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Yan LS, Kang JY, Gu CY, Qiu XY, Li JJ, Cheng BCY, Wang YW, Luo G, Zhang Y. Schisandra chinensis lignans ameliorate hepatic inflammation and steatosis in methionine choline-deficient diet-fed mice by modulating the gut-liver axis. JOURNAL OF ETHNOPHARMACOLOGY 2025; 348:119801. [PMID: 40222688 DOI: 10.1016/j.jep.2025.119801] [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: 11/10/2024] [Revised: 04/09/2025] [Accepted: 04/10/2025] [Indexed: 04/15/2025]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE Schisandra chinensis is used as a traditional Chinese medicine to treat a variety of diseases. Schisandra chinensis lignans (SCL) are one of the most active components extracted from Schisandrae chinensis fructus, exhibit a broad array of pharmacological properties, especially anti-inflammatory and hepatic lipid-lowering effects, suggesting SCL may have potential anti-nonalcoholic steatohepatitis (NASH) ability. However, the therapeutic efficacy of SCL against NASH and the underlying mechanism of this action remains unclear. AIM OF THE STUDY In the current study, we aimed to investigate the anti-NASH action of SCL and explore the underlying mechanism in vitro and in vivo. We also assess the involvement of the gut-liver axis in the anti-NASH effects of SCL. METHODS Palmitic acid (PA)-treated HepG2 cells, mouse primary hepatocytes (MPHs) and methionine-choline deficient (MCD) diet-fed mice were selected as NASH models. ORO staining and qRT-PCR were performed to assess hepatic steatosis and inflammatory responses, respectively. Masson's trichrome staining was used to detect the liver fibrosis. Protein expression was detected by Western blotting or immunohistochemistry. The changes of gut microbiota were analyzed using 16S rDNA sequencing in mice. The levels of metabolites in liver and feces were measured by metabolomics. RESULTS The results showed that SCL treatment alleviated steatosis and inflammation in palmitic acid (PA)-treated HepG2 cells and mouse primary hepatocytes (MPHs). SCL treatment suppressed the phosphorylation of key components involved in NF-κB signaling and enhanced the expression of fatty acid oxidation (FAO)-related enzymes (e.g. CPT1, HMGCS2, and ACOX1) in PA-treated HepG2 cells. SCL could ameliorate hepatic steatosis and inflammation in NASH mice. SCL also ameliorated intestinal barrier injury and restructured the gut microbiota in NASH mice. SCL also modulated hepatic and colonic bile acid metabolism via FXR signaling. CONCLUSION These findings indicate that SCL treatment ameliorates hepatic inflammation and steatosis in NASH mice, potentially though to the suppression of NF-κB signaling and the promotion of fatty acid β-oxidation. Moreover, SCL could restore gut microbiota-mediated bile acid homeostasis via activation of FXR/FGF15 signaling. Our study presents a pharmacological rationale for using SCL in the management of NASH.
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Affiliation(s)
- Li-Shan Yan
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Jian-Ying Kang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Chun-Yu Gu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Xin-Yu Qiu
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Jia-Jia Li
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | | | - Yi-Wei Wang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Gan Luo
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
| | - Yi Zhang
- School of Chinese Materia Medica, Beijing University of Chinese Medicine, Beijing, PR China.
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Ghallab A, Mandorfer M, Stirnimann G, Geyer J, Lindström E, Luedde T, van der Merwe S, Rashidi-Alavijeh J, Schmidt H, Karpen SJ, Fickert P, Trauner M, Hengstler JG, Dawson PA. Enteronephrohepatic Circulation of Bile Acids and Therapeutic Potential of Systemic Bile Acid Transporter Inhibitors. J Hepatol 2025:S0168-8278(25)02207-X. [PMID: 40414504 DOI: 10.1016/j.jhep.2025.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/27/2025]
Abstract
Together with carriers in liver and small intestine, kidney transporters function to conserve and compartmentalize bile acids in the enteronephrohepatic circulation. In patients with liver disease, systemic bile acid levels are elevated, undergo increased renal glomerular filtration, and contribute to the pathogenesis of cholemic nephropathy and acute kidney injury. In this review, we describe mechanisms for renal bile acid transport and highlight very recent discoveries that challenge current paradigms for the pathogenesis of cholemic nephropathy and renal tubule cast formation. We also discuss the therapeutic potential of inhibiting the kidney apical sodium-dependent bile acid transporter (ASBT) to redirect bile acids into urine for elimination, reduce hepatobiliary accumulation and systemic levels of bile acids, and treat cholemic nephropathy. In conclusion, a deeper understanding of the enteronephrohepatic bile acid axis is providing insights into novel strategies to protect both liver and kidney in patients with liver disease.
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Affiliation(s)
- Ahmed Ghallab
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany
| | | | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | | | - Jassin Rashidi-Alavijeh
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Hartmut Schmidt
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Saul J Karpen
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.
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Heralde FM, Martin ZT, Cagayan MSFS, Uy EV, Ubial PJR, Velarde MC, Llamas-Clark EF. UPLC-QTOF Mass Spectrometry Detection of Four Endocrine Disrupting Chemicals (Methyl Paraben, 2,4-Dichlorophenoxyacetic acid, Monobutyl Phthalate, and Bisphenol A) in Urine of Filipino Women. ACTA MEDICA PHILIPPINA 2025; 59:70-79. [PMID: 40151222 PMCID: PMC11936769 DOI: 10.47895/amp.vi0.9007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 03/29/2025]
Abstract
Background and Objective Endocrine Disrupting Chemicals (EDCs) are ubiquitously found as low-level contaminants and pose serious threat to women's health. EDCs may result in various reproductive disorders, fetal birth and developmental abnormalities, and endocrine and metabolic disorders. EDCs can be detected in body fluids of exposed individuals including blood and urine. This study aimed to detect four EDCs - Methyl Paraben (MP), 2,4-Dichlorophenoxyacetic acid (2,4-D), Monobutyl Phthalate (MBP), and Bisphenol A (BPA) in urine samples of women using Ultra-Performance Liquid Chromatography - Quadrupole Time-of-Flight (UPLC-QTOF) mass spectrometry. Methods Sequential steps of enzymatic deconjugation, liquid-liquid extraction, solid phase extraction, and liquid chromatography separation and mass spectrometry detection were optimized in urine samples. The method was used to analyze 70 urine samples from women of reproductive age. Results The sample preparation method showed a recovery ranging from 86.6% (MBP) to 100 % (2,4-D). The method demonstrated limits of quantitation ranging from 1.52 ng/m(MP) to 6.46 ng/mL(2,4D). Intra-day precisions expressed as relative standard deviation were all below 15% while accuracy was shown to range from 67.10% (2,4-D) to 102.39% (MBP). MP was detected in nine samples (12.86%) with a geometric mean value of 10.15 ng/ml (range: 3.62-52.39 ng/ml). MBP was detected in 68 samples (97.14%) with a geometric mean value of 97.62 ng/ml (range: 15.32-698.18 ng/ml). BPA was detected only once (9.58 ng/ml) while 2, 4-D was not detected in all samples. Conclusion A UPLC-QTOF mass spectrometry method to detect four EDCs at parts per billion level (ng/ml) was adapted and applied for analysis of urine samples. This method can find applicability in routine testing of clinical specimens as well as surveillance and other epidemiological studies.
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Affiliation(s)
- Francisco M. Heralde
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
| | - Zaidy T. Martin
- Department of Biochemistry and Molecular Biology, College of Medicine, University of the Philippines Manila
| | | | - Esterlita V. Uy
- Institute of Child Health and Human Development, National Institutes of Health, University of the Philippines Manila
| | | | - Michael C. Velarde
- Institute of Biology, College of Science, University of the Philippines Diliman
| | - Erlidia F. Llamas-Clark
- Department of Obstetrics and Gynecology, Philippine General Hospital, University of the Philippines Manila
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Luo Z, Zhou W, Xie T, Xu W, Shi C, Xiao Z, Si Y, Ma Y, Ren Q, Di L, Shan J. The role of botanical triterpenoids and steroids in bile acid metabolism, transport, and signaling: Pharmacological and toxicological implications. Acta Pharm Sin B 2024; 14:3385-3415. [PMID: 39220868 PMCID: PMC11365449 DOI: 10.1016/j.apsb.2024.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/28/2024] [Accepted: 04/22/2024] [Indexed: 09/04/2024] Open
Abstract
Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.
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Affiliation(s)
- Zichen Luo
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Zhou
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tong Xie
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Weichen Xu
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chen Shi
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zihan Xiao
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Si
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Yan Ma
- National Institute of Biological Sciences, Beijing 102206, China
| | - Qingling Ren
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Liuqing Di
- Jiangsu Engineering Research Center for Efficient Delivery System of TCM, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jinjun Shan
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Gallucci GM, Hayes CM, Boyer JL, Barbier O, Assis DN, Ghonem NS. PPAR-Mediated Bile Acid Glucuronidation: Therapeutic Targets for the Treatment of Cholestatic Liver Diseases. Cells 2024; 13:1296. [PMID: 39120326 PMCID: PMC11312002 DOI: 10.3390/cells13151296] [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: 06/13/2024] [Revised: 07/18/2024] [Accepted: 07/30/2024] [Indexed: 08/10/2024] Open
Abstract
Cholestatic liver diseases, including primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC), result from an impairment of bile flow that leads to the hepatic retention of bile acids, causing liver injury. Until recently, the only approved treatments for PBC were ursodeoxycholic acid (UDCA) and obeticholic acid (OCA). While these therapies slow the progression of PBC in the early stage of the disease, approximately 40% of patients respond incompletely to UDCA, and advanced cases do not respond. UDCA does not improve survival in patients with PSC, and patients often have dose-limiting pruritus reactions to OCA. Left untreated, these diseases can progress to fibrosis and cirrhosis, resulting in liver failure and the need for transplantation. These shortcomings emphasize the urgent need for alternative treatment strategies. Recently, nuclear hormone receptors have been explored as pharmacological targets for adjunct therapy because they regulate enzymes involved in bile acid metabolism and detoxification. In particular, the peroxisome proliferator-activated receptor (PPAR) has emerged as a therapeutic target for patients with PBC or PSC who experience an incomplete response to UDCA. PPARα is predominantly expressed in the liver, and it plays an essential role in the regulation of cytochrome P450 (CYP) and uridine 5'-diphospho-glucuronosyltransferase (UGT) enzymes, both of which are critical enzyme families involved in the regulation of bile acid metabolism and glucuronidation, respectively. Importantly, PPARα agonists, e.g., fenofibrate, have shown therapeutic benefits in reducing elevated markers of cholestasis in patients with PBC and PSC, and elafibranor, the first PPAR (dual α, β/δ) agonist, has been FDA-approved for the second-line treatment of PBC. Additionally, newer PPAR agonists that target various PPAR isoforms (β/δ, γ) are under development as an adjunct therapy for PBC or PSC, although their impact on glucuronidation pathways are less characterized. This review will focus on PPAR-mediated bile acid glucuronidation as a therapeutic pathway to improve outcomes for patients with PBC and PSC.
