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1
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Zhang C, Wang J. Adverse events associated with obeticholic acid: a real-world, pharmacovigilance study. Expert Opin Drug Saf 2025:1-9. [PMID: 40162628 DOI: 10.1080/14740338.2025.2487144] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2024] [Accepted: 03/17/2025] [Indexed: 04/02/2025]
Abstract
BACKGROUND Primary biliary cholangitis (PBC) is a chronic autoimmune liver disease predominantly affecting middle-aged women. While ursodeoxycholic acid (UDCA) is the first-line treatment, 30-40% of patients do not respond adequately, necessitating alternative therapies like Obeticholic Acid (OCA), an FXR agonist. The long-term safety of OCA remains insufficiently studied. RESEARCH DESIGN AND METHODS This study utilized the US FDA Adverse Event Reporting System (FAERS) to evaluate OCA safety through large-scale data mining, using disproportionality analyses (ROR, PRR, BCPNN, and MGPS) to identify adverse event signals. RESULTS From Q2 2016 to Q1 2024, 5,864 reports linked to OCA usage were identified among 13,245,871 AE reports. Significant signals across 27 System Organ Classes were found, with pruritus (12.54%), fatigue (4.16%), and nausea (1.64%) being the most prevalent adverse events. Severe hepatic events like liver failure were rare (0.6%). Median time to onset of AEs was 178 days. The most common outcomes reported were important medical events (18.6%), hospitalization (17.8%), and death (6.5%). CONCLUSION This study provides key insights into the safety profile of OCA, highlighting the importance of monitoring for pruritus and hepatic complications, particularly within the first six months of treatment.
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Affiliation(s)
- Chunxia Zhang
- Department of Gastroenterology, Inner Mongolia Forestry General Hospital, Yakeshi, Inner Mongolia, China
| | - Jianguo Wang
- Department of Hepatobiliary Surgery, Inner Mongolia Forestry General Hospital, Yakeshi, Inner Mongolia, China
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2
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Sundaram S, Jagadeesan A, Paulraj RS, Sundaram U, Arthur S. Novel Expression of Apical Bile Acid Transport (ASBT) More Proximally Than Distal Ileum Contributing to Enhanced Intestinal Bile Acid Absorption in Obesity. Int J Mol Sci 2024; 25:11452. [PMID: 39519005 PMCID: PMC11547122 DOI: 10.3390/ijms252111452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/28/2024] [Revised: 10/18/2024] [Accepted: 10/23/2024] [Indexed: 11/16/2024] Open
Abstract
Dietary lipid absorption is facilitated by bile acids. In the Zucker rat (ZR) model of obesity, bile acid absorption, mediated by the apical sodium bile acid transporter (ASBT), was increased in villus cells from the distal ileum. However, whether ASBT may be de novo expressed more proximally in the small intestine during obesity to facilitate additional bile acid absorption is not known. For this, starting from the end of the ileum to the mid jejunum, caudal-orally, five intestinal segments of equal length (S1-S5) were separated from lean and obese ZRs (LZR and OZR). Intestinal mucosa obtained from these segments were used for total RNA extraction, RT-qPCR and 3H-TCA uptake. The results showed that bile acid absorption along with the mRNA expression of ASBT and FXR progressively decreased caudal-orally in both LZRs and OZRs but was significantly higher in all small intestinal segments in OZRs. The expression of GATA4 was absent in the distal ileum (S1) in both LZRs and OZRs, but steadily increased along the proximal length in both. However, this steady increase was significantly reduced in the comparative obese proximal intestinal segments S2, S3, S4 and S5. The expressions of bile acid-activated G-protein-coupled bile acid receptor TGR5 and S1PR2 were unaltered in segments S1-S4 but were significantly increased in OZR S5. The paradigm changing observation of this study is that ASBT is expressed more proximally in the small intestine in obesity. This likely increases overall bile acid absorption and thereby lipid absorption in the proximal small intestine in obesity.
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3
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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4
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Xu R, Zhang L, Pan H, Zhang Y. Retinoid X receptor heterodimers in hepatic function: structural insights and therapeutic potential. Front Pharmacol 2024; 15:1464655. [PMID: 39478961 PMCID: PMC11521896 DOI: 10.3389/fphar.2024.1464655] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2024] [Accepted: 09/30/2024] [Indexed: 11/02/2024] Open
Abstract
Nuclear receptors (NRs) are key regulators of multiple physiological functions and pathological changes in the liver in response to a variety of extracellular signaling changes. Retinoid X receptor (RXR) is a special member of the NRs, which not only responds to cellular signaling independently, but also regulates multiple signaling pathways by forming heterodimers with various other NR. Therefore, RXR is widely involved in hepatic glucose metabolism, lipid metabolism, cholesterol metabolism and bile acid homeostasis as well as hepatic fibrosis. Specific activation of particular dimers regulating physiological and pathological processes may serve as important pharmacological targets. So here we describe the basic information and structural features of the RXR protein and its heterodimers, focusing on the role of RXR heterodimers in a number of physiological processes and pathological imbalances in the liver, to provide a theoretical basis for RXR as a promising drug target.
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Affiliation(s)
- Renjie Xu
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Linyue Zhang
- Department of Ultrasound, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hao Pan
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Yong Zhang
- Department of Hepatobiliary Surgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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5
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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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Sun D, Xie C, Zhao Y, Liao J, Li S, Zhang Y, Wang D, Hua K, Gu Y, Du J, Huang G, Huang J. The gut microbiota-bile acid axis in cholestatic liver disease. Mol Med 2024; 30:104. [PMID: 39030473 PMCID: PMC11265038 DOI: 10.1186/s10020-024-00830-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2024] [Accepted: 05/07/2024] [Indexed: 07/21/2024] Open
Abstract
Cholestatic liver diseases (CLD) are characterized by impaired normal bile flow, culminating in excessive accumulation of toxic bile acids. The majority of patients with CLD ultimately progress to liver cirrhosis and hepatic failure, necessitating liver transplantation due to the lack of effective treatment. Recent investigations have underscored the pivotal role of the gut microbiota-bile acid axis in the progression of hepatic fibrosis via various pathways. The obstruction of bile drainage can induce gut microbiota dysbiosis and disrupt the intestinal mucosal barrier, leading to bacteria translocation. The microbial translocation activates the immune response and promotes liver fibrosis progression. The identification of therapeutic targets for modulating the gut microbiota-bile acid axis represents a promising strategy to ameliorate or perhaps reverse liver fibrosis in CLD. This review focuses on the mechanisms in the gut microbiota-bile acids axis in CLD and highlights potential therapeutic targets, aiming to lay a foundation for innovative treatment approaches.
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Affiliation(s)
- Dayan Sun
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Chuanping Xie
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yong Zhao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Junmin Liao
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Shuangshuang Li
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yanan Zhang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Dingding Wang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Kaiyun Hua
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Yichao Gu
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Jingbin Du
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China
| | - Guoxian Huang
- Department of Pediatric Surgery, Women and Children's Hospital, School of Medicine, Xiamen University, Xiamen, Fujian, 361000, China
| | - Jinshi Huang
- Department of Neonatal Surgery, Beijing Children's Hospital, Capital Medical University, National Center for Children's Health, No. 56 Nalishi Road, Xicheng District, Beijing, 100045, China.
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7
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Newman NK, Monnier PM, Rodrigues RR, Gurung M, Vasquez-Perez S, Hioki KA, Greer RL, Brown K, Morgun A, Shulzhenko N. Host response to cholestyramine can be mediated by the gut microbiota. MICROBIOME RESEARCH REPORTS 2024; 3:40. [PMID: 39741955 PMCID: PMC11684918 DOI: 10.20517/mrr.2023.82] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 12/30/2023] [Revised: 06/09/2024] [Accepted: 06/24/2024] [Indexed: 01/03/2025]
Abstract
Background: The gut microbiota has been implicated as a major factor contributing to metabolic diseases and the response to drugs used for the treatment of such diseases. In this study, we tested the effect of cholestyramine, a bile acid sequestrant that reduces blood cholesterol, on the murine gut microbiota and metabolism. We also explored the hypothesis that some effects of this drug on systemic metabolism can be attributed to alterations in the gut microbiota. Methods: We used a Western diet (WD) for 8 weeks to induce metabolic disease in mice, then treated some mice with cholestyramine added to WD. Metabolic phenotyping, gene expression in liver and ileum, and microbiota 16S rRNA genes were analyzed. Then, transkingdom network analysis was used to find candidate microbes for the cholestyramine effect. Results: We observed that cholestyramine decreased glucose and epididymal fat levels and detected dysregulation of genes known to be regulated by cholestyramine in the liver and ileum. Analysis of gut microbiota showed increased alpha diversity in cholestyramine-treated mice, with fourteen taxa showing restoration of relative abundance to levels resembling those in mice fed a control diet. Using transkingdom network analysis, we inferred two amplicon sequence variants (ASVs), one from the Lachnospiraceae family (ASV49) and the other from the Muribaculaceae family (ASV1), as potential regulators of cholestyramine effects. ASV49 was also negatively linked with glucose levels, further indicating its beneficial role. Conclusion: Our results indicate that the gut microbiota has a role in the beneficial effects of cholestyramine and suggest specific microbes as targets of future investigations.
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Affiliation(s)
- Nolan K. Newman
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Philip M. Monnier
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Richard R. Rodrigues
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Manoj Gurung
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Stephany Vasquez-Perez
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kaito A. Hioki
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Renee L. Greer
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
| | - Kevin Brown
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Andrey Morgun
- Department of Pharmaceutical Sciences, College of Pharmacy, Oregon State University, Corvallis, OR 97331, USA
| | - Natalia Shulzhenko
- Department of Biomedical Sciences, Carson College of Veterinary Medicine, Oregon State University, Corvallis, OR 97331, USA
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8
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Lee DN, Yang SB, Kweon S, Lee JH, Lee KJ, Ryu Y, Shin DW, Kim YJ, Lee YK, Park J. Design and development of novel self-assembled catechol-modified bile acid conjugates as pH-responsive apical sodium-dependent bile acid transporter targeting nanoparticles. Biomaterials 2024; 308:122539. [PMID: 38552366 DOI: 10.1016/j.biomaterials.2024.122539] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2023] [Revised: 02/21/2024] [Accepted: 03/18/2024] [Indexed: 05/03/2024]
Abstract
Catechol-based biomaterials demonstrate biocompatibility, making them suitable for a wide range of therapeutic applications when integrated into various molecular frameworks. However, the development of orally available catechol-based biomaterials has been hindered by significant pH variations and complex interactions in the gastrointestinal (GI) tract. In this study, we introduce a novel catechol-modified bile acid (CMBA), which is synthesized by anchoring the FDA-approved drug, ursodeoxycholic acid to the neurotransmitter dopamine. This modification could form a new apical sodium-dependent bile acid transporter (ASBT) inhibitor (ASBTi) due to the bile acid moiety. The computational analysis using the TRAnsient Pockets in Proteins (TRAPP) module, coupled with MD simulations, revealed that CMBA exhibits a strong binding affinity at residues 51-55 of ASBT with a low inhibitory constant (Ki) value. Notably, in slightly alkaline biological conditions, CMBA molecules self-assemble into carrier-free nanoparticles with an average size of 240.2 ± 44.2 nm, while maintaining their ability to bind with ASBT. When administered orally, CMBA accumulates in the ileum and liver over 24 h, exhibiting significant therapeutic effects on bile acid (BA) metabolism in a high-fat diet (HFD)-fed mouse model. This study underscores the therapeutic potential of the newly developed catechol-based, pH-responsive ASBT-inhibiting nanoparticles presenting a promising avenue for advancing therapy.
