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1
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Ghallab A, Mandorfer M, Stirnimann G, Geyer J, Lindström E, Luedde T, van der Merwe S, Rashidi-Alavijeh J, Schmidt H, Karpen SJ, Fickert P, Trauner M, Hengstler JG, Dawson PA. Enteronephrohepatic Circulation of Bile Acids and Therapeutic Potential of Systemic Bile Acid Transporter Inhibitors. J Hepatol 2025:S0168-8278(25)02207-X. [PMID: 40414504 DOI: 10.1016/j.jhep.2025.05.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 05/06/2025] [Accepted: 05/07/2025] [Indexed: 05/27/2025]
Abstract
Together with carriers in liver and small intestine, kidney transporters function to conserve and compartmentalize bile acids in the enteronephrohepatic circulation. In patients with liver disease, systemic bile acid levels are elevated, undergo increased renal glomerular filtration, and contribute to the pathogenesis of cholemic nephropathy and acute kidney injury. In this review, we describe mechanisms for renal bile acid transport and highlight very recent discoveries that challenge current paradigms for the pathogenesis of cholemic nephropathy and renal tubule cast formation. We also discuss the therapeutic potential of inhibiting the kidney apical sodium-dependent bile acid transporter (ASBT) to redirect bile acids into urine for elimination, reduce hepatobiliary accumulation and systemic levels of bile acids, and treat cholemic nephropathy. In conclusion, a deeper understanding of the enteronephrohepatic bile acid axis is providing insights into novel strategies to protect both liver and kidney in patients with liver disease.
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Affiliation(s)
- Ahmed Ghallab
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany; Forensic Medicine and Toxicology Department, Faculty of Veterinary Medicine, South Valley University, Qena, Egypt.
| | - Mattias Mandorfer
- Vienna Hepatic Hemodynamic Lab, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Guido Stirnimann
- University Clinic for Visceral Surgery and Medicine, Inselspital University Hospital, University of Bern, 3010 Bern, Switzerland
| | - Joachim Geyer
- Institute of Pharmacology and Toxicology, Justus Liebig University Giessen, Biomedical Research Center Seltersberg, Schubertstr. 81, 35392 Giessen, Germany
| | | | - Tom Luedde
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Duesseldorf, Medical Faculty at Heinrich-Heine-University, 40225 Dusseldorf, Germany
| | | | - Jassin Rashidi-Alavijeh
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Hartmut Schmidt
- Clinic for Gastroenterology, Hepatology and Transplantation Medicine, University hospital Essen, Essen, Germany; Department of Gastroenterology and Hepatology, UZ Leuven, Leuven, Belgium
| | - Saul J Karpen
- Stravitz-Sanyal Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, VA, United States
| | - Peter Fickert
- Department of Medicine, Division of Gastroenterology and Hepatology, Medical University Graz, Austria
| | - Michael Trauner
- Hans Popper Laboratory of Molecular Hepatology, Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, 1090 Vienna, Austria
| | - Jan G Hengstler
- Department of Toxicology, Leibniz Research Centre for Working Environment and Human Factors, Technical University Dortmund, Ardeystr. 67, 44139, Dortmund, Germany
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, United States.