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Affiliation(s)
- Gina M. Gallucci
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - Colleen M. Hayes
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
| | - James L. Boyer
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, USA
| | - Olivier Barbier
- Faculty of Pharmacy, Laval University, Québec, QC G1V 0A6, Canada
| | - David N. Assis
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, USA
| | - Nisanne S. Ghonem
- Department of Biomedical and Pharmaceutical Sciences, College of Pharmacy, University of Rhode Island, Kingston, RI 02881, USA
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Mohanty I, Allaband C, Mannochio-Russo H, El Abiead Y, Hagey LR, Knight R, Dorrestein PC. The changing metabolic landscape of bile acids - keys to metabolism and immune regulation. Nat Rev Gastroenterol Hepatol 2024; 21:493-516. [PMID: 38575682 DOI: 10.1038/s41575-024-00914-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 02/14/2024] [Indexed: 04/06/2024]
Abstract
Bile acids regulate nutrient absorption and mitochondrial function, they establish and maintain gut microbial community composition and mediate inflammation, and they serve as signalling molecules that regulate appetite and energy homeostasis. The observation that there are hundreds of bile acids, especially many amidated bile acids, necessitates a revision of many of the classical descriptions of bile acids and bile acid enzyme functions. For example, bile salt hydrolases also have transferase activity. There are now hundreds of known modifications to bile acids and thousands of bile acid-associated genes, especially when including the microbiome, distributed throughout the human body (for example, there are >2,400 bile salt hydrolases alone). The fact that so much of our genetic and small-molecule repertoire, in both amount and diversity, is dedicated to bile acid function highlights the centrality of bile acids as key regulators of metabolism and immune homeostasis, which is, in large part, communicated via the gut microbiome.
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Affiliation(s)
- Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Celeste Allaband
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA
| | - Helena Mannochio-Russo
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Yasin El Abiead
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, San Diego, CA, USA
| | - Rob Knight
- Department of Pediatrics, University of California San Diego School of Medicine, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Computer Science and Engineering, University of California San Diego, La Jolla, CA, USA
- Department of Bioengineering, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Department of Pharmacology, University of California San Diego, La Jolla, CA, USA.
- Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA.
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Alotaibi AZ, AlMalki RH, Al Mogren M, Sebaa R, Alanazi M, Jacob M, Alodaib A, Alfares A, Abdel Rahman AM. Exploratory Untargeted Metabolomics of Dried Blood Spot Samples from Newborns with Maple Syrup Urine Disease. Int J Mol Sci 2024; 25:5720. [PMID: 38891907 PMCID: PMC11171634 DOI: 10.3390/ijms25115720] [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: 04/15/2024] [Revised: 05/20/2024] [Accepted: 05/21/2024] [Indexed: 06/21/2024] Open
Abstract
Currently, tandem mass spectrometry-based newborn screening (NBS), which examines targeted biomarkers, is the first approach used for the early detection of maple syrup urine disease (MSUD) in newborns, followed by confirmatory genetic mutation tests. However, these diagnostic approaches have limitations, demanding the development of additional tools for the diagnosis/screening of MUSD. Recently, untargeted metabolomics has been used to explore metabolic profiling and discover the potential biomarkers/pathways of inherited metabolic diseases. Thus, we aimed to discover a distinctive metabolic profile and biomarkers/pathways for MSUD newborns using untargeted metabolomics. Herein, untargeted metabolomics was used to analyze dried blood spot (DBS) samples from 22 MSUD and 22 healthy control newborns. Our data identified 210 altered endogenous metabolites in MSUD newborns and new potential MSUD biomarkers, particularly L-alloisoleucine, methionine, and lysoPI. In addition, the most impacted pathways in MSUD newborns were the ascorbate and aldarate pathways and pentose and glucuronate interconversions, suggesting that oxidative and detoxification events may occur in early life. Our approach leads to the identification of new potential biomarkers/pathways that could be used for the early diagnosis/screening of MSUD newborns but require further validation studies. Our untargeted metabolomics findings have undoubtedly added new insights to our understanding of the pathogenicity of MSUD, which helps us select the appropriate early treatments for better health outcomes.
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Affiliation(s)
- Abeer Z. Alotaibi
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11652, Saudi Arabia; (A.Z.A.); (M.A.)
| | - Reem H. AlMalki
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
| | - Maha Al Mogren
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
| | - Rajaa Sebaa
- Department of Medical Laboratories, College of Applied Medical Sciences, Shaqra University, Shaqra 11961, Saudi Arabia;
| | - Mohammad Alanazi
- Genome Research Chair, Department of Biochemistry, College of Science, King Saud University, P.O. Box 22452, Riyadh 11652, Saudi Arabia; (A.Z.A.); (M.A.)
| | - Minnie Jacob
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
| | - Ahamd Alodaib
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
| | - Ahmad Alfares
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
| | - Anas M. Abdel Rahman
- Metabolomics Section, Department of Clinical Genomics, Center for Genomics Medicine, King Faisal Specialist Hospital and Research Centre (KFSHRC), Riyadh 11211, Saudi Arabia; (R.H.A.); (M.A.M.); (M.J.); (A.A.); (A.A.)
- Department of Biochemistry and Molecular Medicine, College of Medicine, Alfaisal University, Riyadh 11533, Saudi Arabia
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Mireault M, Rose CF, Karvellas CJ, Sleno L. Perturbations in human bile acid profiles following drug-induced liver injury investigated using semitargeted high-resolution mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2024; 38:e9731. [PMID: 38469943 DOI: 10.1002/rcm.9731] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2024] [Revised: 02/13/2024] [Accepted: 02/15/2024] [Indexed: 03/13/2024]
Abstract
RATIONALE Acetaminophen (APAP) overdose is the leading cause of acute liver failure (ALF) in North America. To investigate the effect of drug-induced liver injury (DILI) on circulating bile acid (BA) profiles, serum from ALF patients and healthy controls were analyzed using a semitargeted high-resolution mass spectrometry approach to measure BAs in their unconjugated and amidated forms and their glucuronide and sulfate conjugates. METHODS Human serum samples from 20 healthy volunteers and 34 ALF patients were combined with deuterated BAs and extracted, prior to liquid chromatography high-resolution tandem mass spectrometry analysis. A mix of 46 standards helped assign 26 BAs in human serum by accurate mass and retention time matching. Moreover, other isomers of unconjugated and amidated BAs, as well as glucuronide and sulfate conjugates, were assigned by accurate mass filtering. In vitro incubations of standard BAs provided increased information for certain peaks of interest. RESULTS A total of 275 BA metabolites, with confirmed or putative assignments, were measured in human serum samples. APAP overdose significantly influenced the levels of most BAs, promoting glycine conjugation, and, to a lesser extent, taurine conjugation. When patient outcome was considered, 11 BAs were altered significantly, including multiple sulfated species. Although many of the BAs measured did not have exact structures assigned, several putatively identified BAs of interest were further characterized using in vitro incubations. CONCLUSION An optimized chromatographic separation tailored to BAs of ranging polarities was combined with accurate mass measurements to investigate the effect that DILI has on their complex profiles and metabolism to a much wider extent than previously possible. The analysis of complex BA profiles enabled in-depth analysis of the BA metabolism perturbations in ALF, including certain metabolites related to patient outcomes.
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Affiliation(s)
- Myriam Mireault
- Department of Chemistry/CERMO-FC, Université du Québec à Montréal (UQAM), Montreal, Quebec, Canada
| | - Christopher F Rose
- Hepato-Neuro Lab, CRCHUM, Montréal, Quebec, Canada
- Department of Medicine, Université de Montréal, Montréal, Quebec, Canada
| | - Constantine J Karvellas
- Department of Critical Care Medicine and Gastroenterology/Hepatology, University of Alberta, Edmonton, Alberta, Canada
| | - Lekha Sleno
- Department of Chemistry/CERMO-FC, Université du Québec à Montréal (UQAM), Montreal, Quebec, Canada
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Mohanty I, Mannochio-Russo H, Schweer JV, El Abiead Y, Bittremieux W, Xing S, Schmid R, Zuffa S, Vasquez F, Muti VB, Zemlin J, Tovar-Herrera OE, Moraïs S, Desai D, Amin S, Koo I, Turck CW, Mizrahi I, Kris-Etherton PM, Petersen KS, Fleming JA, Huan T, Patterson AD, Siegel D, Hagey LR, Wang M, Aron AT, Dorrestein PC. The underappreciated diversity of bile acid modifications. Cell 2024; 187:1801-1818.e20. [PMID: 38471500 DOI: 10.1016/j.cell.2024.02.019] [Citation(s) in RCA: 58] [Impact Index Per Article: 58.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2023] [Revised: 11/30/2023] [Accepted: 02/15/2024] [Indexed: 03/14/2024]
Abstract
The repertoire of modifications to bile acids and related steroidal lipids by host and microbial metabolism remains incompletely characterized. To address this knowledge gap, we created a reusable resource of tandem mass spectrometry (MS/MS) spectra by filtering 1.2 billion publicly available MS/MS spectra for bile-acid-selective ion patterns. Thousands of modifications are distributed throughout animal and human bodies as well as microbial cultures. We employed this MS/MS library to identify polyamine bile amidates, prevalent in carnivores. They are present in humans, and their levels alter with a diet change from a Mediterranean to a typical American diet. This work highlights the existence of many more bile acid modifications than previously recognized and the value of leveraging public large-scale untargeted metabolomics data to discover metabolites. The availability of a modification-centric bile acid MS/MS library will inform future studies investigating bile acid roles in health and disease.
