms19113630. [PMID: 30453651 PMCID: PMC6274770 DOI: 10.3390/ijms19113630] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Revised: 11/14/2018] [Accepted: 11/14/2018] [Indexed: 02/06/2023] Open
Abstract
Structural and functional studies have provided numerous insights over the past years on how members of the nuclear hormone receptor superfamily tightly regulate the expression of drug-metabolizing enzymes and transporters. Besides the role of the farnesoid X receptor (FXR) in the transcriptional control of bile acid transport and metabolism, this review provides an overview on how this metabolic sensor prevents the accumulation of toxic byproducts derived from endogenous metabolites, as well as of exogenous chemicals, in coordination with the pregnane X receptor (PXR) and the constitutive androstane receptor (CAR). Decrypting this network should provide cues to better understand how these metabolic nuclear receptors participate in physiologic and pathologic processes with potential validation as therapeutic targets in human disabilities and cancers.
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Fernández-Murga ML, Petrov PD, Conde I, Castell JV, Goméz-Lechón MJ, Jover R. Advances in drug-induced cholestasis: Clinical perspectives, potential mechanisms and in vitro systems. Food Chem Toxicol 2018; 120:196-212. [PMID: 29990576 DOI: 10.1016/j.fct.2018.07.017] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 07/05/2018] [Accepted: 07/06/2018] [Indexed: 12/12/2022]
Abstract
Despite growing research, drug-induced liver injury (DILI) remains a serious issue of increasing importance to the medical community that challenges health systems, pharmaceutical industries and drug regulatory agencies. Drug-induced cholestasis (DIC) represents a frequent manifestation of DILI in humans, which is characterised by an impaired canalicular bile flow resulting in a detrimental accumulation of bile constituents in blood and tissues. From a clinical point of view, cholestatic DILI generates a wide spectrum of presentations and can be a diagnostic challenge. The drug classes mostly associated with DIC are anti-infectious, anti-diabetic, anti-inflammatory, psychotropic and cardiovascular agents, steroids, and other miscellaneous drugs. The molecular mechanisms of DIC have been investigated since the 1980s but they remain debatable. It is recognised that altered expression and/or function of hepatobiliary membrane transporters underlies some forms of cholestasis, and this and other concomitant mechanisms are very likely in DIC. Deciphering these processes may pave the ways for diagnosis, prognosis and prevention, for which currently major gaps and caveats exist. In this review, we summarise recent advances in the field of DIC, including clinical aspects, the potential mechanisms postulated so far and the in vitro systems that can be useful to investigate and identify new cholestatic drugs.
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Affiliation(s)
- M Leonor Fernández-Murga
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Petar D Petrov
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain
| | - Isabel Conde
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain
| | - Jose V Castell
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain
| | - M José Goméz-Lechón
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain.
| | - Ramiro Jover
- Unidad de Hepatología Experimental, Instituto de Investigación Sanitaria La Fe (IIS La Fe), Valencia, Spain; Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBEREHD), Madrid, Spain; Departamento de Bioquímica y Biología Molecular, Facultad de Medicina, Universidad de Valencia, Spain.
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Kim KH, Choi JM, Li F, Arizpe A, Wooton-Kee CR, Anakk S, Jung SY, Finegold MJ, Moore DD. Xenobiotic Nuclear Receptor Signaling Determines Molecular Pathogenesis of Progressive Familial Intrahepatic Cholestasis. Endocrinology 2018; 159:2435-2446. [PMID: 29718219 PMCID: PMC7263843 DOI: 10.1210/en.2018-00110] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 04/20/2018] [Indexed: 01/14/2023]
Abstract
Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We previously reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and a small heterodimer partner (SHP; NR0B2) [double knockout (DKO)], which has strong similarities to human PFIC5. We compared the pathogenesis of DKO livers with that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2. Both models exhibit severe hepatomegaly and hepatic BA accumulation, but DKO showed greater circulating BA and liver injury, and Bsep-/- had milder phenotypes. Molecular profiling of BAs uncovered specific enrichment of cholic acid (CA)-derived BAs in DKO livers but chenodeoxycholate-derived BAs in Bsep-/- livers. Transcriptomic and proteomic analysis revealed specific activation of CA synthesis and alternative basolateral BA transport in DKO but increased chenodeoxycholic acid synthesis and canalicular transport in Bsep-/-. The constitutive androstane receptor (CAR)/pregnane X receptor (PXR)-CYP2B/CYP2C axis is activated in DKO livers but not in other cholestasis models. Loss of this axis in Fxr:Shp:Car:Pxr quadruple knockouts blocked Cyp2b/Cyp2c gene induction, impaired bilirubin conjugation/elimination, and increased liver injury. Differential CYP2B expression in DKO and Bsep-/- was recapitulated in human PFIC5 and PFIC2 livers. In conclusion, loss of FXR/SHP results in distinct molecular pathogenesis and CAR/PXR activation, which promotes Cyp2b/Cyp2c gene transcription and bilirubin clearance. CAR/PXR activation was not observed in Bsep-/- mice or PFIC2 patients. These findings provide a deeper understanding of the heterogeneity of intrahepatic cholestasis.