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Affiliation(s)
- Dong-Nyeong Lee
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Seong-Bin Yang
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Seho Kweon
- Department of Molecular Medicine and Biopharmaceutical Science, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, Republic of Korea; College of Pharmacy, Research Institute of Pharmaceutical Sciences, Chonnam National University, Gwangju, 61186, Republic of Korea
| | - Jun-Hyuck Lee
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Kyeong-Ju Lee
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Yeonsu Ryu
- Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Dong Wook Shin
- College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Young Jun Kim
- Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea
| | - Yong-Kyu Lee
- Department of Green Bio Engineering, Graduate School, Korea National University of Transportation, Chungju, 27469, Republic of Korea.
| | - Jooho Park
- BK21 Program, Department of Applied Life Science, Konkuk University, Chungju, 27478, Republic of Korea; Department of Biomedical Chemistry, College of Biomedical and Health Science, Konkuk University, Chungju, 27478, Republic of Korea.
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9
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van Hooff MC, Werner E, van der Meer AJ. Treatment in primary biliary cholangitis: Beyond ursodeoxycholic acid. Eur J Intern Med 2024; 124:14-21. [PMID: 38307734 DOI: 10.1016/j.ejim.2024.01.030] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2023] [Revised: 01/17/2024] [Accepted: 01/19/2024] [Indexed: 02/04/2024]
Abstract
Primary biliary cholangitis (PBC) is a rare cholestatic immune-mediated liver disease. The clinical course varies from mild to severe, with a substantial group of patients developing cirrhosis within a decade. These patients are at risk of hepatocellular carcinoma, decompensation and liver failure. First line Ursodeoxycholic acid (UDCA) treatment improves the cholestatic surrogate markers, and was recently associated with a favorable survival free of liver transplantation, even in case of an incomplete biochemical response. However, despite adequate UDCA therapy, patients remain at risk of liver disease progression. Therefore, on-treatment multifactor-based risk stratification is necessary to identify patients in need of additional therapy. This requires a personalized approach; especially as recent studies suggest that complete biochemical normalization as most stringent response criterion might be preferred in selected patients to optimize their outcome. Today, stricter biochemical goals might actually be reachable with the addition of farnesoid X receptor or peroxisome proliferator-activated receptor agonists, or, in highly-selected cases, use of corticosteroids. Randomized controlled trials showed improvements in the key biochemical surrogate markers with the addition of these drugs, which have also been associated with improved clinical outcome. Considering this evolving PBC landscape, with more versatile treatment options and treatment goals, this review recapitulates the recent insight in UDCA therapy, the selection of patients with a residual risk of liver disease progression and the results of the currently available second line treatment options.
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Affiliation(s)
- M C van Hooff
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - E Werner
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands
| | - A J van der Meer
- Department of Gastroenterology and Hepatology, Erasmus MC, University Medical Center Rotterdam, Doctor Molewaterplein 40, NA building, Floor 6, Rotterdam 3015 GD, the Netherlands.
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10
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Cheng Z, Chen Y, Schnabl B, Chu H, Yang L. Bile acid and nonalcoholic steatohepatitis: Molecular insights and therapeutic targets. J Adv Res 2024; 59:173-187. [PMID: 37356804 PMCID: PMC11081971 DOI: 10.1016/j.jare.2023.06.009] [Citation(s) in RCA: 9] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/06/2023] [Accepted: 06/20/2023] [Indexed: 06/27/2023] Open
Abstract
BACKGROUND Nonalcoholic steatohepatitis (NASH) has been the second most common cause of liver transplantation in the United States. To date, NASH pathogenesis has not been fully elucidated but is multifactorial, involving insulin resistance, obesity, metabolic disorders, diet, dysbiosis, and gene polymorphism. An effective and approved therapy for NASH has also not been established. Bile acid is long known to have physiological detergent function in emulsifying and absorbing lipids and lipid-soluble molecules within the intestinal lumen. With more and more in-depth understandings of bile acid, it has been deemed to be a pivotal signaling molecule, which is capable of regulating lipid and glucose metabolism, liver inflammation, and fibrosis. In recent years, a plethora of studies have delineated that disrupted bile acid homeostasis is intimately correlated with NASH disease severity. AIMS The review aims to clarify the role of bile acid in hepatic lipid and glucose metabolism, liver inflammation, as well as liver fibrosis, and discusses the safety and efficacy of some pharmacological agents targeting bile acid and its associated pathways for NASH. KEY SCIENTIFIC CONCEPTS OF REVIEW Bile acid has a salutary effect on hepatic metabolic disorders, which can ameliorate liver fat accumulation and insulin resistance mainly through activating Takeda G-protein coupled receptor 5 and farnesoid X receptor. Moreover, bile acid also exerts anti-inflammation and anti-fibrosis properties. Furthermore, bile acid has great potential in nonalcoholic liver disease stratification and treatment of NASH.
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Affiliation(s)
- Zilu Cheng
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Yixiong Chen
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China
| | - Bernd Schnabl
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Huikuan Chu
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
| | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan, Hubei Province 430022, China.
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11
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Burchat N, Vidola J, Pfreundschuh S, Sharma P, Rizzolo D, Guo GL, Sampath H. Intestinal stearoyl-CoA desaturase-1 regulates energy balance via alterations in bile acid homeostasis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.01.12.575400. [PMID: 38260602 PMCID: PMC10802577 DOI: 10.1101/2024.01.12.575400] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/24/2024]
Abstract
Background and Aims Stearoyl-CoA desaturase-1 (SCD1) converts saturated fatty acids into monounsaturated fatty acids and plays an important regulatory role in lipid metabolism. Previous studies have demonstrated that mice deficient in SCD1 are protected from diet-induced obesity and hepatic steatosis due to altered lipid esterification and increased energy expenditure. Previous studies in our lab have shown that intestinal SCD1 modulates intestinal and plasma lipids and alters cholesterol metabolism. Here we investigated a novel role for intestinal SCD1 in the regulation of systemic energy balance. Methods To interrogate the role of intestinal SCD1 in modulating whole body metabolism, intestine-specific Scd1 knockout (iKO) mice were maintained on standard chow diet or challenged with a high-fat diet (HFD). Studies included analyses of bile acid content and composition, metabolic phenotyping including body composition, indirect calorimetry, glucose tolerance analyses, and assessment of bile acid signaling pathways. Results iKO mice displayed elevated plasma and hepatic bile acid content and decreased fecal bile acid excretion, associated with increased expression of the ileal bile acid uptake transporter, Asbt . These increases were associated with increased expression of TGR5 targets, including Dio2 in brown adipose tissue and elevated plasma glucagon-like peptide-1 levels. Upon HFD challenge, iKO mice had reduced metabolic efficiency apparent through decreased weight gain despite higher food intake. Concomitantly, energy expenditure was increased, and glucose tolerance was improved in HFD-fed iKO mice. Conclusion Our results indicate that deletion of intestinal SCD1 has significant impacts on bile acid metabolism and whole-body energy balance, likely via activation of TGR5.
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Calton CM, Carothers K, Ramamurthy S, Jagadish N, Phanindra B, Garcia A, Viswanathan VK, Halpern MD. Clostridium scindens exacerbates experimental necrotizing enterocolitis via upregulation of the apical sodium-dependent bile acid transporter. Am J Physiol Gastrointest Liver Physiol 2024; 326:G25-G37. [PMID: 37933481 PMCID: PMC11208032 DOI: 10.1152/ajpgi.00102.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/12/2023] [Revised: 10/19/2023] [Accepted: 11/01/2023] [Indexed: 11/08/2023]
Abstract
Necrotizing enterocolitis (NEC) is the most common gastrointestinal emergency in premature infants. Evidence indicates that bile acid homeostasis is disrupted during NEC: ileal bile acid levels are elevated in animals with experimental NEC, as is expression of the apical sodium-dependent bile acid transporter (Asbt). In addition, bile acids, which are synthesized in the liver, are extensively modified by the gut microbiome, including via the conversion of primary bile acids to more cytotoxic secondary forms. We hypothesized that the addition of bile acid-modifying bacteria would increase susceptibility to NEC in a neonatal rat model of the disease. The secondary bile acid-producing species Clostridium scindens exacerbated both incidence and severity of NEC. C. scindens upregulated the bile acid transporter Asbt and increased levels of intraenterocyte bile acids. Treatment with C. scindens also altered bile acid profiles and increased hydrophobicity of the ileal intracellular bile acid pool. The ability of C. scindens to enhance NEC requires bile acids, as pharmacological sequestration of ileal bile acids protects animals from developing disease. These findings indicate that bile acid-modifying bacteria can contribute to NEC pathology and provide additional evidence for the role of bile acids in the pathophysiology of experimental NEC.NEW & NOTEWORTHY Necrotizing enterocolitis (NEC), a life-threatening gastrointestinal emergency in premature infants, is characterized by dysregulation of bile acid homeostasis. We demonstrate that administering the secondary bile acid-producing bacterium Clostridium scindens enhances NEC in a neonatal rat model of the disease. C. scindens-enhanced NEC is dependent on bile acids and driven by upregulation of the ileal bile acid transporter Asbt. This is the first report of bile acid-modifying bacteria exacerbating experimental NEC pathology.
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Affiliation(s)
- Christine M Calton
- Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States
| | - Katelyn Carothers
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States
| | - Shylaja Ramamurthy
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States
| | - Neha Jagadish
- Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States
| | - Bhumika Phanindra
- Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States
| | - Anett Garcia
- Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States
| | - V K Viswanathan
- School of Animal and Comparative Biomedical Sciences, University of Arizona, Tucson, Arizona, United States
| | - Melissa D Halpern
- Department of Pediatrics and Steele Children's Research Center, University of Arizona, Tucson, Arizona, United States
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13
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Yang J, Chen X, Liu T, Shi Y. Potential role of bile acids in the pathogenesis of necrotizing enterocolitis. Life Sci 2024; 336:122279. [PMID: 37995935 DOI: 10.1016/j.lfs.2023.122279] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2023] [Revised: 11/13/2023] [Accepted: 11/15/2023] [Indexed: 11/25/2023]
Abstract
Necrotizing enterocolitis (NEC) is one of the most common acute gastrointestinal diseases in preterm infants. Recent studies have found that NEC is not only caused by changes in the intestinal environment but also by the failure of multiple systems and organs, including the liver. The accumulation of bile acids (BAs) in the ileum and the disorder of ileal BA transporters are related to the ileum injury of NEC. Inflammatory factors such as tumor necrosis factor (TNF)-α and interleukin (IL)-18 secreted by NEC also play an important role in regulating intrahepatic BA transporters. As an important link connecting the liver and intestinal circulation, the bile acid metabolic pathway plays an important role in the regulation of intestinal microbiota, cell proliferation, and barrier protection. In this review, we focus on how bile acids explore the dynamic changes of bile acid metabolism in necrotizing enterocolitis and the potential therapeutic value of targeting the bile acid signaling pathways.