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Ganguly S, Chattopadhyay T, Kazi R, Das S, Malik B, Ml U, Iyer PS, Kashiv M, Singh A, Ghadge A, Nair SD, Sonawane MS, Kolthur-Seetharam U. Consumption of sucrose-water rewires macronutrient uptake and utilization mechanisms in a tissue specific manner. J Nutr Biochem 2025; 139:109850. [PMID: 39889860 DOI: 10.1016/j.jnutbio.2025.109850] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2024] [Revised: 10/31/2024] [Accepted: 01/25/2025] [Indexed: 02/03/2025]
Abstract
Consumption of sugar-sweetened beverages (SSBs) have been linked to metabolic dysfunction, obesity, diabetes and enhanced risk of cardiovascular diseases across all age-groups globally. Decades of work that have provided insights into pathophysiological manifestations of sucrose overfeeding have employed paradigms that rarely mimic human consumption of SSBs. Thus, our understanding of multiorgan cross-talk and molecular and/or cellular mechanisms, which operate across scales and drive physiological derangement is still poor. By employing a paradigm of sucrose water feeding in mice that closely resembles chronic SSB consumption in humans (10% sucrose in water), we have unraveled hitherto unknown tissue-specific mechanistic underpinnings, which contribute towards perturbed physiology. Our findings illustrate that systemic impaired glucose homeostasis, mediated by hepatic gluconeogenesis and insulin resistance, does not involve altered gene expression programs in the liver. We have discovered the pivotal role of the small intestine, which in conjunction with liver and muscles, drives dyshomeostasis. Importantly, we have uncovered rewiring of molecular mechanisms in the proximal intestine that is either causal or consequential to systemic ill-effects of chronic sucrose water consumption including dysfunction of liver and muscle mitochondria. Tissue-specific molecular signatures, which we have unveiled as the primary outcome, clearly indicate that inefficient utilization of glucose is exacerbated by enhanced uptake by the gut. Besides providing systems-wide mechanistic insights, we propose that consumption of SSBs causes intestinal 'molecular addiction' for deregulated absorption of hexose-sugars, and drives diseases such as diabetes and obesity.
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Affiliation(s)
- Saptarnab Ganguly
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Tandrika Chattopadhyay
- Centre for innovation in molecular and pharmaceutical sciences, Dr. Reddy's Institute of Life Sciences, Hyderabad, Telangana, India
| | - Rubina Kazi
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Souparno Das
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Bhavisha Malik
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Uthpala Ml
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Padmapriya S Iyer
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mohit Kashiv
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Anshit Singh
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Amita Ghadge
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India
| | - Shyam D Nair
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India
| | - Mahendra S Sonawane
- Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India.
| | - Ullas Kolthur-Seetharam
- Tata Institute of Fundamental Research, Subject Board of Biology, Hyderabad, Telangana, India; Department of Biological Sciences, Tata Institute of Fundamental Research, Mumbai, Maharashtra, India; Development and Aging (ARUMDA), Advanced Research Unit on Metabolism, Tata Institute of Fundamental Research, Hyderabad, Telangana, India; Centre for DNA Fingerprinting and Diagnostics, Hyderabad, Telangana, India.
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3
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Chaudhari SN, Chen Y, Ferraz-Bannitz R, Cummings C, Sheehan A, Querol PC, Ozturk B, Wang H, D'Agostino G, Ye F, Sheu EG, Devlin AS, Patti ME. Alterations in intestinal bile acid transport provide a therapeutic target in patients with post-bariatric hypoglycaemia. Nat Metab 2025; 7:792-807. [PMID: 40186075 DOI: 10.1038/s42255-025-01262-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Accepted: 03/05/2025] [Indexed: 04/07/2025]
Abstract
While Roux-en-Y gastric bypass is an effective treatment for obesity and type 2 diabetes, up to one-third of patients develop post-bariatric hypoglycaemia (PBH). Individuals with PBH exhibit increased postprandial secretion of the intestinal hormone fibroblast growth factor 19 (FGF19, Fgf15 in mice). However, the underlying mechanisms contributing to PBH remain uncertain. Here we demonstrate that faecal and plasma bile acid (BA) profiles are significantly altered in postoperative individuals with PBH versus those without hypoglycaemia. Furthermore, altered BAs in PBH induce FGF19 secretion in intestinal cells in a manner dependent on the apical sodium-dependent BA transporter (ASBT). We demonstrate that ASBT inhibition reduces Fgf15 expression and increases postprandial glucose in hypoglycaemic mice. Our data suggest that dysregulation of luminal BA profiles and transport may contribute to PBH and provide proof of concept that ASBT inhibition could be developed as a new therapeutic strategy for PBH.