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Affiliation(s)
- Kang Ho Kim
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Jong Min Choi
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Feng Li
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Center for Drug Discovery, Baylor College of Medicine, Houston, Texas
| | - Armando Arizpe
- School of Natural Science, University of Texas at Austin, Austin, Texas
| | - Clavia Ruth Wooton-Kee
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, Illinois
| | - Sung Yun Jung
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Verna and Marrs McLean Department of Biochemistry and Molecular Biology, Baylor College of Medicine, Houston, Texas
| | - Milton J Finegold
- Department of Pathology and Immunology, Texas Children’s Hospital, Baylor College of Medicine, Houston, Texas
| | - David D Moore
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas
- Correspondence: David D. Moore, PhD, Department of Molecular and Cellular Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030. E-mail:
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43
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Jiang LL, Zhao DS, Fan YX, Yu Q, Lai YS, Li P, Li HJ. Transcriptome analysis to assess the cholestatic hepatotoxicity induced by Polygoni Multiflori Radix: Up-regulation of key enzymes of cholesterol and bile acid biosynthesis. J Proteomics 2018; 177:40-47. [PMID: 29438852 DOI: 10.1016/j.jprot.2018.02.014] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/29/2018] [Accepted: 02/08/2018] [Indexed: 12/17/2022]
Abstract
Polygoni Multiflori Radix (PMR) has been commonly used as a tonic in China for centuries. However, PMR-associated hepatotoxicity is becoming a safety issue. Cholestasis often occurs in PMR-induced hepatotoxicity in clinical medicine, but the exact mechanism is not completely understood. An RNA-Seq method was employed, in the present study, to explore the molecular mechanism of cholestatic liver injury induced by PMR, characterized by the hepatic transcriptional response in rats exposed to 1 and 20 g/kg PMR for 90 days. Pathological changes seen in rat livers exposed to PMR included increased bile ducts in portal areas and biliary epithelial cell hyperplasia, which were accompanied by the elevation of serum biochemistries. Dose-dependent increases in the expression of 14 transcripts encoding enzymes involved in the cholesterol biosynthetic pathway were identified. Furthermore, cholesterol 7-alpha hydroxylase (Cyp7a1), a rate-limiting enzyme in the synthesis of bile acids (BAs) from cholesterol, was found to be upregulated by PMR treatment. Protein analysis by western blot suggested that expression of 3-hydroxy-3-methylglutaryl CoA reductase (Hmgcr) and Cyp7a1 were increased in a dose-dependent manner. Collectively, the present study demonstrates that PMR upregulates key enzymes for biosynthesis of cholesterol and BA, which poses the risk of cholestatic liver injury. SIGNIFICANCE To the best of our knowledge, this is the first transcriptome analysis to highlight the main molecular changes occurring in rats chronic exposed to PMR. We have identified 39 specific differentially expressed genes (DEGs) that were present in various comparisons. A total of 14 of these altered gene transcripts were associated with cholesterol biosynthesis. Another factor of great importance in our opinion seemed to be the enhancement of bile acid (BA) biosynthesis, which were closely linked to cholesterol biosynthesis or metabolism. Our findings suggested that the disturbance on balance of BA formation and elimination might lead to a BA overload in hepatocytes, thereby resulting in liver injury.
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Affiliation(s)
- Li-Long Jiang
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Dong-Sheng Zhao
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ya-Xi Fan
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Qiong Yu
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Yi-Sheng Lai
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Ping Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China
| | - Hui-Jun Li
- State Key Laboratory of Natural Medicines, China Pharmaceutical University, Nanjing, China.