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Affiliation(s)
- Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Helena Mannochio-Russo
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Joshua V Schweer
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Department of Chemistry and Biochemistry, University of California, San Diego, San Diego, CA, USA
| | - Yasin El Abiead
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Wout Bittremieux
- Department of Computer Science, University of Antwerp, 2020 Antwerpen, Belgium
| | - Shipei Xing
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, Vancouver, BC, Canada
| | - Robin Schmid
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Simone Zuffa
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Felipe Vasquez
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Valentina B Muti
- Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA, USA; Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA
| | - Jasmine Zemlin
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA
| | - Omar E Tovar-Herrera
- Department of Life Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Goldman Sonnenfeldt School of Sustainability and Climate Change, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel
| | - Sarah Moraïs
- Department of Life Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Goldman Sonnenfeldt School of Sustainability and Climate Change, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel
| | - Dhimant Desai
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA
| | - Shantu Amin
- Department of Pharmacology, Penn State University College of Medicine, Hershey, PA, USA
| | - Imhoi Koo
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA
| | - Christoph W Turck
- Max Planck Institute of Psychiatry, Proteomics and Biomarkers, Kraepelinstrasse 2-10, Munich 80804, Germany; Key Laboratory of Animal Models and Human Disease Mechanisms of Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650201, China
| | - Itzhak Mizrahi
- Department of Life Sciences, Ben-Gurion University of the Negev, Be'er Sheva, Israel; Goldman Sonnenfeldt School of Sustainability and Climate Change, Ben-Gurion University of the Negev, Be'er Sheva 84105, Israel
| | - Penny M Kris-Etherton
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Kristina S Petersen
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Jennifer A Fleming
- Department of Nutritional Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Tao Huan
- Department of Chemistry, Faculty of Science, University of British Columbia, Vancouver Campus, Vancouver, BC, Canada
| | - Andrew D Patterson
- Center for Molecular Toxicology and Carcinogenesis, Department of Veterinary and Biomedical Sciences, Pennsylvania State University, University Park, PA, USA
| | - Dionicio Siegel
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California, San Diego, San Diego, CA, USA
| | - Mingxun Wang
- Department of Computer Science and Engineering, University of California, Riverside, Riverside, CA, USA
| | - Allegra T Aron
- Department of Chemistry and Biochemistry, University of Denver, Denver, CO 80210, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California, San Diego, La Jolla, CA, USA; Collaborative Mass Spectrometry Innovation Center, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA; Department of Pharmacology, University of California, San Diego, La Jolla, CA 92093, USA; Center for Microbiome Innovation, University of California, San Diego, La Jolla, CA 92093, USA.
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10
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Aljarboa AS, Alhusaini AM, Sarawi WS, Mohammed R, Ali RA, Hasan IH. The implication of LPS/TLR4 and FXR receptors in hepatoprotective efficacy of indole-3-acetic acid and chenodeoxycholic acid. Life Sci 2023; 334:122182. [PMID: 37863258 DOI: 10.1016/j.lfs.2023.122182] [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: 08/27/2023] [Revised: 10/05/2023] [Accepted: 10/14/2023] [Indexed: 10/22/2023]
Abstract
AIM Valproic acid (VPA) belongs to the first-generation antiepileptic drugs, yet its prolonged use can cause life-threatening liver damage. The importance of our study is to investigate the protective effect of indole-3-acetic acid (IAA), chenodeoxycholic acid (CDCA) and their combination on VPA-induced liver injury focusing on lipopolysaccharides (LPS)/toll-like receptor 4 (TLR4) pathway and farnesoid X receptor (FXR). METHODS Thirty rats were randomly assigned into five groups, normal control group, VPA group received 500 mg/kg of VPA intraperitoneally. The remaining groups were orally treated with either 40 mg/kg of IAA, 90 mg/kg of CDCA, or a combination of both, along with VPA. All treatments were administered one hour after the administration of VPA for three weeks. KEY FINDINGS VPA group showed significant elevations in the liver weight/body weight ratio, serum aminotransferases, triglyceride, and total cholesterol levels. Hepatic glutathione (GSH) level and superoxide dismutase (SOD) activity were significantly decreased, while malondialdehyde (MDA) level, tumor necrosis factor-α (TNF-α), interleukin-1beta (IL-1β), lipopolysaccharide (LPS) and caspase 3 were significantly increased. Likewise, immunohistochemical analysis revealed that TLR4 expression was elevated, whereas FXR expression was downregulated in hepatocytes. IAA substantially ameliorated all previously altered parameters, whereas CDCA treatment showed a partial improvement compared to IAA. Surprisingly, combination therapy of IAA with CDCA showed an additive effect only in the hepatic expression of TLR4 and FXR proteins. SIGNIFICANCE IAA could be a promising protective agent against VPA-induced liver injury.
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Affiliation(s)
- Amjad S Aljarboa
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
| | - Ahlam M Alhusaini
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
| | - Wedad S Sarawi
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
| | - Raeesa Mohammed
- Department of Histology, College of Medicine, King Saud University, P.O. Box 2925, Riyadh 11461, Saudi Arabia.
| | - Rehab A Ali
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
| | - Iman H Hasan
- Department of Pharmacology and Toxicology, College of Pharmacy, King Saud University, P.O. Box 22452, Riyadh 11495, Saudi Arabia.
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11
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Tveter KM, Mezhibovsky E, Wu Y, Roopchand DE. Bile acid metabolism and signaling: Emerging pharmacological targets of dietary polyphenols. Pharmacol Ther 2023; 248:108457. [PMID: 37268113 PMCID: PMC10528343 DOI: 10.1016/j.pharmthera.2023.108457] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/03/2023] [Accepted: 05/22/2023] [Indexed: 06/04/2023]
Abstract
Beyond their role as emulsifiers of lipophilic compounds, bile acids (BAs) are signaling endocrine molecules that show differential affinity and specificity for a variety of canonical and non-canonical BA receptors. Primary BAs (PBAs) are synthesized in the liver while secondary BAs (SBAs) are gut microbial metabolites of PBA species. PBAs and SBAs signal to BA receptors that regulate downstream pathways of inflammation and energy metabolism. Dysregulation of BA metabolism or signaling has emerged as a feature of chronic disease. Dietary polyphenols are non-nutritive plant-derived compounds associated with decreased risk of metabolic syndrome, type-2 diabetes, hepatobiliary and cardiovascular disease. Evidence suggests that the health promoting effects of dietary polyphenols are linked to their ability to alter the gut microbial community, the BA pool, and BA signaling. In this review we provide an overview of BA metabolism and summarize studies that link the cardiometabolic improvements of dietary polyphenols to their modulation of BA metabolism and signaling pathways, and the gut microbiota. Finally, we discuss approaches and challenges in deciphering cause-effect relationships between dietary polyphenols, BAs, and gut microbes.
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Affiliation(s)
- Kevin M Tveter
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Esther Mezhibovsky
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA.
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12
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Sun T, Liu X, Su Y, Wang Z, Cheng B, Dong N, Wang J, Shan A. The efficacy of anti-proteolytic peptide R7I in intestinal inflammation, function, microbiota, and metabolites by multi-omics analysis in murine bacterial enteritis. Bioeng Transl Med 2023; 8:e10446. [PMID: 36925697 PMCID: PMC10013768 DOI: 10.1002/btm2.10446] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2022] [Revised: 10/21/2022] [Accepted: 10/30/2022] [Indexed: 11/11/2022] Open
Abstract
Increased antibiotic resistance poses a major limitation in tackling inflammatory bowel disease and presents a large challenge for global health care. Antimicrobial peptides (AMPs) are a potential class of antimicrobial agents. Here, we have designed the potential oral route for antimicrobial peptide R7I with anti-proteolytic properties to deal with bacterial enteritis in mice. The results revealed that R7I protected the liver and gut from damage caused by inflammation. RNA-Seq analysis indicated that R7I promoted digestion and absorption in the small intestine by upregulating transmembrane transporter activity, lipid and small molecule metabolic processes and other pathways, in addition to upregulating hepatic steroid biosynthesis and fatty acid degradation. For the gut microbiota, Clostridia were significantly reduced in the R7I-treated group, and Odoribacteraceae, an efficient isoalloLCA-synthesizing strain, was the main dominant strain, protecting the gut from potential pathogens. In addition, we further discovered that R7I reduced the accumulation of negative organic acid metabolites. Overall, R7I exerted better therapeutic and immunomodulatory potential in the bacterial enteritis model, greatly reduced the risk of disease onset, and provided a reference for the in vivo application of antimicrobial peptides.