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Affiliation(s)
- Jiahui Yang
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Xiaoyu Chen
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Tianjing Liu
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
| | - Yongyan Shi
- Department of Pediatrics, Shengjing Hospital of China Medical University, Shenyang 110004, China.
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14
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Zhang M, Xiao B, Chen X, Ou B, Wang S. Physical exercise plays a role in rebalancing the bile acids of enterohepatic axis in non-alcoholic fatty liver disease. Acta Physiol (Oxf) 2024; 240:e14065. [PMID: 38037846 DOI: 10.1111/apha.14065] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2023] [Revised: 10/09/2023] [Accepted: 11/15/2023] [Indexed: 12/02/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered as one of the most common diseases of lipid metabolism disorders, which is closely related to bile acids disorders and gut microbiota disorders. Bile acids are synthesized from cholesterol in the liver, and processed by gut microbiota in intestinal tract, and participate in metabolic regulation through the enterohepatic circulation. Bile acids not only promote the consumption and absorption of intestinal fat but also play an important role in biological metabolic signaling network, affecting fat metabolism and glucose metabolism. Studies have demonstrated that exercise plays an important role in regulating the composition and function of bile acid pool in enterohepatic axis, which maintains the homeostasis of the enterohepatic circulation and the health of the host gut microbiota. Exercise has been recommended by several health guidelines as the first-line intervention for patients with NAFLD. Can exercise alter bile acids through the microbiota in the enterohepatic axis? If so, regulating bile acids through exercise may be a promising treatment strategy for NAFLD. However, the specific mechanisms underlying this potential connection are largely unknown. Therefore, in this review, we tried to review the relationship among NAFLD, physical exercise, bile acids, and gut microbiota through the existing data and literature, highlighting the role of physical exercise in rebalancing bile acid and microbial dysbiosis.
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Affiliation(s)
- Minyu Zhang
- School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
| | - Biyang Xiao
- College of Life Sciences, Zhaoqing University, Zhaoqing, China
| | - Xiaoqi Chen
- College of Life Sciences, Zhaoqing University, Zhaoqing, China
| | - Bingming Ou
- College of Life Sciences, Zhaoqing University, Zhaoqing, China
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou, China
| | - Songtao Wang
- School of Physical Education and Sports Science, South China Normal University, Guangzhou, China
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15
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Xiang D, Yang J, Liu L, Yu H, Gong X, Liu D. The regulation of tissue-specific farnesoid X receptor on genes and diseases involved in bile acid homeostasis. Biomed Pharmacother 2023; 168:115606. [PMID: 37812893 DOI: 10.1016/j.biopha.2023.115606] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2023] [Revised: 09/23/2023] [Accepted: 09/26/2023] [Indexed: 10/11/2023] Open
Abstract
Bile acids (BAs) facilitate the absorption of dietary lipids and vitamins and have also been identified as signaling molecules involved in regulating their own metabolism, glucose and lipid metabolism, as well as immunity. Disturbances in BA homeostasis are associated with various enterohepatic and metabolic diseases, such as cholestasis, nonalcoholic steatohepatitis, inflammatory bowel disease, and obesity. As a key regulator, the nuclear orphan receptor farnesoid X receptor (FXR, NR1H4) precisely regulates BA homeostasis by transcriptional regulation of genes involved in BA synthesis, metabolism, and enterohepatic circulation. FXR is widely regarded as the most potential therapeutic target. Obeticholic acid is the only FXR agonist approved to treat patients with primary biliary cholangitis, but its non-specific activation of systemic FXR also causes high-frequency side effects. In recent years, developing tissue-specific FXR-targeting drugs has become a research highlight. This article provides a comprehensive overview of the role of tissue-specific intestine/liver FXR in regulating genes involved in BA homeostasis and briefly discusses tissue-specific FXR as a therapeutic target for treating diseases. These findings provide the basis for the development of tissue-specific FXR modulators for the treatment of enterohepatic and metabolic diseases associated with BA dysfunction.
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Affiliation(s)
- Dong Xiang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Lu Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Hengyi Yu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China
| | - Xuepeng Gong
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital Affiliated with Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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16
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Usui S, Zhu Q, Komori H, Iwamoto Y, Nishiuchi T, Shirasaka Y, Tamai I. Apple-derived extracellular vesicles modulate the expression of human intestinal bile acid transporter ASBT/SLC10A2 via downregulation of transcription factor RARα. Drug Metab Pharmacokinet 2023; 52:100512. [PMID: 37517353 DOI: 10.1016/j.dmpk.2023.100512] [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: 02/04/2023] [Revised: 04/22/2023] [Accepted: 04/24/2023] [Indexed: 08/01/2023]
Abstract
PURPOSE Plant-derived extracellular vesicles (EVs) have been reported to exert biological activity on intestinal tissues by delivering their contents into intestinal cells. We previously reported that ASBT/SLC10A2 mRNA was downregulated by apple-derived extracellular vesicles (APEVs). ASBT downregulation is effective in the treatment of cholestasis and chronic constipation, similar to the beneficial effects of apples. Therefore, this study aimed to establish the mechanism of ASBT downregulation by APEVs, focusing on microRNAs present in APEVs. RESULTS APEVs downregulated the expression of ASBT, but no significant effect on SLC10A2-3'UTR was observed. Proteomics revealed that APEVs decreased the expression of RARα/NR1B1. The binding of RARα to SLC10A2 promoter was also decreased by APEVs. The stability of NR1B1 mRNA was attenuated by APEVs and its 3'UTR was found to be a target for APEVs. Apple microRNAs that were predicted to interact with NR1B1-3'UTR were present in APEVs, and their mimics suppressed NR1B1 mRNA expression. CONCLUSIONS Suppression of ASBT by APEVs was indirectly mediated by the downregulation of RARα, and its stability was lowered by microRNAs present in APEVs. This study suggested that macromolecules in food directly affect intestinal function by means of EVs that stabilize them and facilitate their cellular uptake.
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Affiliation(s)
- Shinya Usui
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Qiunan Zhu
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Hisakazu Komori
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Yui Iwamoto
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Takumi Nishiuchi
- Research Center for Experimental Modeling of Human Disease, Kanazawa University, Ishikawa, 920-0934, Japan
| | - Yoshiyuki Shirasaka
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan
| | - Ikumi Tamai
- Faculty of Pharmaceutical Sciences, Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kakuma-machi, Kanazawa, 920-1192, Japan.
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17
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Li Z, Yuan H, Chu H, Yang L. The Crosstalk between Gut Microbiota and Bile Acids Promotes the Development of Non-Alcoholic Fatty Liver Disease. Microorganisms 2023; 11:2059. [PMID: 37630619 PMCID: PMC10459427 DOI: 10.3390/microorganisms11082059] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2023] [Revised: 07/27/2023] [Accepted: 08/01/2023] [Indexed: 08/27/2023] Open
Abstract
Recently the roles of gut microbiota are highly regarded in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). The intestinal bacteria regulate the metabolism of bile acids depending on bile salt hydrolase (BSH), 7-dehydroxylation, hydroxysteroid dehydrogenase (HSDH), or amide conjugation reaction, thus exerting effects on NAFLD development through bile acid receptors such as farnesoid X receptor (FXR), Takeda G-protein-coupled bile acid protein 5 (TGR5), and vitamin D receptor (VDR), which modulate nutrient metabolism and insulin sensitivity via interacting with downstream molecules. Reversely, the composition of gut microbiota is also affected by the level of bile acids in turn. We summarize the mutual regulation between the specific bacteria and bile acids in NAFLD and the latest clinical research based on microbiota and bile acids, which facilitate the development of novel treatment modalities in NAFLD.
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Affiliation(s)
| | | | | | - Ling Yang
- Division of Gastroenterology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, 1277 Jiefang Avenue, Wuhan 430022, China; (Z.L.); (H.Y.); (H.C.)
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18
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Okamoto N, Fujinaga D, Yamanaka N. Steroid hormone signaling: What we can learn from insect models. VITAMINS AND HORMONES 2023; 123:525-554. [PMID: 37717997 DOI: 10.1016/bs.vh.2022.12.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Ecdysteroids are a group of steroid hormones in arthropods with pleiotropic functions throughout their life history. Ecdysteroid research in insects has made a significant contribution to our current understanding of steroid hormone signaling in metazoans, but how far can we extrapolate our findings in insects to other systems, such as mammals? In this chapter, we compare steroid hormone signaling in insects and mammals from multiple perspectives and discuss similarities and differences between the two lineages. We also highlight a few understudied areas and remaining questions of steroid hormone biology in metazoans and propose potential future research directions.
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Affiliation(s)
- Naoki Okamoto
- Life Science Center for Survival Dynamics, Tsukuba Advanced Research Alliance (TARA), University of Tsukuba, Tsukuba, Ibaraki, Japan
| | - Daiki Fujinaga
- Department of Entomology, University of California, Riverside, CA, United States
| | - Naoki Yamanaka
- Department of Entomology, University of California, Riverside, CA, United States.
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19
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Meadows V, Marakovits C, Ekser B, Kundu D, Zhou T, Kyritsi K, Pham L, Chen L, Kennedy L, Ceci L, Wu N, Carpino G, Zhang W, Isidan A, Meyer A, Owen T, Gaudio E, Onori P, Alpini G, Francis H. Loss of apical sodium bile acid transporter alters bile acid circulation and reduces biliary damage in cholangitis. Am J Physiol Gastrointest Liver Physiol 2023; 324:G60-G77. [PMID: 36410025 PMCID: PMC9799145 DOI: 10.1152/ajpgi.00112.2022] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Revised: 11/15/2022] [Accepted: 11/16/2022] [Indexed: 11/22/2022]
Abstract
Primary sclerosing cholangitis (PSC) is characterized by increased ductular reaction (DR), liver fibrosis, hepatic total bile acid (TBA) levels, and mast cell (MC) infiltration. Apical sodium BA transporter (ASBT) expression increases in cholestasis, and ileal inhibition reduces PSC phenotypes. FVB/NJ and multidrug-resistant 2 knockout (Mdr2-/-) mice were treated with control or ASBT Vivo-Morpholino (VM). We measured 1) ASBT expression and MC presence in liver/ileum; 2) liver damage/DR; 3) hepatic fibrosis/inflammation; 4) biliary inflammation/histamine serum content; and 5) gut barrier integrity/hepatic bacterial translocation. TBA/BA composition was measured in cholangiocyte/hepatocyte supernatants, intestine, liver, serum, and feces. Shotgun analysis was performed to ascertain microbiome changes. In vitro, cholangiocytes were treated with BAs ± ASBT VM, and histamine content and farnesoid X receptor (FXR) signaling were determined. Treated cholangiocytes were cocultured with MCs, and FXR signaling, inflammation, and MC activation were measured. Human patients were evaluated for ASBT/MC expression and histamine/TBA content in bile. Control patient- and PSC patient-derived three-dimensional (3-D) organoids were generated; ASBT, chymase, histamine, and fibroblast growth factor-19 (FGF19) were evaluated. ASBT VM in Mdr2-/- mice decreased 1) biliary ASBT expression, 2) PSC phenotypes, 3) hepatic TBA, and 4) gut barrier integrity compared with control. We found alterations between wild-type (WT) and Mdr2-/- mouse microbiome, and ASBT/MC and bile histamine content increased in cholestatic patients. BA-stimulated cholangiocytes increased MC activation/FXR signaling via ASBT, and human PSC-derived 3-D organoids secrete histamine/FGF19. Inhibition of hepatic ASBT ameliorates cholestatic phenotypes by reducing cholehepatic BA signaling, biliary inflammation, and histamine levels. ASBT regulation of hepatic BA signaling offers a therapeutic avenue for PSC.NEW & NOTEWORTHY We evaluated knockdown of the apical sodium bile acid transporter (ASBT) using Vivo-Morpholino in Mdr2KO mice. ASBT inhibition decreases primary sclerosing cholangitis (PSC) pathogenesis by reducing hepatic mast cell infiltration, altering bile acid species/cholehepatic shunt, and regulating gut inflammation/dysbiosis. Since a large cohort of PSC patients present with IBD, this study is clinically important. We validated findings in human PSC and PSC-IBD along with studies in novel human 3-D organoids formed from human PSC livers.