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Affiliation(s)
- Snehal N Chaudhari
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
- Department of Biochemistry, University of Wisconsin-Madison, Madison, WI, USA
| | - Yingjia Chen
- Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - Rafael Ferraz-Bannitz
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Cameron Cummings
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Amanda Sheehan
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Pilar Casanova Querol
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Berkcan Ozturk
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Hanna Wang
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA
| | - Gabriel D'Agostino
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Fei Ye
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA
| | - Eric G Sheu
- Laboratory for Surgical and Metabolic Research, Department of Surgery, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
| | - A Sloan Devlin
- Department of Biological Chemistry and Molecular Pharmacology, Blavatnik Institute, Harvard Medical School, Boston, MA, USA.
| | - Mary-Elizabeth Patti
- Department of Integrative Physiology and Metabolism, Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, MA, USA.
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Subedi L, Bamjan AD, Phuyal S, Shim JH, Cho SS, Seo JB, Chang KY, Byun Y, Kweon S, Park JW. An oral liraglutide nanomicelle formulation conferring reduced insulin-resistance and long-term hypoglycemic and lipid metabolic benefits. J Control Release 2025; 378:637-655. [PMID: 39709071 DOI: 10.1016/j.jconrel.2024.12.039] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2024] [Revised: 11/20/2024] [Accepted: 12/15/2024] [Indexed: 12/23/2024]
Abstract
Type 2 diabetes is a chronic disease characterized by insulin resistance and often worsened by obesity. Effective management involves the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) to assist with glycemic control and weight management. However, these drugs must be administered subcutaneously due to their low oral bioavailability. We developed an oral liraglutide (LRG) formulation by electrostatic complexation of GLP-1 RA with bile acid derivatives and nanomicelle (NM) formation, with non-ionic surfactant n-dodecyl-β-d-maltoside (DDM). The optimized formulation, LDD[1:2:4]-NM, had a mean particle size of 75.9 ± 5.60 nm and a permeability 1347 % higher than that of unformulated LRG when tested in Caco-2/HT29-MTX-E12 cell monolayers. In rats, oral bioavailability was 4.63-fold higher than that of unformulated LRG (1.11 ± 0.20 % vs. 5.14 ± 0.63 %). The absorption mechanism included clathrin-mediated endocytosis, macropinocytosis, and an ASBT-mediated pathway. A 12-week oral treatment consisting of a daily dose of 20 mg LDD[1:2:4]-NM/kg significantly reduced glycohemoglobin levels, a marker of diabetic control, and the HOMA-IR index, a marker of insulin resistance. The weight of epididymal and inguinal white adipose tissue and brown adipose tissue (BAT) was also reduced. Moreover, LDD[1:2:4]-NM had a greater impact on BAT activation, pro-inflammatory gene expression, and lipid metabolism than subcutaneous LRG. This study showed that an oral NM formulation can efficiently deliver LRG. Long-term treatment led to improved hyperglycemic effects, insulin resistance, and modulated lipid metabolism. LDD[1:2:4]-NM is thus a promising oral therapeutic option for the management of type 2 diabetes, potentially transforming treatment paradigms based on the availability of a more convenient administration route.
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Affiliation(s)
- Laxman Subedi
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Arjun Dhwoj Bamjan
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Susmita Phuyal
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Jung-Hyun Shim
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Seung-Sik Cho
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | - Jong Bae Seo
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea
| | | | - Youngro Byun
- Research Institute of Pharmaceutical Sciences, College of Pharmacy, Seoul National University, Seoul 08826, Republic of Korea
| | - Seho Kweon
- College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea.
| | - Jin Woo Park
- Department of Biomedicine, Health & Life Convergence Sciences, BK21 Four, Biomedical and Healthcare Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea; College of Pharmacy and Natural Medicine Research Institute, Mokpo National University, Jeonnam 58554, Republic of Korea.