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Affiliation(s)
- Taotao Sun
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Xuesheng Liu
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Yunzhe Su
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Zihang Wang
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Baojing Cheng
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Na Dong
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Jiajun Wang
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
| | - Anshan Shan
- Laboratory of Molecular Nutrition and Immunity, the Institute of Animal NutritionNortheast Agricultural UniversityHarbinChina
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13
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Semi-Targeted Profiling of Bile Acids by High-Resolution Mass Spectrometry in a Rat Model of Drug-Induced Liver Injury. Int J Mol Sci 2023; 24:ijms24032489. [PMID: 36768813 PMCID: PMC9917070 DOI: 10.3390/ijms24032489] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/21/2023] [Accepted: 01/24/2023] [Indexed: 02/01/2023] Open
Abstract
Using a semi-targeted approach, we have investigated the effect of acetaminophen on circulating bile acid profiles in rats, including many known bile acids and potential isomeric structures, as well as glucuronide and sulfate conjugates. The chromatographic separation was based on an optimized reverse-phase method exhibiting excellent resolution for a complex mix of bile acids using a solid-core C18 column, coupled to a high-resolution quadrupole time-of-flight system. The semi-targeted workflow consisted of first assigning all peaks detectable in samples from 46 known bile acids contained in a standard mix, as well as additional peaks for other bile acid isomers. The presence of glucuronide and sulfate conjugates was also examined based on their elemental formulae and detectable peaks with matching exact masses were added to the list of features for statistical analysis. In this study, rats were administered acetaminophen at four different doses, from 75 to 600 mg/kg, with the highest dose being a good model of drug-induced liver injury. Statistically significant changes were found by comparing bile acid profiles between dosing levels. Some tentatively assigned conjugates were further elucidated using in vitro metabolism incubations with rat liver fractions and standard bile acids. Overall, 13 identified bile acids, 23 tentatively assigned bile acid isomers, and 9 sulfate conjugates were found to increase significantly at the highest acetaminophen dose, and thus could be linked to drug-induced liver injury.
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14
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Cerra B, Venturoni F, Souma M, Ceccarelli G, Lozza AM, Passeri D, De Franco F, Baxendale IR, Pellicciari R, Macchiarulo A, Gioiello A. Development of 3α,7α-dihydroxy-6α-ethyl-24-nor-5β-cholan-23-sulfate sodium salt (INT-767): Process optimization, synthesis and characterization of metabolites. Eur J Med Chem 2022; 242:114652. [PMID: 36049273 DOI: 10.1016/j.ejmech.2022.114652] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 07/27/2022] [Accepted: 07/31/2022] [Indexed: 11/29/2022]
Abstract
Herein we report our synthetic efforts in supporting the development of the bile alcohol sulfate INT-767, a FXR/TGR5 dual agonist with remarkable therapeutic potential for liver disorders. We describe the process development to a final route for large scale preparation and analogues synthesis. Key sequences include Grignard addition, a one-pot two-step shortening-reduction of the carboxylic side chain, and the final sulfation reaction. The necessity for additional steps such as the protection/deprotection of hydroxyl groups at the steroidal body was also evaluated for step-economy and formation of side-products. Critical bottlenecks such as the side chain degradation have been tackled using flow technology before scaling-up individual steps. The final synthetic route may be successfully employed to produce the amount of INT-767 required to support late-stage clinical development of the compound. Furthermore, potential metabolites have been synthesized, characterized and evaluated for their ability to modulate FXR and TGR5 receptors providing key reference standards for future drug investigations, as well as offering further insights into the structure-activity relationships of this class of compounds.
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Affiliation(s)
- Bruno Cerra
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Francesco Venturoni
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Maria Souma
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Giada Ceccarelli
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Anna Maria Lozza
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Daniela Passeri
- TES Pharma, Via Palmiro Togliatti 20, 06073, Taverne di Corciano, Perugia, Italy
| | - Francesca De Franco
- TES Pharma, Via Palmiro Togliatti 20, 06073, Taverne di Corciano, Perugia, Italy
| | - Ian R Baxendale
- Department of Chemistry, Durham University, South Road, Durham, United Kingdom
| | - Roberto Pellicciari
- TES Pharma, Via Palmiro Togliatti 20, 06073, Taverne di Corciano, Perugia, Italy
| | - Antonio Macchiarulo
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy
| | - Antimo Gioiello
- Laboratory of Medicinal and Advanced Synthetic Chemistry, Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo 1, 06122, Perugia, Italy.
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15
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Ratiner K, Shapiro H, Goldenberg K, Elinav E. Time-limited diets and the gut microbiota in cardiometabolic disease. J Diabetes 2022; 14:377-393. [PMID: 35698246 PMCID: PMC9366560 DOI: 10.1111/1753-0407.13288] [Citation(s) in RCA: 17] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/15/2022] [Revised: 05/11/2022] [Accepted: 05/26/2022] [Indexed: 12/12/2022] Open
Abstract
In recent years, intermittent fasting (IF), including periodic fasting and time-restricted feeding (TRF), has been increasingly suggested to constitute a promising treatment for cardiometabolic diseases (CMD). A deliberate daily pause in food consumption influences the gut microbiome and the host circadian clock, resulting in improved cardiometabolic health. Understanding the molecular mechanisms by which circadian host-microbiome interactions affect host metabolism and immunity may add a potentially important dimension to effective implementation of IF diets. In this review, we discuss emerging evidence potentially linking compositional and functional alterations of the gut microbiome with IF impacts on mammalian metabolism and risk of development of hypertension, type 2 diabetes (T2D), obesity, and their long-term micro- and macrovascular complications. We highlight the challenges and unknowns in causally linking diurnal bacterial signals with dietary cues and downstream metabolic consequences and means of harnessing these signals toward future microbiome integration into precision medicine.
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Affiliation(s)
- Karina Ratiner
- Systems Immunology DepartmentWeizmann Institute of ScienceRehovotIsrael
| | - Hagit Shapiro
- Systems Immunology DepartmentWeizmann Institute of ScienceRehovotIsrael
| | - Kim Goldenberg
- Systems Immunology DepartmentWeizmann Institute of ScienceRehovotIsrael
| | - Eran Elinav
- Systems Immunology DepartmentWeizmann Institute of ScienceRehovotIsrael
- Microbiome & Cancer Division, DKFZHeidelbergGermany
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16
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Donadei C, Angeletti A, Cappuccilli M, Conti M, Conte D, Zappulo F, De Giovanni A, Malvi D, Aldini R, Roda A, La Manna G. Adaptive Mechanisms of Renal Bile Acid Transporters in a Rat Model of Carbon Tetrachloride-Induced Liver Cirrhosis. J Clin Med 2022; 11:jcm11030636. [PMID: 35160088 PMCID: PMC8836491 DOI: 10.3390/jcm11030636] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2021] [Revised: 01/19/2022] [Accepted: 01/23/2022] [Indexed: 02/04/2023] Open
Abstract
Background: Acute kidney injury (AKI) is common in advanced liver cirrhosis, a consequence of reduced kidney perfusion due to splanchnic arterial vasodilation and intrarenal vasoconstriction. It clinically manifests as hepatorenal syndrome type 1, type 2, or as acute tubular necrosis. Beyond hemodynamic factors, an additional mechanism may be hypothesized to explain the renal dysfunction during liver cirrhosis. Recent evidence suggest that such mechanisms may be closely related to obstructive jaundice. Methods: Given the not completely elucidated role of bile acids in kidney tissue damage, this study developed a rat model of AKI with liver cirrhosis induction by carbon tetrachloride (CCl4) inhalation for 12 weeks. Histological analyses of renal and liver biopsies were performed at sacrifice. Organic anion tubular transporter distribution and apoptosis in kidney cells were analyzed by immunohistochemistry. Circulating and urinary markers of inflammation and tubular injury were assayed in 21 treated rats over time (1, 2, 4, 8, and 12 weeks of CCl4 administration) and 5 controls. Results: No renal histopathological alterations were found at sacrifice. Comparing treated rats with controls, organic anion transporters were differentially expressed and localized. High serum bile acid values were detected in cirrhotic animals, while caspase-3 staining was negative in both groups. Increased levels of serum inflammatory and urinary tubular injury biomarkers were observed during cirrhosis progression, with a peak after 4 and 8 weeks of treatment. Conclusions: These findings suggest possible adaptive tubular mechanisms for bile acid transporters in response to cirrhosis-induced AKI.
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Affiliation(s)
- Chiara Donadei
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Andrea Angeletti
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
- Division of Nephrology, Dialysis and Transplantation, IRCCS Istituto Giannina Gaslini, Genoa Largo Gaslini, 16148 Genoa, Italy
| | - Maria Cappuccilli
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Massimiliano Conti
- Department of Pharmacy and Biotechnology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy;
| | - Diletta Conte
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Fulvia Zappulo
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
| | - Alessio De Giovanni
- Department of Experimental, Diagnostic and Specialty Medicine—DIMES, “F. Addarii” Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (A.D.G.); (D.M.)
| | - Deborah Malvi
- Department of Experimental, Diagnostic and Specialty Medicine—DIMES, “F. Addarii” Institute of Oncology and Transplant Pathology, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (A.D.G.); (D.M.)
| | - Rita Aldini
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy; (R.A.); (A.R.)
| | - Aldo Roda
- Department of Chemistry “G. Ciamician”, Alma Mater Studiorum University of Bologna, 40126 Bologna, Italy; (R.A.); (A.R.)
| | - Gaetano La Manna
- Nephrology, Dialysis and Renal Transplant Unit, IRCCS—Azienda Ospedaliero-Universitaria di Bologna, Alma Mater Studiorum University of Bologna, 40138 Bologna, Italy; (C.D.); (A.A.); (M.C.); (D.C.); (F.Z.)