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Abstract
Emerging evidence points to a strong association between the gut microbiota and the risk, development and progression of gastrointestinal cancers such as colorectal cancer (CRC) and hepatocellular carcinoma (HCC). Bile acids, produced in the liver, are metabolized by enzymes derived from intestinal bacteria and are critically important for maintaining a healthy gut microbiota, balanced lipid and carbohydrate metabolism, insulin sensitivity and innate immunity. Given the complexity of bile acid signalling and the direct biochemical interactions between the gut microbiota and the host, a systems biology perspective is required to understand the liver-bile acid-microbiota axis and its role in gastrointestinal carcinogenesis to reverse the microbiota-mediated alterations in bile acid metabolism that occur in disease states. An examination of recent research progress in this area is urgently needed. In this Review, we discuss the mechanistic links between bile acids and gastrointestinal carcinogenesis in CRC and HCC, which involve two major bile acid-sensing receptors, farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (TGR5). We also highlight the strategies and cutting-edge technologies to target gut-microbiota-dependent alterations in bile acid metabolism in the context of cancer therapy.
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Affiliation(s)
- Wei Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, USA
| | - Guoxiang Xie
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
- University of Hawaii Cancer Center, 701 Ilalo Street, Honolulu, Hawaii 96813, USA
| | - Weiping Jia
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Department of Endocrinology & Metabolism, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
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45
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Afonso MB, Rodrigues PM, Simão AL, Gaspar MM, Carvalho T, Borralho P, Bañales JM, Castro RE, Rodrigues CMP. miRNA-21 ablation protects against liver injury and necroptosis in cholestasis. Cell Death Differ 2017; 25:857-872. [PMID: 29229992 DOI: 10.1038/s41418-017-0019-x] [Citation(s) in RCA: 91] [Impact Index Per Article: 11.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/07/2017] [Revised: 10/10/2017] [Accepted: 10/20/2017] [Indexed: 01/04/2023] Open
Abstract
Inhibition of microRNA-21 (miR-21) prevents necroptosis in the mouse pancreas. Necroptosis contributes to hepatic necro-inflammation in the common bile duct ligation (BDL) murine model. We aimed to evaluate the role of miR-21 in mediating deleterious processes associated with cholestasis. Mechanistic studies established a functional link between miR-21 and necroptosis through cyclin-dependent kinase 2-associated protein 1 (CDK2AP1). miR-21 expression increased in the liver of primary biliary cholangitis (PBC) patients and BDL wild-type (WT) mice at both 3 and 14 days. Notably, under BDL, miR-21 -/- mice displayed decreased liver injury markers in serum compared with WT mice, accompanied by reduced hepatocellular degeneration, oxidative stress and fibrosis. Hallmarks of necroptosis were decreased in the liver of BDL miR-21 -/- mice, via relieved repression of CDK2AP1. Further, miR-21 -/- mice displayed improved adaptive response of bile acid homeostasis. In conclusion, miR-21 ablation ameliorates liver damage and necroptosis in BDL mice. Inhibition of miR-21 should arise as a promising approach to treat cholestasis.
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Affiliation(s)
- Marta B Afonso
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Pedro M Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - André L Simão
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Maria M Gaspar
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Tânia Carvalho
- Histology and Comparative Pathology Laboratory, Instituto de Medicina Molecular, Lisbon, Portugal
| | - Paula Borralho
- Escola Superior de Tecnologia da Saúde de Lisboa (ESTEsL), Lisbon, Portugal.,Instituto de Anatomia Patológica, Universidade de Lisboa, Lisbon, Portugal.,Hospital Cuf Descobertas, Lisbon, Portugal
| | - Jesús M Bañales
- Department of Liver and Gastrointestinal Diseases, Biodonostia Research Institute - Donostia University Hospital - University of the Basque Country (UPV/EHU), CIBERehd, Ikerbasque, San Sebastian, Spain
| | - Rui E Castro
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal
| | - Cecília M P Rodrigues
- Research Institute for Medicines (iMed.ULisboa), Faculty of Pharmacy, Universidade de Lisboa, Lisbon, Portugal.
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Gabbia D, Pozza AD, Albertoni L, Lazzari R, Zigiotto G, Carrara M, Baldo V, Baldovin T, Floreani A, Martin SD. Pregnane X receptor and constitutive androstane receptor modulate differently CYP3A-mediated metabolism in early- and late-stage cholestasis. World J Gastroenterol 2017; 23:7519-7530. [PMID: 29204052 PMCID: PMC5698245 DOI: 10.3748/wjg.v23.i42.7519] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Revised: 09/18/2017] [Accepted: 10/17/2017] [Indexed: 02/06/2023] Open
Abstract
AIM To ascertain whether cholestasis affects the expression of two CYP3A isoforms (CYP3A1 and CYP3A2) and of pregnane X receptor (PXR) and constitutive androstane receptor (CAR).