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Affiliation(s)
- Vik Meadows
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Corinn Marakovits
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Burcin Ekser
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Debjyoti Kundu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Tianhao Zhou
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Konstantina Kyritsi
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Linh Pham
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lixian Chen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Lindsey Kennedy
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Richard L. Roudebush Department of Veterans Affairs Medical Center, Indianapolis, Indiana
| | - Ludovica Ceci
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Nan Wu
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Guido Carpino
- Department of Movement, Human and Health Sciences, University of Rome "Foro Italico," Rome, Italy
| | - Wenjun Zhang
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Abdulkadir Isidan
- Department of Surgery, Indiana University School of Medicine, Indianapolis, Indiana
| | - Alison Meyer
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Travis Owen
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
| | - Eugenio Gaudio
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Paolo Onori
- Department of Anatomical, Histological, Forensic Medicine and Orthopedics Sciences, Sapienza University of Rome, Rome, Italy
| | - Gianfranco Alpini
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Richard L. Roudebush Department of Veterans Affairs Medical Center, Indianapolis, Indiana
| | - Heather Francis
- Division of Gastroenterology and Hepatology, Department of Medicine, Indiana University School of Medicine, Indianapolis, Indiana
- Richard L. Roudebush Department of Veterans Affairs Medical Center, Indianapolis, Indiana
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Laue T, Baumann U. Odevixibat: an investigational inhibitor of the ileal bile acid transporter (IBAT) for the treatment of biliary atresia. Expert Opin Investig Drugs 2022; 31:1143-1150. [PMID: 36440482 DOI: 10.1080/13543784.2022.2151890] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
INTRODUCTION Biliary atresia (BA) is a rare, non-curable cholestasis-causing disease in infancy, due to progressive ascending bile duct sclerosis. Even after restoration of bile flow following Kasai portoenterostomy, about half of these children need a liver transplant by their 2nd birthday, due to progressive fibrosis. Toxicity of bile acids may play a central role in disease progression, but drug therapies are not yet available. With ileal bile acid transporter (IBAT) inhibitors, there is a potential novel drug option that inhibits the absorption of bile acids in the small intestine. As a result of reduced bile acid accumulation in the cholestatic liver, it may be possible to delay hepatic remodeling. AREAS COVERED This review summarizes the dataset on bile acids and the potential effects of odevixibat, an IBAT inhibitor, in children with BA. EXPERT OPINION Systemic reduction of bile acids with the aim of preventing inflammation, and thus liver remodeling, is a novel, promising, therapeutic concept. In principle, however, the time until diagnosis and surgical treatment of BA should still be kept as short as possible in order to minimize liver remodeling before medical intervention can be initiated. IBAT inhibitors may add to the medical options in limiting disease progression in BA.
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Affiliation(s)
- Tobias Laue
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
| | - Ulrich Baumann
- Division of Paediatric Gastroenterology and Hepatology, Department of Paediatric Liver, Kidney and Metabolic Diseases, Hannover Medical School, Hannover, Germany
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21
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Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
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Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
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22
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Zhou S, You H, Qiu S, Yu D, Bai Y, He J, Cao H, Che Q, Guo J, Su Z. A new perspective on NAFLD: Focusing on the crosstalk between peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR). Biomed Pharmacother 2022; 154:113577. [PMID: 35988420 DOI: 10.1016/j.biopha.2022.113577] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Revised: 08/10/2022] [Accepted: 08/16/2022] [Indexed: 11/19/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD) is primarily caused by abnormal lipid metabolism and the accumulation of triglycerides in the liver. NAFLD is also associated with hepatic steatosis and nutritional and energy imbalances and is a chronic liver disease associated with a number of factors. Nuclear receptors play a key role in balancing energy and nutrient metabolism, and the peroxisome proliferator-activated receptor alpha (PPARα) and farnesoid X receptor (FXR) regulate lipid metabolism genes, controlling hepatocyte lipid utilization and regulating bile acid (BA) synthesis and transport. They play an important role in lipid metabolism and BA homeostasis. At present, PPARα and FXR are the most promising targets for the treatment of NAFLD among nuclear receptors. This review focuses on the crosstalk mechanisms and transcriptional regulation of PPARα and FXR in the pathogenesis of NAFLD and summarizes PPARα and FXR drugs in clinical trials, laying a theoretical foundation for the targeted treatment of NAFLD and the development of novel therapeutic strategies.
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Affiliation(s)
- Shipeng Zhou
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Huimin You
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Shuting Qiu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Dawei Yu
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China
| | - Yan Bai
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Jincan He
- School of Public Health, Guangdong Pharmaceutical University, Guangzhou 510310, China
| | - Hua Cao
- School of Chemistry and Chemical Engineering, Guangdong Pharmaceutical University, Zhongshan 528458, China
| | - Qishi Che
- Guangzhou Rainhome Pharm & Tech Co., Ltd, Science City, Guangzhou 510663, China
| | - Jiao Guo
- Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
| | - Zhengquan Su
- Guangdong Engineering Research Center of Natural Products and New Drugs, Guangdong Provincial University Engineering Technology Research Center of Natural Products and Drugs, Guangdong Pharmaceutical University, Guangzhou 510006, China; Guangdong Metabolic Disease Research Center of Integrated Chinese and Western Medicine, Key Laboratory of Glucolipid Metabolic Disorder, Ministry of Education of China, Guangdong TCM Key Laboratory for Metabolic Diseases, Guangdong Pharmaceutical University, Guangzhou 510006, China.
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23
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Noh K, Chow ECY, Quach HP, Groothuis GMM, Tirona RG, Pang KS. Significance of the Vitamin D Receptor on Crosstalk with Nuclear Receptors and Regulation of Enzymes and Transporters. AAPS J 2022; 24:71. [PMID: 35650371 DOI: 10.1208/s12248-022-00719-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 05/16/2022] [Indexed: 11/30/2022] Open
Abstract
The vitamin D receptor (VDR), in addition to other nuclear receptors, the pregnane X receptor (PXR) and constitutive androstane receptor (CAR), is involved in the regulation of enzymes, transporters and receptors, and therefore intimately affects drug disposition, tissue health, and the handling of endogenous and exogenous compounds. This review examines the role of 1α,25-dihydroxyvitamin D3 or calcitriol, the natural VDR ligand, on activation of the VDR and its crosstalk with other nuclear receptors towards the regulation of enzymes and transporters, notably many of the cytochrome P450s including CYP3A4 and sulfotransferase 2A1 (SULT2A1) as well as cholesterol 7α-hydroxylase (CYP7A1). Moreover, the VDR upregulates the intestinal channel, TRPV6, for calcium absorption, LDL receptor-related protein 1 (LRP1) and receptor for advanced glycation end products (RAGE) in brain for β-amyloid peptide efflux and influx, the sodium phosphate transporters (NaPi), the apical sodium-dependent bile acid transporter (ASBT) and organic solute transporters (OSTα-OSTβ) for bile acid absorption and efflux, respectively, the renal organic anion transporter 3 (OAT3) and several of the ATP-binding cassette protein transporters-the multidrug resistance protein 1 (MDR1) and the multidrug resistance-associated proteins (MRPs). Hence, the role of the VDR is increasingly being recognized for its therapeutic potential and pharmacologic activity, giving rise to drug-drug interactions (DDI). Therapeutically, ligand-activated VDR shows anti-inflammatory effects towards the suppression of inflammatory mediators, improves cognition by upregulating amyloid-beta (Aβ) peptide clearance in brain, and maintains phosphate, calcium, and parathyroid hormone (PTH) balance and kidney function and bone health, demonstrating the crucial roles of the VDR in disease progression and treatment of diseases.
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Affiliation(s)
- Keumhan Noh
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Drug Metabolism and Pharmacokinetics, Biogen, 225 Binney Street, Cambridge, Massachusetts, 02142, USA
| | - Edwin C Y Chow
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.,Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, Maryland, USA
| | - Holly P Quach
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada
| | - Geny M M Groothuis
- Pharmacokinetics, Toxicology and Targeting, Department of Pharmacy, Groningen Research Institute of Pharmacy, University of Groningen, Groningen, The Netherlands
| | - Rommel G Tirona
- Department of Physiology and Pharmacology, Schulich School of Medicine and Dentistry, University of Western Ontario, London, Ontario, N6A 5C1, Canada
| | - K Sandy Pang
- Department of Pharmaceutical Sciences, Leslie Dan Faculty of Pharmacy, University of Toronto, 144 College Street, Toronto, Ontario, M5S 3M2, Canada.
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24
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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. Int J Mol Sci 2022; 23:ijms23116046. [PMID: 35682726 PMCID: PMC9181207 DOI: 10.3390/ijms23116046] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.