- Correspondence: ; Tel.: +39-051-214-4577
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17
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Landerer S, Kalthoff S, Strassburg CP. UDP-glucuronosyltransferases mediate coffee-associated reduction of liver fibrosis in bile duct ligated humanized transgenic UGT1A mice. Hepatobiliary Surg Nutr 2021; 10:766-781. [PMID: 35004944 DOI: 10.21037/hbsn-20-9] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/06/2020] [Accepted: 04/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Coffee consumption has been shown to reduce the risk of liver fibrosis and is capable of inducing human UDP-glucuronosyltransferase (UGT) 1A genes. UGT1A enzymes act as indirect antioxidants catalyzing the elimination of reactive metabolites, which in turn are potent initiators of profibrotic mechanisms. The aim of this study was to analyze the role of UGT1A genes as effectors of the protective properties of coffee in bile duct ligation (BDL) induced liver fibrosis. METHODS Fourteen days BDL with and without coffee pre- and co-treatment was performed in htgUGT1A-WT and htgUGT1A-SNP mice. Hepatic UGT1A mRNA expression levels, serum bilirubin and aminotransferase activities were determined. Liver fibrosis was assessed by collagen deposition, computational analysis of Sirius red tissue staining and expression of profibrotic marker genes. Oxidative stress was measured by hepatic peroxidase concentrations and immunofluorescence staining. RESULTS UGT1A transcription was differentially activated in the livers of htgUGT1A-WT mice after BDL, in contrast to a reduced or absent induction in the presence of SNPs. Co-treated (coffee + BDL) htgUGT1A-WT-mice showed significantly increased UGT1A expression and protein levels and a considerably higher induction compared to water drinking WT mice (BDL), whereas in co-treated htgUGT1A-SNP mice absolute expression levels remained below those observed in htgUGT1A-WT mice. Collagen deposition, oxidative stress and the expression of profibrotic markers inversely correlated with UGT1A expression levels in htgUGT1A-WT and SNP mice after BDL and coffee + BDL co-treatment. CONCLUSIONS Coffee exerts hepatoprotective and antioxidative effects via activation of UGT1A enzymes. Attenuated hepatic fibrosis as a result of coffee-mediated UGT1A induction during cholestasis was detected, while the protective action of coffee was lower in a common low-function UGT1A SNP haplotype present in 10% of the Caucasian population. This study suggests that coffee consumption might constitute a potential strategy to support the conventional treatment of cholestasis-related liver diseases.
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Affiliation(s)
- Steffen Landerer
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Sandra Kalthoff
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
| | - Christian P Strassburg
- Department of Internal Medicine I, University Hospital Bonn, Venusberg-Campus 1, Bonn, Germany
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18
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Gallucci GM, Trottier J, Hemme C, Assis DN, Boyer JL, Barbier O, Ghonem NS. Adjunct Fenofibrate Up-regulates Bile Acid Glucuronidation and Improves Treatment Response For Patients With Cholestasis. Hepatol Commun 2021; 5:2035-2051. [PMID: 34558841 PMCID: PMC8631103 DOI: 10.1002/hep4.1787] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Revised: 06/10/2021] [Accepted: 06/25/2021] [Indexed: 12/26/2022] Open
Abstract
Accumulation of cytotoxic bile acids (BAs) during cholestasis can result in liver failure. Glucuronidation, a phase II metabolism pathway responsible for BA detoxification, is regulated by peroxisome proliferator-activated receptor alpha (PPARα). This study investigates the efficacy of adjunct fenofibrate therapy to up-regulate BA-glucuronidation and reduce serum BA toxicity during cholestasis. Adult patients with primary biliary cholangitis (PBC, n = 32) and primary sclerosing cholangitis (PSC, n = 23), who experienced an incomplete response while receiving ursodiol monotherapy (13-15 mg/kg/day), defined as serum alkaline phosphatase (ALP) ≥ 1.5 times the upper limit of normal, received additional fenofibrate (145-160 mg/day) as standard of care. Serum BA and BA-glucuronide concentrations were measured by liquid chromatography-mass spectrometry. Combination therapy with fenofibrate significantly decreased elevated serum ALP (-76%, P < 0.001), aspartate transaminase, alanine aminotransferase, bilirubin, total serum BAs (-54%), and increased serum BA-glucuronides (+2.1-fold, P < 0.01) versus ursodiol monotherapy. The major serum BA-glucuronides that were favorably altered following adjunct fenofibrate include hyodeoxycholic acid-6G (+3.7-fold, P < 0.01), hyocholic acid-6G (+2.6-fold, P < 0.05), chenodeoxycholic acid (CDCA)-3G (-36%), and lithocholic acid (LCA)-3G (-42%) versus ursodiol monotherapy. Fenofibrate also up-regulated the expression of uridine 5'-diphospho-glucuronosyltransferases and multidrug resistance-associated protein 3 messenger RNA in primary human hepatocytes. Pearson's correlation coefficients identified strong associations between serum ALP and metabolic ratios of CDCA-3G (r2 = 0.62, P < 0.0001), deoxycholic acid (DCA)-3G (r2 = 0.48, P < 0.0001), and LCA-3G (r2 = 0.40, P < 0.001), in ursodiol monotherapy versus control. Receiver operating characteristic analysis identified serum BA-glucuronides as measures of response to therapy. Conclusion: Fenofibrate favorably alters major serum BA-glucuronides, which correlate with reduced serum ALP levels and improved outcomes. A PPARα-mediated anti-cholestatic mechanism is involved in detoxifying serum BAs in patients with PBC and PSC who have an incomplete response on ursodiol monotherapy and receive adjunct fenofibrate. Serum BA-glucuronides may serve as a noninvasive measure of treatment response in PBC and PSC.
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Affiliation(s)
- Gina M. Gallucci
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
| | - Jocelyn Trottier
- Laboratory of Molecular PharmacologyEndocrinology and Nephrology AxisCHU de Québec Research CenterLavalQuébecCanada
| | - Christopher Hemme
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
- RI‐INBRE Bioinformatics CoreKingstonRIUSA
| | | | | | - Olivier Barbier
- Laboratory of Molecular PharmacologyEndocrinology and Nephrology AxisCHU de Québec Research CenterLavalQuébecCanada
- Faculty of PharmacyLaval UniversityLavalQuébecCanada
| | - Nisanne S. Ghonem
- College of Pharmacy, Biomedical and Pharmaceutical SciencesUniversity of Rhode IslandKingstonRIUSA
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19
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Alamoudi JA, Li W, Gautam N, Olivera M, Meza J, Mukherjee S, Alnouti Y. Bile acid indices as biomarkers for liver diseases I: Diagnostic markers. World J Hepatol 2021; 13:433-455. [PMID: 33959226 PMCID: PMC8080550 DOI: 10.4254/wjh.v13.i4.433] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/05/2021] [Revised: 02/11/2021] [Accepted: 03/22/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Hepatobiliary diseases result in the accumulation of toxic bile acids (BA) in the liver, blood, and other tissues which may contribute to an unfavorable prognosis. AIM To discover and validate diagnostic biomarkers of cholestatic liver diseases based on the urinary BA profile. METHODS We analyzed urine samples by liquid chromatography-tandem mass spectrometry and compared the urinary BA profile between 300 patients with hepatobiliary diseases vs 103 healthy controls by statistical analysis. The BA profile was characterized using BA indices, which quantifies the composition, metabolism, hydrophilicity, and toxicity of the BA profile. BA indices have much lower inter- and intra-individual variability compared to absolute concentrations of BA. In addition, BA indices demonstrate high area under the receiver operating characteristic curves, and changes of BA indices are associated with the risk of having a liver disease, which demonstrates their use as diagnostic biomarkers for cholestatic liver diseases. RESULTS Total and individual BA concentrations were higher in all patients. The percentage of secondary BA (lithocholic acid and deoxycholic acid) was significantly lower, while the percentage of primary BA (chenodeoxycholic acid, cholic acid, and hyocholic acid) was markedly higher in patients compared to controls. In addition, the percentage of taurine-amidation was higher in patients than controls. The increase in the non-12α-OH BA was more profound than 12α-OH BA (cholic acid and deoxycholic acid) causing a decrease in the 12α-OH/ non-12α-OH ratio in patients. This trend was stronger in patients with more advanced liver diseases as reflected by the model for end-stage liver disease score and the presence of hepatic decompensation. The percentage of sulfation was also higher in patients with more severe forms of liver diseases. CONCLUSION BA indices have much lower inter- and intra-individual variability compared to absolute BA concentrations and changes of BA indices are associated with the risk of developing liver diseases.
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Affiliation(s)
- Jawaher Abdullah Alamoudi
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Wenkuan Li
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Nagsen Gautam
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Marco Olivera
- Department of Internal Medicine, College of Medicine, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Jane Meza
- Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, United States
| | - Sandeep Mukherjee
- Department of Internal Medicine, College of Medicine, Creighton University Medical Center, Omaha, NE 68124, United States
| | - Yazen Alnouti
- Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, Omaha, NE 68198, United States.
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20
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Multi-species transcriptome meta-analysis of the response to retinoic acid in vertebrates and comparative analysis of the effects of retinol and retinoic acid on gene expression in LMH cells. BMC Genomics 2021; 22:146. [PMID: 33653267 PMCID: PMC7923837 DOI: 10.1186/s12864-021-07451-2] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 02/18/2021] [Indexed: 12/21/2022] Open
Abstract
Background Retinol (RO) and its active metabolite retinoic acid (RA) are major regulators of gene expression in vertebrates and influence various processes like organ development, cell differentiation, and immune response. To characterize a general transcriptomic response to RA-exposure in vertebrates, independent of species- and tissue-specific effects, four publicly available RNA-Seq datasets from Homo sapiens, Mus musculus, and Xenopus laevis were analyzed. To increase species and cell-type diversity we generated RNA-seq data with chicken hepatocellular carcinoma (LMH) cells. Additionally, we compared the response of LMH cells to RA and RO at different time points. Results By conducting a transcriptome meta-analysis, we identified three retinoic acid response core clusters (RARCCs) consisting of 27 interacting proteins, seven of which have not been associated with retinoids yet. Comparison of the transcriptional response of LMH cells to RO and RA exposure at different time points led to the identification of non-coding RNAs (ncRNAs) that are only differentially expressed (DE) during the early response. Conclusions We propose that these RARCCs stand on top of a common regulatory RA hierarchy among vertebrates. Based on the protein sets included in these clusters we were able to identify an RA-response cluster, a control center type cluster, and a cluster that directs cell proliferation. Concerning the comparison of the cellular response to RA and RO we conclude that ncRNAs play an underestimated role in retinoid-mediated gene regulation. Supplementary Information The online version contains supplementary material available at 10.1186/s12864-021-07451-2.