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Shijing T, Yinping P, Qiong Y, Deshuai L, Liancai Z, Jun T, Shaoyong L, Bochu W. Synthesis of TUDCA from chicken bile: immobilized dual-enzymatic system for producing artificial bear bile substitute. Microb Cell Fact 2024; 23:326. [PMID: 39623449 PMCID: PMC11613824 DOI: 10.1186/s12934-024-02592-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2024] [Accepted: 11/12/2024] [Indexed: 12/06/2024] Open
Abstract
Bear bile, a valuable animal-derived medicinal substance primarily composed of tauroursodeoxycholic acid (TUDCA), is widely distributed in the medicinal market across various countries due to its significant therapeutic potential. Given the extreme cruelty involved in bear bile extraction, researchers are focusing on developing synthetic bear bile powder as a more humane alternative. This review presents an industrially practical and environmentally friendly process for producing an artificial substitute for bear bile powder using inexpensive and readily available chicken bile powder through an immobilized 7α-,7β-HSDH dual-enzymatic syste. Current technology has facilitated the industrial production of TUDCA from Tauodeoxycholic acid (TCDCA) using chicken bile powder. The review begins by examining the chemical composition, structure, and properties of bear bile, followed by an outline of the pharmacological mechanisms and manufacturing methods of TUDCA, covering chemical synthesis and biotransformation methods, and a discussion on their respective advantages and disadvantages. Finally, the process of converting chicken bile powder into bear bile powder using an immobilized 7α-Hydroxysteroid Dehydrogenases(7α-HSDH) with 7β- Hydroxysteroid Dehydrogenases (7β-HSDH) dual-enzyme system is thoroughly explained. The main objective of this review is to propose a comprehensive strategy for the complete synthesis of artificial bear bile from chicken bile within a controlled laboratory setting.
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Affiliation(s)
- Tang Shijing
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Pan Yinping
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Yang Qiong
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China
| | - Lou Deshuai
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Zhu Liancai
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
| | - Tan Jun
- Chongqing Key Laboratory of Medicinal Resources in the Three Gorges Reservoir Region, School of Biological & Chemical Engineering, Chongqing University of Education, Chongqing, 400067, People's Republic of China
| | - Liu Shaoyong
- Shanghai Kaibao Pharmaceutical Co., LTD., Shanghai, 200030, People's Republic of China
| | - Wang Bochu
- Key Laboratory of Biorheological Science and Technology (Chongqing University), Ministry of Education, College of Bioengineering, Chongqing University, No. 174, Shapingba Main Street, Chongqing, 400030, People's Republic of China.
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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7
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Zhang N, Guo D, Guo N, Yang D, Yan H, Yao J, Xiao H, Shao M, Guan Y, Zhang G. Integration of UPLC-MS/MS-based metabolomics and desorption electrospray ionization-mass spectrometry imaging reveals that Shouhui Tongbian Capsule alleviates slow transit constipation by regulating bile acid metabolism. J Chromatogr B Analyt Technol Biomed Life Sci 2024; 1247:124331. [PMID: 39369590 DOI: 10.1016/j.jchromb.2024.124331] [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: 07/28/2024] [Revised: 09/09/2024] [Accepted: 09/28/2024] [Indexed: 10/08/2024]
Abstract
Slow transit constipation (STC) is a common intestinal disorder. Some studies reported that Shouhui Tongbian Capsule (SHTB) can effectively mitigate STC symptoms. A detailed understanding of the changes in the endogenous metabolite profile of rats is crucial for a more accurate comprehension of the molecular pathological characteristics of SHTB in treating STC. In the present study, a method integrating metabolomics based on Ultra-performance liquid chromatography-tandem mass spectrometry (UPLC-MS/MS) and Desorption electrospray ionization (DESI)-mass spectrometry imaging (MSI) was proposed to investigate serum, feces and colon tissue metabolic alterations of STC rats induced by diphenoxylate and the effect of SHTB treatment on metabolism. Then, Enzyme-linked immunosorbent assay (ELISA) and Western blot (WB) analysis for verifying the potential mechanism of SHTB in treating STC. As a result, we first indicated that