METHODS Cholestasis was induced by bile duct ligation in 16 male Wistar rats; whereas 8 sham-operated rats were used as controls. Severity of cholestasis was assessed on histological examination of liver sections, and serum concentrations of albumin, AST, ALT, GGT, ALPK and bilirubin. Gene and protein expressions of PXR, CAR, CYP3A1 and CYP3A2 were assessed by means of qRT-PCR and Western blot, respectively. Alterations in CYP3A activity were measured by calculating the kinetic parameters of 4-OH and 1’-OH-midazolam hydroxylation, marker reactions for CYP3A enzymes.
RESULTS The mRNA and protein expression of CYP3A1 increased significantly in mild cholestasis (P < 0.01). At variance, mRNA and protein expression of CYP3A2 didn’t change in mild cholestasis, whereas the expression and activity of both CYP3A1 and CYP3A2 decreased dramatically when cholestasis became severe. Consistently with these observations, the nuclear expression of both PXR and CAR, which was measured because they both translocate into the cell nucleus after their activation, virtually disappeared in the late stage of cholestatic injury, after an initial increase. These results indicate that early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently, probably as consequence of the different activation of PXR and CAR.
CONCLUSION Early- and late-stage cholestasis affects CYP3A-mediated drug metabolism differently. PXR and CAR might be targeted therapeutically to promote CYP3A-mediated liver detoxification.
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Affiliation(s)
- Daniela Gabbia
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Arianna Dalla Pozza
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Laura Albertoni
- Department of Medicine, General Pathology and Cytopathology Unit, University of Padova, Padova 35131, Italy
| | - Roberta Lazzari
- Department of Cardiac, Thoracic, and Vascular Sciences, Hygiene and Public Health Unit, University of Padova, Padova 35131, Italy
| | - Giorgia Zigiotto
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Maria Carrara
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
| | - Vincenzo Baldo
- Department of Cardiac, Thoracic, and Vascular Sciences, Hygiene and Public Health Unit, University of Padova, Padova 35131, Italy
| | - Tatjana Baldovin
- Department of Cardiac, Thoracic, and Vascular Sciences, Hygiene and Public Health Unit, University of Padova, Padova 35131, Italy
| | - Annarosa Floreani
- Department of Surgery, Oncology and Gastroenterology, University of Padova, Padova 35131, Italy
| | - Sara De Martin
- Department of Pharmaceutical and Pharmacological Sciences, University of Padova, Padova 35131, Italy
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Ronca V, Carbone M, Bernuzzi F, Malinverno F, Mousa HS, Gershwin ME, Invernizzi P. From pathogenesis to novel therapies in the treatment of primary biliary cholangitis. Expert Rev Clin Immunol 2017; 13:1121-1131. [DOI: 10.1080/1744666x.2017.1391093] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Affiliation(s)
- Vincenzo Ronca
- Department of Medicine, S. Paolo Hospital, University of Milan, Milan, Italy
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Marco Carbone
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Francesca Bernuzzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Federica Malinverno
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
| | - Hani S. Mousa
- School of Clinical Medicine, University of Cambridge, Cambridge Biomedical Campus, CB2 0AH, United Kingdom
| | - M. Eric Gershwin
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
| | - Pietro Invernizzi
- Program for Autoimmune Liver Diseases, International Center for Digestive Health, Department of Medicine and Surgery, University of Milano-Bicocca, Milan, Italy
- Division of Rheumatology, Allergy, and Clinical Immunology, University of California at Davis, Davis, CA, USA
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Increased hepatic ABCA1 transporter is associated with hypercholesterolemia in a cholestatic rat model and primary biliary cholangitis patients. Med Mol Morphol 2017; 50:227-237. [DOI: 10.1007/s00795-017-0166-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2017] [Accepted: 06/23/2017] [Indexed: 01/22/2023]
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He L, Zhou X, Huang N, Li H, Li T, Yao K, Tian Y, Hu CAA, Yin Y. Functions of pregnane X receptor in self-detoxification. Amino Acids 2017; 49:1999-2007. [PMID: 28534176 DOI: 10.1007/s00726-017-2435-0] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2017] [Accepted: 05/03/2017] [Indexed: 12/19/2022]
Abstract
Pregnane X receptor (PXR, NR1I2), a member of the nuclear receptor superfamily, is a crucial regulator of nutrient metabolism and metabolic detoxification such as metabolic syndrome, xenobiotic metabolism, inflammatory responses, glucose, cholesterol and lipid metabolism, and endocrine homeostasis. Notably, much experimental and clinical evidence show that PXR senses xenobiotics and triggers the detoxification response to prevent diseases such as diabetes, obesity, intestinal inflammatory diseases and liver fibrosis. In this review we summarize recent advances on remarkable metabolic and regulatory versatility of PXR, and we emphasizes its role and potential implication as an effective modulator of self-detoxification in animals and humans.