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21
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Tran QT, Tran VH, Sendler M, Doller J, Wiese M, Bolsmann R, Wilden A, Glaubitz J, Modenbach JM, Thiel FG, de Freitas Chama LL, Weiss FU, Lerch MM, Aghdassi AA. Role of Bile Acids and Bile Salts in Acute Pancreatitis: From the Experimental to Clinical Studies. Pancreas 2021; 50:3-11. [PMID: 33370017 PMCID: PMC7748038 DOI: 10.1097/mpa.0000000000001706] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 10/27/2020] [Indexed: 12/12/2022]
Abstract
ABSTRACT Acute pancreatitis (AP) is one of the most common gastroenterological disorders leading to hospitalization. It has long been debated whether biliary AP, about 30% to 50% of all cases, is induced by bile acids (BAs) when they reach the pancreas via reflux or via the systemic blood circulation.Besides their classical function in digestion, BAs have become an attractive research target because of their recently discovered property as signaling molecules. The underlying mechanisms of BAs have been investigated in various studies. Bile acids are internalized into acinar cells through specific G-protein-coupled BA receptor 1 and various transporters. They can further act via different receptors: the farnesoid X, ryanodine, and inositol triphosphate receptor. Bile acids induce a sustained Ca2+ influx from the endoplasmic reticulum and release of Ca2+ from acidic stores into the cytosol of acinar cells. The overload of intracellular Ca2+ results in mitochondrial depolarization and subsequent acinar cell necrosis. In addition, BAs have a biphasic effect on pancreatic ductal cells. A more detailed characterization of the mechanisms through which BAs contribute to the disease pathogenesis and severity will greatly improve our understanding of the underlying pathophysiology and may allow for the development of therapeutic and preventive strategies for gallstone-inducedAP.
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Affiliation(s)
- Quang Trung Tran
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
- Department of Internal Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Van Huy Tran
- Department of Internal Medicine, Hue University of Medicine and Pharmacy, Hue University, Hue, Vietnam
| | - Matthias Sendler
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Julia Doller
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Mats Wiese
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Robert Bolsmann
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Anika Wilden
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Juliane Glaubitz
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | | | | | | | - Frank Ulrich Weiss
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Markus M. Lerch
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
| | - Ali A. Aghdassi
- From the Department of Medicine A, University Medicine Greifswald, Greifswald, Germany
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22
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Grant SM, DeMorrow S. Bile Acid Signaling in Neurodegenerative and Neurological Disorders. Int J Mol Sci 2020; 21:E5982. [PMID: 32825239 PMCID: PMC7503576 DOI: 10.3390/ijms21175982] [Citation(s) in RCA: 102] [Impact Index Per Article: 20.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 08/18/2020] [Accepted: 08/19/2020] [Indexed: 12/13/2022] Open
Abstract
Bile acids are commonly known as digestive agents for lipids. The mechanisms of bile acids in the gastrointestinal track during normal physiological conditions as well as hepatic and cholestatic diseases have been well studied. Bile acids additionally serve as ligands for signaling molecules such as nuclear receptor Farnesoid X receptor and membrane-bound receptors, Takeda G-protein-coupled bile acid receptor and sphingosine-1-phosphate receptor 2. Recent studies have shown that bile acid signaling may also have a prevalent role in the central nervous system. Some bile acids, such as tauroursodeoxycholic acid and ursodeoxycholic acid, have shown neuroprotective potential in experimental animal models and clinical studies of many neurological conditions. Alterations in bile acid metabolism have been discovered as potential biomarkers for prognosis tools as well as the expression of various bile acid receptors in multiple neurological ailments. This review explores the findings of recent studies highlighting bile acid-mediated therapies and bile acid-mediated signaling and the roles they play in neurodegenerative and neurological diseases.
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Affiliation(s)
- Stephanie M. Grant
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Sharon DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
- Research Division, Central Texas Veterans Healthcare System, Austin, TX 78712, USA
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23
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Meech R, Hu DG, McKinnon RA, Mubarokah SN, Haines AZ, Nair PC, Rowland A, Mackenzie PI. The UDP-Glycosyltransferase (UGT) Superfamily: New Members, New Functions, and Novel Paradigms. Physiol Rev 2019; 99:1153-1222. [DOI: 10.1152/physrev.00058.2017] [Citation(s) in RCA: 103] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
UDP-glycosyltransferases (UGTs) catalyze the covalent addition of sugars to a broad range of lipophilic molecules. This biotransformation plays a critical role in elimination of a broad range of exogenous chemicals and by-products of endogenous metabolism, and also controls the levels and distribution of many endogenous signaling molecules. In mammals, the superfamily comprises four families: UGT1, UGT2, UGT3, and UGT8. UGT1 and UGT2 enzymes have important roles in pharmacology and toxicology including contributing to interindividual differences in drug disposition as well as to cancer risk. These UGTs are highly expressed in organs of detoxification (e.g., liver, kidney, intestine) and can be induced by pathways that sense demand for detoxification and for modulation of endobiotic signaling molecules. The functions of the UGT3 and UGT8 family enzymes have only been characterized relatively recently; these enzymes show different UDP-sugar preferences to that of UGT1 and UGT2 enzymes, and to date, their contributions to drug metabolism appear to be relatively minor. This review summarizes and provides critical analysis of the current state of research into all four families of UGT enzymes. Key areas discussed include the roles of UGTs in drug metabolism, cancer risk, and regulation of signaling, as well as the transcriptional and posttranscriptional control of UGT expression and function. The latter part of this review provides an in-depth analysis of the known and predicted functions of UGT3 and UGT8 enzymes, focused on their likely roles in modulation of levels of endogenous signaling pathways.
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Affiliation(s)
- Robyn Meech
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Dong Gui Hu
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Ross A. McKinnon
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Siti Nurul Mubarokah
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Alex Z. Haines
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Pramod C. Nair
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Andrew Rowland
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
| | - Peter I. Mackenzie
- Department of Clinical Pharmacology and Flinders Centre for Innovation in Cancer, Flinders University College of Medicine and Public Health, Flinders Medical Centre, Bedford Park, South Australia, Australia
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ANXA2, PRKCE, and OXT are critical differentially genes in Nonalcoholic fatty liver disease. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2019; 12:131-137. [PMID: 31191837 PMCID: PMC6536018] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
AIM Identification of prominent genes which are involved in onset and progress of steatosis stage of Nonalcoholic fatty liver disease (NAFLD) is the aim of this study. BACKGROUND NAFLD is characterized by accumulation of lipids in hepatocytes. The patients with steatosis (the first stage of NAFLD) will come across nonalcoholic steatohepatitis (NASH) and finally hepatic cirrhosis. There is correlation between cirrhosis and hepatic cancer. However, ultrasonography is used to diagnose NAFLD, biopsy is the precise diagnostic method. METHODS Gene expression profiles of 14 steatosis patients and 14 controls are retrieved from gene expression omnibus (GEO) and after statistical validation top 250 differentially expressed genes (DEGs) were determined. The characterized DEGs were included in network analysis and the central DEGs were identified. Gene ontology (GO) performed by ClueGO analysis of DEGs to determine critical biological terms. Role of prominent DEGs in steatosis is discussed in details. RESULTS Numbers of 31 significant DEGs including 20 up-regulated and 11 down-regulated ones were determined. Nine biological groups including 27 terms were recognized. Negative regulation of low-density lipoprotein particle receptor catabolic process, TRAM-dependent toll-like receptor signaling pathway, and regulation of hindgut contraction which were related to ANXA2, PRKCE, and OXT respectively were determined as critical biological term groups and DEGS. CONCLUSION Deregulation of ANXA2, PRKCE, and OXT is a critical event in steatosis. It seems these three genes are suitable biomarker to diagnosis of steatosis.
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25
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Li CY, Dempsey JL, Wang D, Lee S, Weigel KM, Fei Q, Bhatt DK, Prasad B, Raftery D, Gu H, Cui JY. PBDEs Altered Gut Microbiome and Bile Acid Homeostasis in Male C57BL/6 Mice. Drug Metab Dispos 2018; 46:1226-1240. [PMID: 29769268 PMCID: PMC6053593 DOI: 10.1124/dmd.118.081547] [Citation(s) in RCA: 55] [Impact Index Per Article: 7.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2018] [Accepted: 05/11/2018] [Indexed: 12/14/2022] Open
Abstract
Polybrominated diphenyl ethers (PBDEs) are persistent environmental contaminants with well characterized toxicities in host organs. Gut microbiome is increasingly recognized as an important regulator of xenobiotic biotransformation; however, little is known about its interactions with PBDEs. Primary bile acids (BAs) are metabolized by the gut microbiome into more lipophilic secondary BAs that may be absorbed and interact with certain host receptors. The goal of this study was to test our hypothesis that PBDEs cause dysbiosis and aberrant regulation of BA homeostasis. Nine-week-old male C57BL/6 conventional (CV) and germ-free (GF) mice were orally gavaged with corn oil (10 mg/kg), BDE-47 (100 μmol/kg), or BDE-99 (100 μmol/kg) once daily for 4 days (n = 3-5/group). Gut microbiome was characterized using 16S rRNA sequencing of the large intestinal content in CV mice. Both BDE-47 and BDE-99 profoundly decreased the alpha diversity of gut microbiome and differentially regulated 45 bacterial species. Both PBDE congeners increased Akkermansia muciniphila and Erysipelotrichaceae Allobaculum spp., which have been reported to have anti-inflammatory and antiobesity functions. Targeted metabolomics of 56 BAs was conducted in serum, liver, and small and large intestinal content of CV and GF mice. BDE-99 increased many unconjugated BAs in multiple biocompartments in a gut microbiota-dependent manner. This correlated with an increase in microbial 7α-dehydroxylation enzymes for secondary BA synthesis and increased expression of host intestinal transporters for BA absorption. Targeted proteomics showed that PBDEs downregulated host BA-synthesizing enzymes and transporters in livers of CV but not GF mice. In conclusion, there is a novel interaction between PBDEs and the endogenous BA-signaling through modification of the "gut-liver axis".