SHTB significantly improved intestinal peristalsis and low fecal water content in STC rats. Furthermore, after treatment with SHTB, the thickness of muscle layers was increased, demonstrated SHTB's effectiveness in reducing intestinal injury in STC rats. Besides, bile acid (BA) metabolomics based on UPLC-MS/MS revealed significant increase in serum levels of Cholic acid (CA), Deoxycholic acid (DCA), Chenodeoxycholic acid (CDCA), Ursodeoxycholic acid (UDCA), and Glycolithocholic acid (GLCA), whereas the contents of CA and DCA in feces were significantly decreased in STC rats. Nonetheless, they returned to the control levels after the SHTB administration. ELISA results showed that SHTB significantly hindered the excessive reabsorption of BAs by inhibiting apical sodium-dependent bile acid transporter (ASBT), organic solute transporter alpha (OSTα) and organic solute transporter beta (OSTβ) in the ileum tissue of STC rats. Furthermore, the DESI-MSI analysis revealed that SHTB remarkably enhanced DCA in the colon tissue of STC rats. The WB results indicated that SHTB reinstated Takeda G-protein-coupled receptor 5 (TGR5) expression, a receptor for BAs and a key regulator of colonic motility. Consequently, DCA exerted its effects on TGR5, leading to the promotion of colonic motility. This study provided more comprehensive and detailed information about the BA metabolomics in the serum, feces and colon of STC rats. These findings highlighted the promising potential of metabolomics based on UPLC-MS/MS and DESI-MSI method for application in the study of STC diseases.
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Affiliation(s)
- Na Zhang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China; School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Dong Guo
- Department of Neurology, Liaocheng People's Hospital, Liaocheng 252000, Shandong, China
| | - Na Guo
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Dawei Yang
- Zhong Yuan Academy of Biological Medicine, Liaocheng People's Hospital, Liaocheng 252000, China
| | - Han Yan
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Jingchun Yao
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Shandong, China
| | - He Xiao
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Shandong, China
| | - Mingguo Shao
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Shandong, China
| | - Yongxia Guan
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Shandong, China.
| | - Guimin Zhang
- State Key Laboratory of Integration and Innovation of Classic Formula and Modern Chinese Medicine, Lunan Pharmaceutical Group Co. Ltd., Shandong, China.
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8
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Kashobwe L, Sadrabadi F, Braeuning A, Leonards PEG, Buhrke T, Hamers T. In vitro screening of understudied PFAS with a focus on lipid metabolism disruption. Arch Toxicol 2024; 98:3381-3395. [PMID: 38953992 PMCID: PMC11402862 DOI: 10.1007/s00204-024-03814-2] [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: 02/04/2024] [Accepted: 06/26/2024] [Indexed: 07/04/2024]
Abstract
Per- and polyfluoroalkyl substances (PFAS) are man-made chemicals used in many industrial applications. Exposure to PFAS is associated with several health risks, including a decrease in infant birth weight, hepatoxicity, disruption of lipid metabolism, and decreased immune response. We used the in vitro cell models to screen six less studied PFAS [perfluorooctane sulfonamide (PFOSA), perfluoropentanoic acid (PFPeA), perfluoropropionic acid (PFPrA), 6:2 fluorotelomer alcohol (6:2 FTOH), 6:2 fluorotelomer sulfonic acid (6:2 FTSA), and 8:2 fluorotelomer sulfonic acid (8:2 FTSA)] for their capacity to activate nuclear receptors and to cause differential expression of genes involved in lipid metabolism. Cytotoxicity assays were run in parallel to exclude that observed differential gene expression was due to cytotoxicity. Based on the cytotoxicity assays and gene expression studies, PFOSA was shown to be more potent than other tested PFAS. PFOSA decreased the gene expression of crucial genes involved in bile acid synthesis and detoxification, cholesterol synthesis, bile acid and cholesterol transport, and lipid metabolism regulation. Except for 6:2 FTOH and 8:2 FTSA, all tested PFAS downregulated PPARA gene expression. The reporter gene assay also showed that 8:2 FTSA transactivated the farnesoid X receptor (FXR). Based on this study, PFOSA, 6:2 FTSA, and 8:2 FTSA were prioritized for further studies to confirm and understand their possible effects on hepatic lipid metabolism.