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25
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Wang Y, Zhao J, Li Q, Liu J, Sun Y, Zhang K, Fan M, Qian H, Li Y, Wang L. L-Arabinose improves hypercholesterolemia via regulating bile acid metabolism in high-fat-high-sucrose diet-fed mice. Nutr Metab (Lond) 2022; 19:30. [PMID: 35428331 PMCID: PMC9013033 DOI: 10.1186/s12986-022-00662-8] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/25/2022] [Accepted: 03/29/2022] [Indexed: 11/10/2022] Open
Abstract
Background Hypercholesterolemia is closely associated with an increased risk of cardiovascular diseases. l-Arabinose exhibited hypocholesterolemia properties, but underlying mechanisms have not been sufficiently investigated. This study aimed to elucidate the mechanisms of l-arabinose on hypocholesterolemia involving the enterohepatic circulation of bile acids. Methods Thirty six-week-old male mice were randomly divided into three groups: the control group and the high-fat-high-sucrose diet (HFHSD)-fed group were gavaged with distilled water, and the l-arabinose-treated group were fed HFHSD and received 400 mg/kg/day l-arabinose for 12 weeks. Serum and liver biochemical parameters, serum and fecal bile acid, cholesterol and bile acid metabolism-related gene and protein expressions in the liver and small intestine were analyzed. Results l-Arabinose supplementation significantly reduced body weight gain, lowered circulating low-density lipoprotein cholesterol (LDL-C) while increasing high-density lipoprotein cholesterol (HDL-C) levels, and efficiently alleviated hepatic inflammation and lipid accumulations in HFHSD-fed mice. l-Arabinose inhibited cholesterol synthesis via downregulation of 3-hydroxy-3-methylglutaryl-CoA reductase (HMGCR). Additionally, l-arabinose might facilitate reverse cholesterol transport, evidenced by the increased mRNA expressions of low-density lipoprotein receptor (LDL-R) and scavenger receptor class B type 1 (SR-B1). Furthermore, l-arabinose modulated ileal reabsorption of bile acids mainly through downregulation of ileal bile acid-binding protein (I-BABP) and apical sodium-dependent bile acid transporter (ASBT), resulting in the promotion of hepatic synthesis of bile acids via upregulation of cholesterol-7α-hydroxylase (CYP7A1). Conclusions l-Arabinose supplementation exhibits hypocholesterolemic effects in HFHSD-fed mice primarily due to regulation of bile acid metabolism-related pathways. Supplementary Information The online version contains supplementary material available at 10.1186/s12986-022-00662-8.
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Affiliation(s)
- Yu Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Jiajia Zhao
- College of Cooking Science and Technology, Jiangsu College of Tourism, Yangzhou, 225000, China
| | - Qiang Li
- China National Institute of Standardization, No. 4 Zhichun Road, Haidian District, Beijing, China
| | - Jinxin Liu
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yujie Sun
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Kuiliang Zhang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Mingcong Fan
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Haifeng Qian
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China
| | - Yan Li
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China.
| | - Li Wang
- State Key Laboratory of Food Science and Technology, School of Food Science and Technology, Jiangnan University, Wuxi, 214122, China.
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26
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Purohit A, Alam MJ, Kandiyal B, Shalimar, Das B, Banerjee SK. Gut microbiome and non-alcoholic fatty liver disease. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2022; 191:187-206. [DOI: 10.1016/bs.pmbts.2022.07.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/15/2022]
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27
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Abstract
Maralixibat (Livmarli™) is an orally-administered, small-molecule ileal bile acid transporter (IBAT) inhibitor being developed by Mirum Pharmaceuticals for the treatment of rare cholestatic liver diseases including Alagille syndrome (ALGS), progressive familial intrahepatic cholestasis (PFIC) and biliary atresia. Maralixibat received its first approval on 29 September 2021, in the USA, for use in the treatment of cholestatic pruritus in patients with ALGS 1 year of age and older. Maralixibat is also under regulatory review for ALGS in Europe, and clinical development for cholestatic liver disorders including ALGS in patients under 1 year of age, PFIC and biliary atresia is continuing in several other countries. This article summarises the milestones in the development of maralixibat leading to this first approval for ALGS.
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Affiliation(s)
- Matt Shirley
- Springer Nature, Mairangi Bay, Private Bag 65901, Auckland, 0754, New Zealand.
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28
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Ho AMC, Winham SJ, McCauley BM, Kundakovic M, Robertson KD, Sun Z, Ordog T, Webb LM, Frye MA, Veldic M. Plasma Cell-Free DNA Methylomics of Bipolar Disorder With and Without Rapid Cycling. Front Neurosci 2021; 15:774037. [PMID: 34916903 PMCID: PMC8669968 DOI: 10.3389/fnins.2021.774037] [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: 09/10/2021] [Accepted: 11/01/2021] [Indexed: 11/21/2022] Open
Abstract
Rapid cycling (RC) burdens bipolar disorder (BD) patients further by causing more severe disability and increased suicidality. Because diagnosing RC can be challenging, RC patients are at risk of rapid decline due to delayed suitable treatment. Here, we aimed to identify the differences in the circulating cell-free DNA (cfDNA) methylome between BD patients with and without RC. The cfDNA methylome could potentially be developed as a diagnostic test for BD RC. We extracted cfDNA from plasma samples of BD1 patients (46 RC and 47 non-RC). cfDNA methylation levels were measured by 850K Infinium MethylationEPIC array. Principal component analysis (PCA) was conducted to assess global differences in methylome. cfDNA methylation levels were compared between RC groups using a linear model adjusted for age and sex. PCA suggested differences in methylation profiles between RC groups (p = 0.039) although no significant differentially methylated probes (DMPs; q > 0.15) were found. The top four CpG sites which differed between groups at p < 1E-05 were located in CGGPB1, PEX10, NR0B2, and TP53I11. Gene set enrichment analysis (GSEA) on top DMPs (p < 0.05) showed significant enrichment of gene sets related to nervous system tissues, such as neurons, synapse, and glutamate neurotransmission. Other top notable gene sets were related to parathyroid regulation and calcium signaling. To conclude, our study demonstrated the feasibility of utilizing a microarray method to identify circulating cfDNA methylation sites associated with BD RC and found the top differentially methylated CpG sites were mostly related to the nervous system and the parathyroid.
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Affiliation(s)
- Ada Man-Choi Ho
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
| | - Stacey J Winham
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Bryan M McCauley
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Marija Kundakovic
- Department of Biological Sciences, Fordham University, New York, NY, United States
| | - Keith D Robertson
- Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Zhifu Sun
- Department of Health Science Research, Mayo Clinic, Rochester, MN, United States
| | - Tamas Ordog
- Department of Physiology and Biomedical Engineering, Mayo Clinic, Rochester, MN, United States
| | - Lauren M Webb
- Mayo Clinic Alix School of Medicine, Rochester, MN, United States
| | - Mark A Frye
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
| | - Marin Veldic
- Department of Psychiatry and Psychology, Mayo Clinic, Rochester, MN, United States
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29
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Radun R, Trauner M. Role of FXR in Bile Acid and Metabolic Homeostasis in NASH: Pathogenetic Concepts and Therapeutic Opportunities. Semin Liver Dis 2021; 41:461-475. [PMID: 34289507 PMCID: PMC8492195 DOI: 10.1055/s-0041-1731707] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD) has become the most prevalent cause of liver disease, increasingly contributing to the burden of liver transplantation. In search for effective treatments, novel strategies addressing metabolic dysregulation, inflammation, and fibrosis are continuously emerging. Disturbed bile acid (BA) homeostasis and microcholestasis via hepatocellular retention of potentially toxic BAs may be an underappreciated factor in the pathogenesis of NAFLD and nonalcoholic steatohepatitis (NASH) as its progressive variant. In addition to their detergent properties, BAs act as signaling molecules regulating cellular homeostasis through interaction with BA receptors such as the Farnesoid X receptor (FXR). Apart from being a key regulator of BA metabolism and enterohepatic circulation, FXR regulates metabolic homeostasis and has immune-modulatory effects, making it an attractive therapeutic target in NAFLD/NASH. In this review, the molecular basis and therapeutic potential of targeting FXR with a specific focus on restoring BA and metabolic homeostasis in NASH is summarized.
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Affiliation(s)
- Richard Radun
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
| | - Michael Trauner
- Department of Internal Medicine III, Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Medical University of Vienna, Austria
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30
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Simbrunner B, Trauner M, Reiberger T. Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 2021; 54:1243-1262. [PMID: 34555862 PMCID: PMC9290708 DOI: 10.1111/apt.16602] [Citation(s) in RCA: 54] [Impact Index Per Article: 13.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
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Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
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31
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Miyata M, Tanaka T, Takahashi K, Funaki A, Sugiura Y. Cholesterol-lowering effects of taurine through the reduction of ileal FXR signaling due to the alteration of ileal bile acid composition. Amino Acids 2021; 53:1523-1532. [PMID: 34596761 DOI: 10.1007/s00726-021-03068-7] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 08/14/2021] [Indexed: 01/05/2023]
Abstract
Studies using animal models of hypercholesterolemia have established that taurine reduces cholesterol levels; however, the precise mechanism underlying this cholesterol-lowering effect is unclear. This study addressed this issue by investigating whether bile acid/farnesoid X receptor (FXR) signaling is involved in taurine-mediated cholesterol-lowering effect. Fxr-null and wild-type mice were administered 2% (w/v) taurine in their drinking water and fed a control diet or control diet supplemented with 1% (w/w) cholesterol (cholesterol diet) for 10 days. Taurine intake did not significantly alter hepatic and serum total cholesterol (TC) levels and bile acid compositions of the liver and intestinal lumen in Fxr-null and wild-type mice fed the control diet. By changing to a cholesterol diet, taurine intake significantly decreased hepatic and serum cholesterol levels in wild-type mice. In contrast, it significantly decreased hepatic, not serum, cholesterol levels in Fxr-null mice. Taurine intake significantly altered the bile acid composition of the intestinal lumen in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. An increase in FXR antagonistic bile acids was detected in the intestinal lumen of taurine-treated wild-type mice fed a cholesterol diet. Taurine intake reduced the ileal expression of FXR target genes fibroblast growth factor 15 (Fgf15) and small heterodimer partner (Shp). In contrast, it enhanced the hepatic expression of cholesterol 7α-hydroxylase (Cyp7a1) in wild-type mice fed a cholesterol diet, but not in Fxr-null mice. These results suggest that taurine is partially involved in cholesterol lowering by reducing the ileal FXR signaling due to the alteration of ileal bile acid composition.