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Affiliation(s)
- Cindy Yanfei Li
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Joseph L Dempsey
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Dongfang Wang
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - SooWan Lee
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Kris M Weigel
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Qiang Fei
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Deepak Kumar Bhatt
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Bhagwat Prasad
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Daniel Raftery
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Haiwei Gu
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
| | - Julia Yue Cui
- Departments of Environmental and Occupational Health Sciences (C.Y.F., J.L.D., S.L., K.M.W., J.Y.C.) and Pharmaceutics (D.K.B., B.P.) and Northwest Metabolomics Research Center, Department of Anesthesiology and Pain Medicine (D.W., Q.F., D.R.), University of Washington, Seattle, Washington; Arizona Metabolomics Laboratory, Center for Metabolic and Vascular Biology, School of Nutrition and Health Promotion, College of Health Solutions, Arizona State University, Phoenix, Arizona (H.G.); Department of Laboratorial Science and Technology, School of Public Health, Peking University, Beijing, P. R. China (D.W.); and Department of Chemistry, Jilin University, Changchun, Jilin Province, P. R. China (Q.F.)
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Urinary Elimination of Bile Acid Glucuronides under Severe Cholestatic Situations: Contribution of Hepatic and Renal Glucuronidation Reactions. Can J Gastroenterol Hepatol 2018; 2018:8096314. [PMID: 29850459 PMCID: PMC5925157 DOI: 10.1155/2018/8096314] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/06/2017] [Accepted: 02/15/2018] [Indexed: 12/23/2022] Open
Abstract
Biliary obstruction, a severe cholestatic complication, causes accumulation of toxic bile acids (BAs) in liver cells. Glucuronidation, catalyzed by UDP-glucuronosyltransferase (UGT) enzymes, detoxifies cholestatic BAs. Using liquid chromatography coupled to tandem mass spectrometry, 11 BA glucuronide (-G) species were quantified in prebiliary and postbiliary stenting serum and urine samples from 17 patients with biliary obstruction. Stenting caused glucuronide- and fluid-specific changes in BA-G levels and BA-G/BA metabolic ratios. In vitro glucuronidation assays with human liver and kidney microsomes revealed that even if renal enzymes generally displayed lower KM values, the two tissues shared similar glucuronidation capacities for BAs. By contrast, major differences between the two tissues were observed when four human BA-conjugating UGTs 1A3, 1A4, 2B4, and 2B7 were analyzed for mRNA and protein levels. Notably, the BA-24G producing UGT1A3 enzyme, abundant in the liver, was not detected in kidney microsomes. In conclusion, the circulating and urinary BA-G profiles are hugely impacted under severe cholestasis. The similar BA-glucuronidating abilities of hepatic and renal extracts suggest that both the liver and kidney may contribute to the urine BA-G pool.
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N-3 Polyunsaturated Fatty Acids Stimulate Bile Acid Detoxification in Human Cell Models. Can J Gastroenterol Hepatol 2018; 2018:6031074. [PMID: 29850457 PMCID: PMC5907406 DOI: 10.1155/2018/6031074] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2017] [Accepted: 02/07/2018] [Indexed: 01/16/2023] Open
Abstract
Cholestasis is characterized by the accumulation of toxic bile acids (BAs) in liver cells. The present study aimed to evaluate the effects of n-3 polyunsaturated fatty acids (n-3 PUFAs), such as docosahexaenoic (DHA) and eicosapentaenoic (EPA) acids, on BA homeostasis and toxicity in human cell models. The effects of EPA and/or DHA on the expression of genes involved in the maintenance of BA homeostasis were analyzed in human hepatoma (HepG2) and colon carcinoma (Caco-2) cells, as well as in primary culture of human intestinal (InEpC) and renal (RPTEC) cells. Extracellular BA species were quantified in culture media using LC-MS/MS. BA-induced toxicity was evaluated using caspase-3 and flow cytometry assays. Gene expression analyses of HepG2 cells reveal that n-3 PUFAs reduce the expression of genes involved in BA synthesis (CYP7A1, CYP27A1) and uptake (NTCP), while activating genes encoding metabolic enzymes (SULT2A1) and excretion transporters (MRP2, MRP3). N-3 PUFAs also generate a less toxic BA pool and prevent the BA-dependent activation of apoptosis in HepG2 cells. Conclusion. The present study reveals that n-3 PUFAs stimulate BA detoxification.
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Mostarda S, Passeri D, Carotti A, Cerra B, Colliva C, Benicchi T, Macchiarulo A, Pellicciari R, Gioiello A. Synthesis, physicochemical properties, and biological activity of bile acids 3-glucuronides: Novel insights into bile acid signalling and detoxification. Eur J Med Chem 2017; 144:349-358. [PMID: 29275233 DOI: 10.1016/j.ejmech.2017.12.034] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2017] [Revised: 11/29/2017] [Accepted: 12/11/2017] [Indexed: 12/21/2022]
Abstract
Glucuronidation is considered an important detoxification pathway of bile acids especially in cholestatic conditions. Glucuronides are less toxic than the parent free forms and are more easily excreted in urine. However, the pathophysiological significance of bile acid glucuronidation is still controversial and debated among the scientific community. Progress in this field has been strongly limited by the lack of appropriate methods for the preparation of pure glucuronides in the amount needed for biological and pharmacological studies. In this work, we have developed a new synthesis of bile acid C3-glucuronides enabling the convenient preparation of gram-scale quantities. The synthesized compounds have been characterized in terms of physicochemical properties and abilities to modulate key nuclear receptors including the farnesoid X receptor (FXR). In particular, we found that C3-glucuronides of chenodeoxycholic acid and lithocholic acid, respectively the most abundant and potentially cytotoxic species formed in patients affected by cholestasis, behave as FXR agonists and positively regulate the gene expression of transporter proteins, the function of which is critical in human conditions related to imbalances of bile acid homeostasis.
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Affiliation(s)
- Serena Mostarda
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | | | - Andrea Carotti
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | - Bruno Cerra
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | | | | | - Antonio Macchiarulo
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy
| | | | - Antimo Gioiello
- Department of Pharmaceutical Sciences, University of Perugia, Via del Liceo, 1, 06123 Perugia, Italy.
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29
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Pallister T, Jackson MA, Martin TC, Zierer J, Jennings A, Mohney RP, MacGregor A, Steves CJ, Cassidy A, Spector TD, Menni C. Hippurate as a metabolomic marker of gut microbiome diversity: Modulation by diet and relationship to metabolic syndrome. Sci Rep 2017; 7:13670. [PMID: 29057986 PMCID: PMC5651863 DOI: 10.1038/s41598-017-13722-4] [Citation(s) in RCA: 193] [Impact Index Per Article: 24.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2017] [Accepted: 09/25/2017] [Indexed: 01/07/2023] Open
Abstract
Reduced gut microbiome diversity is associated with multiple disorders including metabolic syndrome (MetS) features, though metabolomic markers have not been investigated. Our objective was to identify blood metabolite markers of gut microbiome diversity, and explore their relationship with dietary intake and MetS. We examined associations between Shannon diversity and 292 metabolites profiled by the untargeted metabolomics provider Metabolon Inc. in 1529 females from TwinsUK using linear regressions adjusting for confounders and multiple testing (Bonferroni: P < 1.71 × 10-4). We replicated the top results in an independent sample of 420 individuals as well as discordant identical twin pairs and explored associations with self-reported intakes of 20 food groups. Longitudinal changes in circulating levels of the top metabolite, were examined for their association with food intake at baseline and with MetS at endpoint. Five metabolites were associated with microbiome diversity and replicated in the independent sample. Higher intakes of fruit and whole grains were associated with higher levels of hippurate cross-sectionally and longitudinally. An increasing hippurate trend was associated with reduced odds of having MetS (OR: 0.795[0.082]; P = 0.026). These data add further weight to the key role of the microbiome as a potential mediator of the impact of dietary intake on metabolic status and health.
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Affiliation(s)
- Tess Pallister
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK
| | - Matthew A Jackson
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK
| | - Tiphaine C Martin
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK
| | - Jonas Zierer
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.,Institute of Bioinformatics and Systems Biology, Helmholtz Zentrum München, Neuherberg, Germany
| | - Amy Jennings
- Department of Nutrition & Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK
| | | | - Alexander MacGregor
- Department of Nutrition & Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Claire J Steves
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK
| | - Aedin Cassidy
- Department of Nutrition & Preventive Medicine, Norwich Medical School, University of East Anglia, Norwich, UK
| | - Tim D Spector
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK
| | - Cristina Menni
- Department of Twin Research and Genetic Epidemiology, King's College London, London, SE1 7EH, UK.
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30
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Unsworth AJ, Bye AP, Tannetta DS, Desborough MJR, Kriek N, Sage T, Allan HE, Crescente M, Yaqoob P, Warner TD, Jones CI, Gibbins JM. Farnesoid X Receptor and Liver X Receptor Ligands Initiate Formation of Coated Platelets. Arterioscler Thromb Vasc Biol 2017; 37:1482-1493. [PMID: 28619996 PMCID: PMC5526435 DOI: 10.1161/atvbaha.117.309135] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 05/30/2017] [Indexed: 12/20/2022]
Abstract
OBJECTIVES The liver X receptors (LXRs) and farnesoid X receptor (FXR) have been identified in human platelets. Ligands of these receptors have been shown to have nongenomic inhibitory effects on platelet activation by platelet agonists. This, however, seems contradictory with the platelet hyper-reactivity that is associated with several pathological conditions that are associated with increased circulating levels of molecules that are LXR and FXR ligands, such as hyperlipidemia, type 2 diabetes mellitus, and obesity. APPROACH AND RESULTS We, therefore, investigated whether ligands for the LXR and FXR receptors were capable of priming platelets to the activated state without stimulation by platelet agonists. Treatment of platelets with ligands for LXR and FXR converted platelets to the procoagulant state, with increases in phosphatidylserine exposure, platelet swelling, reduced membrane integrity, depolarization of the mitochondrial membrane, and microparticle release observed. Additionally, platelets also displayed features associated with coated platelets such as P-selectin exposure, fibrinogen binding, fibrin generation that is supported by increased serine protease activity, and inhibition of integrin αIIbβ3. LXR and FXR ligand-induced formation of coated platelets was found to be dependent on both reactive oxygen species and intracellular calcium mobilization, and for FXR ligands, this process was found to be dependent on cyclophilin D. CONCLUSIONS We conclude that treatment with LXR and FXR ligands initiates coated platelet formation, which is thought to support coagulation but results in desensitization to platelet stimuli through inhibition of αIIbβ3 consistent with their ability to inhibit platelet function and stable thrombus formation in vivo.