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Affiliation(s)
- Lackson Kashobwe
- Vrije Universiteit Amsterdam, Amsterdam Institute for Life and Environment (A-LIFE), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands.
| | - Faezeh Sadrabadi
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Albert Braeuning
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Pim E G Leonards
- Vrije Universiteit Amsterdam, Amsterdam Institute for Life and Environment (A-LIFE), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
| | - Thorsten Buhrke
- Department of Food Safety, German Federal Institute for Risk Assessment (BfR), Max-Dohrn-Str. 8-10, 10589, Berlin, Germany
| | - Timo Hamers
- Vrije Universiteit Amsterdam, Amsterdam Institute for Life and Environment (A-LIFE), De Boelelaan 1085, 1081 HV, Amsterdam, The Netherlands
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9
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Sudo K, Delmas-Eliason A, Soucy S, Barrack KE, Liu J, Balasubramanian A, Shu CJ, James MJ, Hegner CL, Dionne HD, Rodriguez-Palacios A, Krause HM, O'Toole GA, Karpen SJ, Dawson PA, Schultz D, Sundrud MS. Quantifying Forms and Functions of Enterohepatic Bile Acid Pools in Mice. Cell Mol Gastroenterol Hepatol 2024; 18:101392. [PMID: 39179177 PMCID: PMC11490680 DOI: 10.1016/j.jcmgh.2024.101392] [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: 05/01/2024] [Revised: 08/06/2024] [Accepted: 08/08/2024] [Indexed: 08/26/2024]
Abstract
BACKGROUNDS & AIMS Bile acids (BAs) are core gastrointestinal metabolites with dual functions in lipid absorption and cell signaling. BAs circulate between the liver and distal small intestine (i.e., ileum), yet the dynamics through which complex BA pools are absorbed in the ileum and interact with host intestinal cells in vivo remain poorly understood. Because ileal absorption is rate-limiting in determining which BAs in the intestinal lumen gain access to host intestinal cells and receptors, and at what concentrations, we hypothesized that defining the rates and routes of ileal BA absorption in vivo would yield novel insights into the physiological forms and functions of mouse enterohepatic BA pools. METHODS Using ex vivo mass spectrometry, we quantified 88 BA species and metabolites in the intestinal lumen and superior mesenteric vein of individual wild-type mice, and cage-mates lacking the ileal BA transporter, Asbt/Slc10a2. RESULTS Using these data, we calculated that the pool of BAs circulating through ileal tissue (i.e., the ileal BA pool) in fasting C57BL/6J female mice is ∼0.3 μmol/g. Asbt-mediated transport accounted for ∼80% of this pool and amplified size. Passive permeability explained the remaining ∼20% and generated diversity. Compared with wild-type mice, the ileal BA pool in Asbt-deficient mice was ∼5-fold smaller, enriched in secondary BA species and metabolites normally found in the colon, and elicited unique transcriptional responses on addition to exvivo-cultured ileal explants. CONCLUSIONS This study defines quantitative traits of the mouse enterohepatic BA pool and reveals how aberrant BA metabolism can impinge directly on host intestinal physiology.