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Affiliation(s)
- Masaaki Miyata
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, 2-7-1, Nagata-honmachi, Shimonoseki, 759-6595, Japan.
| | - Tomoyuki Tanaka
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, 2-7-1, Nagata-honmachi, Shimonoseki, 759-6595, Japan
| | - Kazuho Takahashi
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, 2-7-1, Nagata-honmachi, Shimonoseki, 759-6595, Japan
| | - Akihiro Funaki
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, 2-7-1, Nagata-honmachi, Shimonoseki, 759-6595, Japan
| | - Yoshimasa Sugiura
- Department of Food Science and Technology, National Research and Development Agency, Japan Fisheries Research and Education Agency, National Fisheries University, 2-7-1, Nagata-honmachi, Shimonoseki, 759-6595, Japan
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32
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Nguyen JT, Riessen R, Zhang T, Kieffer C, Anakk S. Deletion of Intestinal SHP Impairs Short-term Response to Cholic Acid Challenge in Male Mice. Endocrinology 2021; 162:6189092. [PMID: 33769482 PMCID: PMC8256632 DOI: 10.1210/endocr/bqab063] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/09/2020] [Indexed: 02/07/2023]
Abstract
Small heterodimer partner (SHP) is a crucial regulator of bile acid (BA) transport and synthesis; however, its intestine-specific role is not fully understood. Here, we report that male intestine-specific Shp knockout (IShpKO) mice exhibit higher intestinal BA but not hepatic or serum BA levels compared with the f/f Shp animals when challenged with an acute (5-day) 1% cholic acid (CA) diet. We also found that BA synthetic genes Cyp7a1 and Cyp8b1 are not repressed to the same extent in IShpKO compared with control mice post-CA challenge. Loss of intestinal SHP did not alter Fxrα messenger RNA (mRNA) but increased Asbt (BA ileal uptake transporter) and Ostα (BA ileal efflux transporter) expression even under chow-fed conditions. Surprisingly, the acute CA diet in IShpKO did not elicit the expected induction of Fgf15 but was able to maintain the suppression of Asbt, and Ostα/β mRNA levels. At the protein level, apical sodium-dependent bile acid transporter (ASBT) was downregulated, while organic solute transporter-α/β (OSTα/β) expression was induced and maintained regardless of diet. Examination of ileal histology in IShpKO mice challenged with acute CA diet revealed reduced villi length and goblet cell numbers. However, no difference in villi length, and the expression of BA regulator and transporter genes, was seen between f/f Shp and IShpKO animals after a chronic (14-day) CA diet, suggesting a potential adaptive response. We found the upregulation of the Pparα-Ugt axis after 14 days of CA diet may reduce the BA burden and compensate for the ileal SHP function. Thus, our study reveals that ileal SHP expression contributes to both overall intestinal structure and BA homeostasis.
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Affiliation(s)
- James T Nguyen
- Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Ryan Riessen
- Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Tongyu Zhang
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Collin Kieffer
- Department of Microbiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL 61801, USA
- Correspondence:Sayeepriyadarshini Anakk, Department of Molecular & Integrative Physiology and Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, 450 Medical Science Building, 506 South Matthews Avenue, Urbana, IL 61801, USA. E-mail:
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33
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Wen J, Mercado GP, Volland A, Doden HL, Lickwar CR, Crooks T, Kakiyama G, Kelly C, Cocchiaro JL, Ridlon JM, Rawls JF. Fxr signaling and microbial metabolism of bile salts in the zebrafish intestine. SCIENCE ADVANCES 2021; 7:eabg1371. [PMID: 34301599 PMCID: PMC8302129 DOI: 10.1126/sciadv.abg1371] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/13/2020] [Accepted: 06/07/2021] [Indexed: 05/02/2023]
Abstract
Bile salt synthesis, secretion into the intestinal lumen, and resorption in the ileum occur in all vertebrate classes. In mammals, bile salt composition is determined by host and microbial enzymes, affecting signaling through the bile salt-binding transcription factor farnesoid X receptor (Fxr). However, these processes in other vertebrate classes remain poorly understood. We show that key components of hepatic bile salt synthesis and ileal transport pathways are conserved and under control of Fxr in zebrafish. Zebrafish bile salts consist primarily of a C27 bile alcohol and a C24 bile acid that undergo multiple microbial modifications including bile acid deconjugation that augments Fxr activity. Using single-cell RNA sequencing, we provide a cellular atlas of the zebrafish intestinal epithelium and uncover roles for Fxr in transcriptional and differentiation programs in ileal and other cell types. These results establish zebrafish as a nonmammalian vertebrate model for studying bile salt metabolism and Fxr signaling.
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Affiliation(s)
- Jia Wen
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Gilberto Padilla Mercado
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Alyssa Volland
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Heidi L Doden
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Colin R Lickwar
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Taylor Crooks
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA
| | - Genta Kakiyama
- Department of Internal Medicine, School of Medicine, Virginia Commonwealth University, Richmond, VA, USA
| | - Cecelia Kelly
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jordan L Cocchiaro
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA
| | - Jason M Ridlon
- Carl R. Woese Institute for Genomic Biology, University of Illinois at Urbana Champaign, Urbana, IL, USA.
- Department of Animal Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Division of Nutritional Sciences, University of Illinois at Urbana Champaign, Urbana, IL, USA
- Cancer Center of Illinois, Urbana, IL, USA
| | - John F Rawls
- Department of Molecular Genetics and Microbiology, Duke Microbiome Center, Duke University School of Medicine, Durham, NC, USA.
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Li B, Cai SY, Boyer JL. The role of the retinoid receptor, RAR/RXR heterodimer, in liver physiology. Biochim Biophys Acta Mol Basis Dis 2021; 1867:166085. [PMID: 33497820 PMCID: PMC11152086 DOI: 10.1016/j.bbadis.2021.166085] [Citation(s) in RCA: 29] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2020] [Revised: 01/09/2021] [Accepted: 01/12/2021] [Indexed: 12/31/2022]
Abstract
Activated by retinoids, metabolites of vitamin A, the retinoic acid receptors (RARs) and the retinoid X receptors (RXRs) play important roles in a wide variety of biological processes, including embryo development, homeostasis, cell proliferation, differentiation and death. In this review, we summarized the functional roles of nuclear receptor RAR/RXR heterodimers in liver physiology. Specifically, RAR/RXR modulate the synthesis and metabolism of lipids and bile acids in hepatocytes, regulate cholesterol transport in macrophages, and repress fibrogenesis in hepatic stellate cells. We have also listed the specific genes that carry these functions and how RAR/RXR regulate their expression in liver cells, providing a mechanistic view of their roles in liver physiology. Meanwhile, we pointed out many questions regarding the detailed signaling of RAR/RXR in regulating the expression of liver genes, and hope future studies will address these issues.
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Affiliation(s)
- Baixue Li
- Liver Center, Yale University School of Medicine, New Haven, CT 06520, United States; College of Basic Medical Sciences, Chengdu University of Traditional Chinese Medicine, Chengdu 610075, China.
| | - Shi-Ying Cai
- Liver Center, Yale University School of Medicine, New Haven, CT 06520, United States.
| | - James L Boyer
- Liver Center, Yale University School of Medicine, New Haven, CT 06520, United States.
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Wang M, Liu F, Yao Y, Zhang Q, Lu Z, Zhang R, Liu C, Lin C, Zhu C. Network pharmacology-based mechanism prediction and pharmacological validation of Xiaoyan Lidan formula on attenuating alpha-naphthylisothiocyanate induced cholestatic hepatic injury in rats. JOURNAL OF ETHNOPHARMACOLOGY 2021; 270:113816. [PMID: 33444723 DOI: 10.1016/j.jep.2021.113816] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 01/04/2021] [Accepted: 01/06/2021] [Indexed: 06/12/2023]
Abstract
ETHNOPHARMACOLOGICAL RELEVANCE The well-known Chinese prescription, Xiaoyan Lidan Formula (XYLDF), possesses efficiency of heat-clearing, dampness-eliminating and jaundice-removing. It has long been used clinically for the treatment of hepatobiliary diseases due to intrahepatic cholestasis (IHC). However, the mechanism of XYLDF for its therapeutic effects remains elusive. AIM OF THE STUDY The study aimed to explore the potential targets for liver protective mechanism of XYLDF based on network pharmacology and experimental assays in ANIT-induced cholestatic hepatic injury (CHI) in rats. MATERIALS AND METHODS On the basis of the 29 serum migrant compounds of XYLDF elucidated by UPLC-TOF-MS/MS, a network pharmacology approach was applied for the mechanism prediction. Systematic networks were constructed to identify potential molecular targets, biological processes, and signaling pathways. And the interactions between significantly potential targets and active compounds were simulated by molecular docking. For the mechanism validation, an ANIT-induced rat model was used to evaluate the effects of XYLDF on CHI according to serum biochemistry, bile flow rates, histopathological examination, and the gene and protein expression including enzymes related to synthesis, export, and import of bile acid in liver and ileum, and those of inflammatory cytokines, analyzed by RT-qPCR and WB. RESULTS The results of network pharmacology research indicated TNF (TNF-α), RELA (NF-κB), NR1H4 (FXR), and ICAM1 (ICAM-1) to be the important potential targets of XYLDF for cholestatic liver injury, which are related to bile metabolism and NF-κB-mediated inflammatory signaling. And the molecular docking had pre-validated the prediction of network pharmacology, as the core active compounds of XYLDF had shown strong simulation binding affinity with FXR, followed by NF-κB, TNF-α, and ICAM-1. Meanwhile, the effects of XYLDF after oral administration on ANIT-induced CHI in rats exhibited the decreased levels of transaminases (ALT and AST), TBA, and TBIL in serum, raised bile flow rates, and markedly improved hepatic histopathology. Furthermore, consistent to the above targets prediction and molecular docking, XYLDF significantly up-regulated the expression of FXR, SHP, BSEP, and MRP2, and down-regulated CYP7A1 and NTCP in liver, and promoted expression of IBABP and OSTα/β in ileum, suggesting the activation of FXR-mediated pathway referring to bile acid synthesis, transportation, and reabsorption. Moreover, the lower levels of TNF-α in plasma and liver, as well as the reduced hepatic gene and protein expression of NF-κB, TNF-α, and ICAM-1 after XYLDF treatment revealed the suppression of NF-κB-mediated inflammatory signaling pathway, as evidenced by the inhibition of nuclear translocation of NF-κB. CONCLUSIONS XYLDF exhibited an ameliorative liver protective effect on ANIT-induced cholestatic hepatic injury. The present study has confirmed its mechanism as activating the FXR-regulated bile acid pathway and inhibiting inflammation via the NF-κB signaling pathway.
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MESH Headings
- 1-Naphthylisothiocyanate/toxicity
- Animals
- Bile Acids and Salts/metabolism
- Chemical and Drug Induced Liver Injury/blood
- Chemical and Drug Induced Liver Injury/drug therapy
- Chemical and Drug Induced Liver Injury/pathology
- Cholestasis, Intrahepatic/blood
- Cholestasis, Intrahepatic/chemically induced
- Cholestasis, Intrahepatic/drug therapy
- Cholestasis, Intrahepatic/pathology
- Disease Models, Animal
- Drugs, Chinese Herbal/pharmacology
- Drugs, Chinese Herbal/therapeutic use
- Inflammation/drug therapy
- Inflammation/metabolism
- Male
- Metabolic Networks and Pathways/drug effects
- Molecular Docking Simulation
- NF-kappa B/metabolism
- Protective Agents/pharmacology
- Protective Agents/therapeutic use
- Protein Interaction Maps/drug effects
- Rats, Sprague-Dawley
- Receptors, Cytoplasmic and Nuclear/chemistry
- Receptors, Cytoplasmic and Nuclear/metabolism
- Signal Transduction/drug effects
- Rats
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Affiliation(s)
- Meiqi Wang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Fangle Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Yufeng Yao
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Qiuyu Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Zenghui Lu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Runjing Zhang
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Changhui Liu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China
| | - Chaozhan Lin
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
| | - Chenchen Zhu
- School of Pharmaceutical Sciences, Guangzhou University of Chinese Medicine, No.232 Waihuandong Rd, Guangzhou Higher Education Mega Center, Guangzhou, 510006, China.
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The pathophysiological function of non-gastrointestinal farnesoid X receptor. Pharmacol Ther 2021; 226:107867. [PMID: 33895191 DOI: 10.1016/j.pharmthera.2021.107867] [Citation(s) in RCA: 27] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.