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Affiliation(s)
- Liuqin He
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Changsha, 410125, Hunan, China.,University of the Chinese Academy of Sciences, Beijing, 100049, China
| | - Xihong Zhou
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Changsha, 410125, Hunan, China
| | - Niu Huang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, Hunan, China
| | - Huan Li
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, Hunan, China
| | - Tiejun Li
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Changsha, 410125, Hunan, China.,Hunan Co-Innovation Center of Animal Production Safety, Changsha, 410128, Hunan, China
| | - Kang Yao
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Changsha, 410125, Hunan, China. .,College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, Hunan, China. .,Hunan Co-Innovation Center of Animal Production Safety, Changsha, 410128, Hunan, China.
| | - Yanan Tian
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, Hunan, China.,Department of Veterinary Physiology and Pharmacology, Texas A & M University, College Station, TX, 77843, USA
| | - Chien-An Andy Hu
- Department of Biochemistry and Molecular Biology, University of New Mexico, Health Sciences Center, MSC08 4670, Albuquerque, USA
| | - Yulong Yin
- Key Laboratory of Agro-ecological Processes in Subtropical Region, Institute of Subtropical Agriculture, Chinese Academy of Sciences, Scientific Observing and Experimental Station of Animal Nutrition and Feed Science in South-Central, Ministry of Agriculture, Hunan Provincial Engineering Research Center of Healthy Livestock and Poultry, Changsha, 410125, Hunan, China. .,Hunan Co-Innovation Center of Animal Production Safety, Changsha, 410128, Hunan, China.
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50
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Zeng H, Jiang Y, Chen P, Fan X, Li D, Liu A, Ma X, Xie W, Liu P, Gonzalez FJ, Huang M, Bi H. Schisandrol B protects against cholestatic liver injury through pregnane X receptors. Br J Pharmacol 2017; 174:672-688. [PMID: 28128437 DOI: 10.1111/bph.13729] [Citation(s) in RCA: 50] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/12/2016] [Revised: 01/22/2017] [Accepted: 01/23/2017] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND AND PURPOSE Currently, ursodeoxycholic acid and obeticholic acid are the only two FDA-approved drugs for cholestatic liver diseases. Thus, new therapeutic approaches need to be developed. Here we have evaluated the anti-cholestasis effects of Schisandrol B (SolB), a bioactive compound isolated from Schisandra sphenanthera. EXPERIMENTAL APPROACH Hepatoprotective effect of SolB against intrahepatic cholestasis, induced by lithocholic acid (LCA), was evaluated in mice. Metabolomic analysis and gene analysis were used to assess involvement of pregnane X receptor (PXR). Molecular docking, cell-based reporter gene analysis and knockout mice were used to demonstrate the critical role of the PXR pathway in the anti-cholestasis effects of SolB. KEY RESULTS SolB protected against LCA-induced intrahepatic cholestasis. Furthermore, therapeutic treatment with SolB decreased mortality in cholestatic mice. Metabolomics and gene analysis showed that SolB accelerated metabolism of bile acids, promoted bile acid efflux into the intestine, and induced hepatic expression of the PXR-target genes Cyp3a11, Ugt1a1, and Oatp2, which are involved in bile acid homeostasis. Mechanistic studies showed that SolB activated human PXR and up-regulated PXR target genes in human cell lines. Additionally, SolB did not protect Pxr-null mice from liver injury induced by intrahepatic cholestasis, thus providing genetic evidence that the effect of SolB was PXR-dependent. CONCLUSION AND IMPLICATIONS These findings provide direct evidence for the hepatoprotective effects of SolB against cholestasis by activating PXR. Therefore, SolB may provide a new and effective approach to the prevention and treatment of cholestatic liver diseases.
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Affiliation(s)
- Hang Zeng
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Yiming Jiang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Pan Chen
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Xiaomei Fan
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Dongshun Li
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Aiming Liu
- Medical School of Ningbo University, Ningbo, China
| | - Xiaochao Ma
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Wen Xie
- Center for Pharmacogenetics, Department of Pharmaceutical Sciences, School of Pharmacy, University of Pittsburgh, Pittsburgh, PA, USA
| | - Peiqing Liu
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Min Huang
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
| | - Huichang Bi
- School of Pharmaceutical Sciences, Sun Yat-sen University, Guangzhou, China
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