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Affiliation(s)
- Amanda J Unsworth
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Alexander P Bye
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Dionne S Tannetta
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Michael J R Desborough
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Neline Kriek
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Tanya Sage
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Harriet E Allan
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Marilena Crescente
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Parveen Yaqoob
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Timothy D Warner
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Chris I Jones
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.)
| | - Jonathan M Gibbins
- From the Institute of Cardiovascular and Metabolic Research, School of Biological Sciences (A.J.U., A.P.B., N.K., T.S., M.C., C.I.J., J.M.G.) and Department of Food and Nutritional Sciences (D.S.T., P.Y.), University of Reading, United Kingdom; Oxford Haemophilia and Thrombosis Centre, Oxford Biomedical Research Centre, Churchill Hospital, United Kingdom (M.J.R.D.); Nuffield Division of Clinical Laboratory Sciences, University of Oxford, United Kingdom (M.J.R.D.); and Blizard Institute, Barts & the London School of Medicine & Dentistry, United Kingdom (H.E.A., M.C., T.D.W.).
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31
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Perreault M, Maltais R, Dutour R, Poirier D. Explorative study on the anticancer activity, selectivity and metabolic stability of related analogs of aminosteroid RM-133. Steroids 2016; 115:105-113. [PMID: 27553727 DOI: 10.1016/j.steroids.2016.08.015] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2016] [Revised: 07/29/2016] [Accepted: 08/13/2016] [Indexed: 12/16/2022]
Abstract
RM-133 is a key representative of a new family of aminosteroids reported as potent anticancer agents. Although RM-133 produced interesting results in 4 mouse xenograft cancer models when injected subcutaneously, it needs to be improved to increase its in vivo potency. Thus, to obtain an analog of RM-133 with a better drug potential, a structure-activity relationship study was conducted by synthesizing eleven RM-133-related compounds and addressing their antiproliferative activity on 3 human cancer cells (HL-60, OVCAR-3 and PANC-1) and 3 human normal cell lines (primary ovary, pancreas and renal proximal tubule) as well as their metabolic stability in human liver microsomes. When the 2β-tertiary amine of RM-133 was transformed into a salt or moved to position 3β, the anticancer activity was lost. Modifying the orientation of the side chain of RM-133 increased anticancer activity and selectivity, but led to a drastic loss of stability. The protection of the 3α-hydroxyl of RM-133 by the formation of an ester or a carbamate stabilized the molecule against the phase I metabolic enzymes without affecting its anticancer activity. In comparison to RM-133, the 3-dimethylcarbamate derivative 3 is more selective for cancer cells over normal cells and is much more stable in liver microsomes. Those results support the use of a pro-drug strategy targeting the 3α-hydroxyl of RM-133 as an approach to improve its drug properties. The work presented will enable the development of an optimized anticancer drug of the aminosteroid family that is suitable for a future phase I clinical trial.
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Affiliation(s)
- Martin Perreault
- Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada
| | - René Maltais
- Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada
| | - Raphaël Dutour
- Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada
| | - Donald Poirier
- Laboratory of Medicinal Chemistry, Endocrinology and Nephrology Unit, CHU de Québec - Research Center, Québec (Québec), Canada; Department of Molecular Medicine, Faculty of Medicine, Université Laval, Québec (Québec), Canada.
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32
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Yang F, Tang X, Ding L, zhou Y, Yang Q, Gong J, Wang G, Wang Z, Yang L. Curcumin protects ANIT-induced cholestasis through signaling pathway of FXR-regulated bile acid and inflammation. Sci Rep 2016; 6:33052. [PMID: 27624003 PMCID: PMC5021964 DOI: 10.1038/srep33052] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2016] [Accepted: 08/15/2016] [Indexed: 12/16/2022] Open
Abstract
Cholestasis is a clinically significant symptom and widely associated with liver diseases, however, there are very few effective therapies for cholestasis. Danning tablet (DNT, a Chinese patent medicine preparation) has been clinically used to treat human liver and gallbladder diseases for more than 20 years in China. However, which ingredients of DNT contributed to this beneficial effect and their mechanistic underpinnings have been largely unknown. In the present study, we discovered that DNT not only demonstrated greater benefits for cholecystitis patients after cholecystectomy surgery in clinic but also showed protective effect against alpha-naphthylisothiocyanate (ANIT)-induced cholestasis model in rodent. Curcumin, one major compound derived from DNT, exerted the protective effect against cholestasis through farnesoid X receptor (FXR), which has been focused as potential therapeutic targets for treating cholestasis. The underlying mechanism of curcumin against cholestasis was restoring bile acid homeostasis and antagonizing inflammatory responses in a FXR-dependent manner and in turn contributed to overall cholestasis attenuation. Collectively, curcumin can be served as a potential treatment option for liver injury with cholestasis.
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Affiliation(s)
- Fan Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xiaowen Tang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Lili Ding
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Yue zhou
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Qiaoling Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Junting Gong
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Guangyun Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengtao Wang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li Yang
- The MOE Key Laboratory for Standardization of Chinese Medicines and the Shanghai Key Laboratory of Compound Chinese Medicines Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Center for Chinese Medical Therapy and Systems Biology, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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Bile acids in drug induced liver injury: Key players and surrogate markers. Clin Res Hepatol Gastroenterol 2016; 40:257-266. [PMID: 26874804 DOI: 10.1016/j.clinre.2015.12.017] [Citation(s) in RCA: 63] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2015] [Revised: 12/21/2015] [Accepted: 12/27/2015] [Indexed: 02/04/2023]
Abstract
Bile acid research has gained great momentum since the role of bile acids as key signaling molecules in the enterohepatic circulation was discovered. Their physiological function in regulating their own homeostasis, as well as energy and lipid metabolism make them interesting targets for the pharmaceutical industry in the context of diseases such as bile acid induced diarrhea, bile acid induced cholestasis or nonalcoholic steatohepatitis. Changes in bile acid homeostasis are also linked to various types of drug-induced liver injury (DILI). However, the key question whether bile acids are surrogate markers for monitoring DILI or key pathogenic players in the onset and progression of DILI is under intense investigation. The purpose of this review is to summarize the different facets of bile acids in the context of normal physiology, hereditary defects of bile acid transport and DILI.
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Dawson PA, Karpen SJ. Intestinal transport and metabolism of bile acids. J Lipid Res 2014; 56:1085-99. [PMID: 25210150 DOI: 10.1194/jlr.r054114] [Citation(s) in RCA: 401] [Impact Index Per Article: 36.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2014] [Indexed: 12/17/2022] Open
Abstract
In addition to their classical roles as detergents to aid in the process of digestion, bile acids have been identified as important signaling molecules that function through various nuclear and G protein-coupled receptors to regulate a myriad of cellular and molecular functions across both metabolic and nonmetabolic pathways. Signaling via these pathways will vary depending on the tissue and the concentration and chemical structure of the bile acid species. Important determinants of the size and composition of the bile acid pool are their efficient enterohepatic recirculation, their host and microbial metabolism, and the homeostatic feedback mechanisms connecting hepatocytes, enterocytes, and the luminal microbiota. This review focuses on the mammalian intestine, discussing the physiology of bile acid transport, the metabolism of bile acids in the gut, and new developments in our understanding of how intestinal metabolism, particularly by the gut microbiota, affects bile acid signaling.
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Affiliation(s)
- Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322
| | - Saul J Karpen
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322
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Miao W, Jin Y, Lin X, Fu Z. Differential expression of the main polycyclic aromatic hydrocarbon responsive genes in the extrahepatic tissues of mice. ENVIRONMENTAL TOXICOLOGY AND PHARMACOLOGY 2014; 37:885-894. [PMID: 24681596 DOI: 10.1016/j.etap.2014.03.001] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/10/2013] [Revised: 02/28/2014] [Accepted: 03/01/2014] [Indexed: 06/03/2023]
Abstract
UNLABELLED The hepatic toxic effects, including carcinogenicity and oxidative stress, of polycyclic aromatic hydrocarbons (PAHs) have been extensively studied in recent years. Previous reports have demonstrated that 3-methylcholanthrene (3MC) is capable of altering the expression of aryl hydrocarbon receptor (AHR)-regulated genes and antioxidant genes in liver, but little is known about the expression patterns in other tissues. To investigate whether similar effects could occur in the extrahepatic tissues, adult male ICR mice were received an intraperitoneal injection of 100 mg/kg 3MC and then analyzed after 6 and 24 h. We observed that the constitutive expression of AHR- and antioxidant-related genes was in a tissue-specific manner. Moreover, acute 3MC exposure significantly increased the mRNA levels of Cyp1a1 and Cyp1b1 in all the lung, kidney and heart. As to antioxidant genes, 3MC induced the transcription of glutathione reductase (Gr) in the lung and kidney at 24 h and the transcription of glutathione peroxidase 1 (Gpx1) in the lung and kidney at 6 and 24 h. Glutathione-S-transferase A1 (Gsta1) was significantly reduced in the kidney at 24 h, while no effect was observed in the lung and heart. The mRNA levels of NAD(P)H quinone oxidoreductase 1 (Nqo1) were induced by 3MC in all the lung, kidney and heart. Although the constitutive expression of catalase (Cat) is very low in the heart, the transcription of Cat was significantly induced both at 6 and 24 h. No significant alternation in the transcription of glutathione synthetase (Gss), heme oxygenase 1 (Ho-1) and superoxide dismutase 1 (Sod1) was observed in all tissues. Taken together, ours findings suggested that the expression of AHR- and antioxidant-related genes in a tissue-specific manner with or without treatment of a PAH.
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Affiliation(s)
- Wenyu Miao
- College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Yuanxiang Jin
- College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Xiaojian Lin
- College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China
| | - Zhengwei Fu
- College of Biological and Environmental Engineering, Zhejiang University of Technology, Hangzhou 310032, China.
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