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A Link between Intrahepatic Cholestasis and Genetic Variations in Intracellular Trafficking Regulators. BIOLOGY 2021; 10:biology10020119. [PMID: 33557414 PMCID: PMC7914782 DOI: 10.3390/biology10020119] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/23/2020] [Revised: 01/27/2021] [Accepted: 02/01/2021] [Indexed: 12/20/2022]
Abstract
Simple Summary Cholestasis refers to a medical condition in which the liver is not capable of secreting bile. The consequent accumulation of toxic bile components in the liver leads to liver failure. Cholestasis can be caused by mutations in genes that code for proteins involved in bile secretion. Recently mutations in other genes have been discovered in patients with cholestasis of unknown origin. Interestingly, many of these newly discovered genes code for proteins that regulate the intracellular distribution of other proteins, including those involved in bile secretion. This group of genes thus suggests the deregulated intracellular distribution of bile-secreting proteins as an important but still poorly understood mechanism that underlies cholestasis. To expedite a better understanding of this mechanism, we have reviewed these genes and their mutations and we discuss these in the context of cholestasis. Abstract Intrahepatic cholestasis is characterized by the accumulation of compounds in the serum that are normally secreted by hepatocytes into the bile. Genes associated with familial intrahepatic cholestasis (FIC) include ATP8B1 (FIC1), ABCB11 (FIC2), ABCB4 (FIC3), TJP2 (FIC4), NR1H4 (FIC5) and MYO5B (FIC6). With advanced genome sequencing methodologies, additional mutated genes are rapidly identified in patients presenting with idiopathic FIC. Notably, several of these genes, VPS33B, VIPAS39, SCYL1, and AP1S1, together with MYO5B, are functionally associated with recycling endosomes and/or the Golgi apparatus. These are components of a complex process that controls the sorting and trafficking of proteins, including those involved in bile secretion. These gene variants therefore suggest that defects in intracellular trafficking take a prominent place in FIC. Here we review these FIC-associated trafficking genes and their variants, their contribution to biliary transporter and canalicular protein trafficking, and, when perturbed, to cholestatic liver disease. Published variants for each of these genes have been summarized in table format, providing a convenient reference for those who work in the intrahepatic cholestasis field.
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Wang LX, Frey MR, Kohli R. The Role of FGF19 and MALRD1 in Enterohepatic Bile Acid Signaling. Front Endocrinol (Lausanne) 2021; 12:799648. [PMID: 35116006 PMCID: PMC8804323 DOI: 10.3389/fendo.2021.799648] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/21/2021] [Accepted: 12/13/2021] [Indexed: 12/14/2022] Open
Abstract
Bile acids are the catabolic end products of cholesterol metabolism that are best known for their role in the digestion of lipids. In the last two decades, extensive investigation has shown bile acids to be important signaling molecules in metabolic processes throughout the body. Bile acids are ligands that can bind to several receptors, including the nuclear receptor farnesoid X receptor (FXR) in ileal enterocytes. FXR activation induces the expression of fibroblast growth factor (FGF) 15/19, a hormone that can modulate bile acid levels, repress gluconeogenesis and lipogenesis, and promote glycogen synthesis. Recent studies have described a novel intestinal protein, MAM and LDL Receptor Class A Domain containing 1 (MALRD1) that positively affects FGF15/19 levels. This signaling pathway presents an exciting target for treating metabolic disease and bile acid-related disorders.
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Maroni L, Fianchi F, Miele L, Svegliati Baroni G. The pathophysiology of gut–liver connection. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:97-122. [DOI: 10.1016/b978-0-12-821927-0.00002-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Wren SN, Donovan MG, Selmin OI, Doetschman TC, Romagnolo DF. A Villin-Driven Fxr Transgene Modulates Enterohepatic Bile Acid Homeostasis and Response to an n-6-Enriched High-Fat Diet. Int J Mol Sci 2020; 21:ijms21217829. [PMID: 33105708 PMCID: PMC7659968 DOI: 10.3390/ijms21217829] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2020] [Revised: 10/12/2020] [Accepted: 10/13/2020] [Indexed: 02/06/2023] Open
Abstract
A diet high in n-6 polyunsaturated fatty acids (PUFAs) may contribute to inflammation and tissue damage associated with obesity and pathologies of the colon and liver. One contributing factor may be dysregulation by n-6 fatty acids of enterohepatic bile acid (BA) metabolism. The farnesoid X receptor (FXR) is a nuclear receptor that regulates BA homeostasis in the liver and intestine. This study aims to compare the effects on FXR regulation and BA metabolism of a palm oil-based diet providing 28% energy (28%E) from fat and low n-6 linoleic acid (LA, 2.5%E) (CNTL) with those of a soybean oil-based diet providing 50%E from fat and high (28%E) in LA (n-6HFD). Wild-type (WT) littermates and a transgenic mouse line overexpressing the Fxrα1 isoform under the control of the intestine-specific Villin promoter (Fxrα1TG) were fed the CNTL or n-6HFD starting at weaning through 16 weeks of age. Compared to the CNTL diet, the n-6HFD supports higher weight gain in both WT and FxrαTG littermates; increases the expression of Fxrα1/2, and peroxisome proliferator-activated receptor-γ1 (Pparγ1) in the small intestine, Fxrα1/2 in the colon, and cytochrome P4507A1 (Cyp7a1) and small heterodimer protein (Shp) in the liver; and augments the levels of total BA in the liver, and primary chenodeoxycholic (CDCA), cholic (CA), and β-muricholic (βMCA) acid in the cecum. Intestinal overexpression of the Fxra1TG augments expression of Shp and ileal bile acid-binding protein (Ibabp) in the small intestine and Ibabp in the proximal colon. Conversely, it antagonizes n-6HFD-dependent accumulation of intestinal and hepatic CDCA and CA; hepatic levels of Cyp7a1; and expression of Pparγ in the small intestine. We conclude that intestinal Fxrα1 overexpression represses hepatic de novo BA synthesis and protects against n-6HFD-induced accumulation of human-specific primary bile acids in the cecum.
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Affiliation(s)
- Spencer N. Wren
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
| | - Micah G. Donovan
- Interdisciplinary Cancer Biology Graduate Program, The University of Arizona, Tucson, AZ 85724, USA;
| | - Ornella I. Selmin
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA
| | - Tom C. Doetschman
- Department of Cellular and Molecular Medicine, The University of Arizona, Tucson, AZ 85724, USA;
| | - Donato F. Romagnolo
- Department of Nutritional Sciences, The University of Arizona, Tucson, AZ 85721, USA; (S.N.W.); (O.I.S.)
- The University of Arizona Cancer Center, Tucson, AZ 85724, USA
- Correspondence: ; Tel.: +1-520-626-9108
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Zhang G, Sun X, Wen Y, Shi A, Zhang J, Wei Y, Wu X. Hesperidin alleviates cholestasis via activation of the farnesoid X receptor in vitro and in vivo. Eur J Pharmacol 2020; 885:173498. [PMID: 32841642 DOI: 10.1016/j.ejphar.2020.173498] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2020] [Revised: 08/16/2020] [Accepted: 08/21/2020] [Indexed: 02/06/2023]
Abstract
Cholestasis causes the intrahepatic accumulation of bile acids leading to hepatobiliary injury. Recently obeticholic acid, a farnesoid X receptor (FXR) agonist, was FDA-approved to treat cholestatic liver diseases, providing a new therapeutic strategy for cholestasis. The purpose of the current study was to characterize a novel FXR agonist and verify the anti-cholestatic effect of hesperidin (HP) in vivo and in vitro. Based on a molecular docking study that predicted that HP would bind to FXR, the hepatoprotective effect of HP against cholestasis and hepatotoxicity was evaluated in mice and in normal and FXR-suppressed HepaRG cells. HP prevented bile acid toxicity in HepaRG cells, and this effect was blocked by FXR silencing. HP appears to activate FXR to prevent cholestatic liver injury. Dynamic change analysis of bile acids revealed that HP promoted bile acid excretion into feces and reduced hepatic accumulation via the regulation of the FXR-target genes bile salt export pump, multi-drug resistance-associated protein 2, and Na+-taurocholate cotransporting polypeptide. Furthermore, HP down-regulated enzymes involved in bile acid synthesis including cholesterol 7α-hydroxylase and sterol 27-hydroxylase. HP produced a protective effect against cholestasis via FXR activation, and may be an effective approach for the prevention and treatment of cholestatic liver diseases.
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Affiliation(s)
- Guoqiang Zhang
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Xiaohan Sun
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China; College of Pharmaceutical Science, Lanzhou University, Lanzhou, 730000, China
| | - Yuanjie Wen
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China; College of Pharmaceutical Science, Lanzhou University, Lanzhou, 730000, China
| | - A'xi Shi
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Jianping Zhang
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Yuhui Wei
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China
| | - Xin'an Wu
- Department of Pharmacy, The First Hospital of Lanzhou University, Lanzhou, 730000, China.
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Yang N, Dong YQ, Jia GX, Fan SM, Li SZ, Yang SS, Li YB. ASBT(SLC10A2): A promising target for treatment of diseases and drug discovery. Biomed Pharmacother 2020; 132:110835. [PMID: 33035828 DOI: 10.1016/j.biopha.2020.110835] [Citation(s) in RCA: 49] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2020] [Revised: 09/17/2020] [Accepted: 09/28/2020] [Indexed: 12/14/2022] Open
Abstract
Bile acids has gradually become a new focus in various diseases, and ASBT as a transporter responsible for the reabsorption of ileal bile acids, is a key hinge associated to the bile acids-cholesterol balance and bile acids of enterohepatic circulation. The cumulative studies have also shown that ASBT is a promising target for treatment of liver, gallbladder, intestinal and metabolic diseases. This article briefly reviewed the process of bile acids enterohepatic circulation, as well as the regulations of ASBT expression, covering transcription factors, nuclear receptors and gut microbiota. In addition, the relationship between ASBT and various diseases were discussed in this paper. According to the structural classification of ASBT inhibitors, the research status of ASBT inhibitors and potential ASBT inhibitors of traditional Chinese medicine (such resveratrol, jatrorrhizine in Coptis chinensis) were summarized. This review provides a basis for the development of ASBT inhibitors and the treatment strategy of related diseases.
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Affiliation(s)
- Na Yang
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Ya-Qian Dong
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Guo-Xiang Jia
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Si-Miao Fan
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Shan-Ze Li
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China
| | - Shen-Shen Yang
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China.
| | - Yu-Bo Li
- Tianjin University of Traditional Chinese Medicine, No.10, Poyang Lake Road, Tuanbo New City, Jinghai District, Tianjin 301617, China.
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Apical sodium-dependent bile acid transporter, drug target for bile acid related diseases and delivery target for prodrugs: Current and future challenges. Pharmacol Ther 2020; 212:107539. [PMID: 32201314 DOI: 10.1016/j.pharmthera.2020.107539] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2019] [Accepted: 03/11/2020] [Indexed: 02/06/2023]
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Li T, Chiang JYL. Bile acid-based therapies for non-alcoholic steatohepatitis and alcoholic liver disease. Hepatobiliary Surg Nutr 2020; 9:152-169. [PMID: 32355674 PMCID: PMC7188552 DOI: 10.21037/hbsn.2019.09.03] [Citation(s) in RCA: 51] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2019] [Accepted: 08/26/2019] [Indexed: 12/12/2022]
Abstract
Bile acids are synthesized from cholesterol only in hepatocytes. Bile acids circulating in the enterohepatic system act as physiological detergent molecules to help solubilize biliary cholesterol and emulsify dietary lipids and fat-soluble vitamins in small intestine. Bile acids are signaling molecules that activate nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor TGR5. FXR critically regulates bile acid homeostasis by mediating bile acid feedback inhibition of hepatic bile acid synthesis. In addition, bile acid-activated cellular signaling pathways regulate metabolic homeostasis, immunity, and cell proliferation in various metabolically active organs. In the small and large intestine, gut bacterial enzymes modify primary bile acids to generate secondary bile acids to help shape the bile acid pool composition and subsequent biological effects. In turn, bile acids exhibit anti-microbial properties and modulate gut microbiota to influence host metabolism and immunity. Currently, bile acid-based therapies including systemic and intestine-restricted FXR agonists, TGR5 agonists, fibroblast growth factor 19 analogue, intestine FXR antagonists, and intestine apical sodium-bile acid transporter (ASBT) inhibitors have been developed as promising treatments for non-alcoholic steatohepatitis (NASH). These pharmacological agents improved metabolic and inflammatory disorders via distinct mechanisms of action that are subjects of extensive research interest. More recently, human and experimental alcoholic liver disease (ALD) has been associated with disrupted bile acid homeostasis. In additional, new findings showed that targeting bile acid metabolism and signaling may be promising therapeutic approaches for treating ALD.
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Affiliation(s)
- Tiangang Li
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, KS, USA
| | - John Y. L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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Yu Z, Yang J, Xiang D, Li G, Liu D, Zhang C. Circadian rhythms and bile acid homeostasis: a comprehensive review. Chronobiol Int 2020; 37:618-628. [PMID: 32126853 DOI: 10.1080/07420528.2020.1733590] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Affiliation(s)
- Zaoqin Yu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Jinyu Yang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Xiang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Guodong Li
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Dong Liu
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Chengliang Zhang
- Department of Pharmacy, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
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Elevated Coefficient of Variation in Total Fecal Bile Acids Precedes Diagnosis of Necrotizing Enterocolitis. Sci Rep 2020; 10:249. [PMID: 31937876 PMCID: PMC6959237 DOI: 10.1038/s41598-019-57178-0] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/08/2019] [Accepted: 12/24/2019] [Indexed: 12/15/2022] Open
Abstract
Accumulation of bile acids (BAs) may mediate development of necrotizing enterocolitis (NEC). Serial fecal samples were collected from premature infants with birth weight (BW) ≤ 1800 g, estimated gestational age (EGA) ≤ 32 weeks, and <30 days old prior to initiation of enteral feeding. Nine infants that developed Bell’s Stage ≥ II NEC were matched with control infants based on BW, EGA, day of life (DOL) enteral feeding was initiated and DOL of the first sample. From each subject, five samples matched by DOL collected were analyzed for BA levels and composition. Fifteen individual BA species were measured via LC-MS/MS and total BA levels were measured using the Diazyme Total Bile Acid Assay kit. No statistically significant differences in composition were observed between control and NEC at the level of individual species (p = 0.1133) or grouped BAs (p = 0.0742). However, there was a statistically significant difference (p = 0.000012) in the mean coefficient of variation (CV) between the two groups with infants developing NEC having more than four-fold higher mean CV than controls. Importantly, these variations occurred prior to NEC diagnosis. These data suggest fluctuations in total fecal BA levels could provide the basis for the first predictive clinical test for NEC.
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Brønden A, Knop FK. Gluco-Metabolic Effects of Pharmacotherapy-Induced Modulation of Bile Acid Physiology. J Clin Endocrinol Metab 2020; 105:5601203. [PMID: 31630179 DOI: 10.1210/clinem/dgz025] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/04/2019] [Accepted: 10/04/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT The discovery and characterization of the bile acid specific receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) have facilitated a wealth of research focusing on the link between bile acid physiology and glucose metabolism. Modulation of FXR and TGR5 activation have been demonstrated to affect the secretion of glucagon-like peptide 1, insulin, and glucagon as well as energy expenditure and gut microbiota composition, with potential beneficial effects on glucose metabolism. EVIDENCE ACQUISITION A search strategy based on literature searches in on PubMed with various combinations of the key words FXR, TGR5, agonist, apical sodium-dependent bile acid transporter (ASBT), bile acid sequestrant, metformin, and glucose metabolism has been applied to obtain material for the present review. Furthermore, manual searches including scanning of reference lists in relevant papers and conference proceedings have been performed. EVIDENCE SYNTHESIS This review provides an outline of the link between bile acid and glucose metabolism, with a special focus on the gluco-metabolic impact of treatment modalities with modulating effects on bile acid physiology; including FXR agonists, TGR5 agonists, ASBT inhibitors, bile acid sequestrants, and metformin. CONCLUSIONS Any potential beneficial gluco-metabolic effects of FXR agonists remain to be established, whereas the clinical relevance of TGR5-based treatment modalities seems limited because of substantial safety concerns of TGR5 agonists observed in animal models. The glucose-lowering effects of ASBT inhibitors, bile acid sequestrants, and metformin are at least partly mediated by modulation of bile acid circulation, which might allow an optimization of these bile acid-modulating treatment modalities. (J Clin Endocrinol Metab XX: 00-00, 2019).
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Affiliation(s)
- Andreas Brønden
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Filip K Knop
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Steno Diabetes Copenhagen, DK-2820 Gentofte, Denmark
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Intestinal Absorption of Bile Acids in Health and Disease. Compr Physiol 2019; 10:21-56. [PMID: 31853951 PMCID: PMC7171925 DOI: 10.1002/cphy.c190007] [Citation(s) in RCA: 134] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
The intestinal reclamation of bile acids is crucial for the maintenance of their enterohepatic circulation. The majority of bile acids are actively absorbed via specific transport proteins that are highly expressed in the distal ileum. The uptake of bile acids by intestinal epithelial cells modulates the activation of cytosolic and membrane receptors such as the farnesoid X receptor (FXR) and G protein-coupled bile acid receptor 1 (GPBAR1), which has a profound effect on hepatic synthesis of bile acids as well as glucose and lipid metabolism. Extensive research has focused on delineating the processes of bile acid absorption and determining the contribution of dysregulated ileal signaling in the development of intestinal and hepatic disorders. For example, a decrease in the levels of the bile acid-induced ileal hormone FGF15/19 is implicated in bile acid-induced diarrhea (BAD). Conversely, the increase in bile acid absorption with subsequent overload of bile acids could be involved in the pathophysiology of liver and metabolic disorders such as fatty liver diseases and type 2 diabetes mellitus. This review article will attempt to provide a comprehensive overview of the mechanisms involved in the intestinal handling of bile acids, the pathological implications of disrupted intestinal bile acid homeostasis, and the potential therapeutic targets for the treatment of bile acid-related disorders. Published 2020. Compr Physiol 10:21-56, 2020.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago, Chicago, Illinois, USA
- jesse Brown VA Medical Center, Chicago, Illinois, USA
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Valencia-Rodríguez A, Aquino-Matus J, Vera-Barajas A, Qi X, Méndez-Sánchez N. New therapeutic options for bile acid malabsorption diarrhea. ANNALS OF TRANSLATIONAL MEDICINE 2019; 7:695. [PMID: 31930096 PMCID: PMC6944536 DOI: 10.21037/atm.2019.09.112] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Affiliation(s)
| | - Jorge Aquino-Matus
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
| | | | - Xingshun Qi
- Department of Gastroenterology, General Hospital of Northern Theater Command, Shenyang 110840, China
| | - Nahum Méndez-Sánchez
- Liver Research Unit, Medica Sur Clinic and Foundation, Mexico City, Mexico
- Faculty of Medicine, National Autonomous University of Mexico, Mexico City, Mexico
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Honda A, Miyazaki T, Iwamoto J, Hirayama T, Morishita Y, Monma T, Ueda H, Mizuno S, Sugiyama F, Takahashi S, Ikegami T. Regulation of bile acid metabolism in mouse models with hydrophobic bile acid composition. J Lipid Res 2019; 61:54-69. [PMID: 31645370 DOI: 10.1194/jlr.ra119000395] [Citation(s) in RCA: 137] [Impact Index Per Article: 22.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2019] [Revised: 10/17/2019] [Indexed: 02/07/2023] Open
Abstract
The bile acid (BA) composition in mice is substantially different from that in humans. Chenodeoxycholic acid (CDCA) is an end product in the human liver; however, mouse Cyp2c70 metabolizes CDCA to hydrophilic muricholic acids (MCAs). Moreover, in humans, the gut microbiota converts the primary BAs, cholic acid and CDCA, into deoxycholic acid (DCA) and lithocholic acid (LCA), respectively. In contrast, the mouse Cyp2a12 reverts this action and converts these secondary BAs to primary BAs. Here, we generated Cyp2a12 KO, Cyp2c70 KO, and Cyp2a12/Cyp2c70 double KO (DKO) mice using the CRISPR-Cas9 system to study the regulation of BA metabolism under hydrophobic BA composition. Cyp2a12 KO mice showed the accumulation of DCAs, whereas Cyp2c70 KO mice lacked MCAs and exhibited markedly increased hepatobiliary proportions of CDCA. In DKO mice, not only DCAs or CDCAs but also DCAs, CDCAs, and LCAs were all elevated. In Cyp2c70 KO and DKO mice, chronic liver inflammation was observed depending on the hepatic unconjugated CDCA concentrations. The BA pool was markedly reduced in Cyp2c70 KO and DKO mice, but the FXR was not activated. It was suggested that the cytokine/c-Jun N-terminal kinase signaling pathway and the pregnane X receptor-mediated pathway are the predominant mechanisms, preferred over the FXR/small heterodimer partner and FXR/fibroblast growth factor 15 pathways, for controlling BA synthesis under hydrophobic BA composition. From our results, we hypothesize that these KO mice can be novel and useful models for investigating the roles of hydrophobic BAs in various human diseases.
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Affiliation(s)
- Akira Honda
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan; Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan.
| | - Teruo Miyazaki
- Joint Research Center, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Junichi Iwamoto
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Takeshi Hirayama
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Yukio Morishita
- Diagnostic Pathology Division, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Tadakuni Monma
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Hajime Ueda
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
| | - Seiya Mizuno
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Fumihiro Sugiyama
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Satoru Takahashi
- Laboratory Animal Resource Center, University of Tsukuba, Ibaraki, Japan
| | - Tadashi Ikegami
- Department of Gastroenterology and Hepatology, Tokyo Medical University Ibaraki Medical Center, Ibaraki, Japan
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