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Affiliation(s)
- Koichi Sudo
- Center for Digestive Health, Dartmouth Health, Lebanon, New Hampshire
| | - Amber Delmas-Eliason
- Department of Immunology and Microbiology, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida
| | - Shannon Soucy
- Department of Biomedical Data Science, Geisel School of Medicine, Hanover, New Hampshire
| | - Kaitlyn E Barrack
- Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire
| | - Jiabao Liu
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada
| | - Akshaya Balasubramanian
- Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire
| | | | | | - Courtney L Hegner
- The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida
| | - Henry D Dionne
- Center for Digestive Health, Dartmouth Health, Lebanon, New Hampshire
| | - Alex Rodriguez-Palacios
- Division of Gastroenterology and Liver Disease, Case Western Reserve University School of Medicine, Cleveland, Ohio; Digestive Health Research Institute, Case Western Reserve University School of Medicine, Cleveland, Ohio; Department of Molecular Biology and Microbiology, Case Western Reserve University School of Medicine, Cleveland, Ohio; University Hospitals Research and Education Institute, University Hospitals Cleveland Medical Center, Cleveland, Ohio
| | - Henry M Krause
- Donnelly Centre for Cellular and Biomolecular Research, University of Toronto, Toronto, Ontario, Canada; Department of Molecular Genetics, University of Toronto, Toronto, Ontario, Canada
| | - George A O'Toole
- Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire
| | - Saul J Karpen
- Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia; Stravitz-Sanyal Liver Institute for Liver Disease and Metabolic Health, Virginia Commonwealth University, Richmond, Virginia
| | - Paul A Dawson
- Division of Pediatric Gastroenterology, Department of Pediatrics, Hepatology, and Nutrition, Children's Healthcare of Atlanta and Emory University School of Medicine, Atlanta, Georgia
| | - Daniel Schultz
- Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire
| | - Mark S Sundrud
- Center for Digestive Health, Dartmouth Health, Lebanon, New Hampshire; Department of Immunology and Microbiology, Herbert Wertheim UF Scripps Institute for Biomedical Innovation and Technology, Jupiter, Florida; Department of Microbiology and Immunology, Geisel School of Medicine, Hanover, New Hampshire; The Skaggs Graduate School of Chemical and Biological Sciences, The Scripps Research Institute, Jupiter, Florida; Department of Medicine, Geisel School of Medicine, Dartmouth College, Hanover, New Hampshire; Dartmouth Cancer Center, Lebanon, New Hampshire.
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10
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Nonogaki K, Kaji T. The GLP-1 Receptor Agonist Liraglutide Decreases Primary Bile Acids and Serotonin in the Colon Independently of Feeding in Mice. Int J Mol Sci 2024; 25:7784. [PMID: 39063026 PMCID: PMC11277076 DOI: 10.3390/ijms25147784] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2024] [Revised: 07/03/2024] [Accepted: 07/15/2024] [Indexed: 07/28/2024] Open
Abstract
Liraglutide, a glucagon-like peptide 1 analog used to treat type 2 diabetes and obesity, is a potential new treatment modality for bile acid (BA) diarrhea. Here, we show that administration of liraglutide significantly decreased total BAs, especially the primary BAs, including cholic acid, chenodeoxycholic acid, taurocholic acid, taurochenodeoxycholic acid, glycocholic acid, and β-muricholic acid, in the liver and feces. In addition, liraglutide significantly decreased tryptophan metabolites, including L-tryptophan, serotonin, 5-hydroxy indole-3-acetic acid, L-kynurenine, and xanthurenic acid, in the colon, whereas it significantly increased indole-3-propionic acid. Moreover, the administration of liraglutide remarkably decreased the expression of apical sodium-dependent bile acid transporter, which mediates BA uptake across the apical brush border member in the ileum, ileal BA binding protein, and fibroblast growth factor 15 in association with decreased expression of the BA-activated nuclear receptor farnesoid X receptor and the heteromeric organic solute transporter Ostα/β, which induces BA excretion, in the ileum. Liraglutide acutely decreased body weight and blood glucose levels in association with decreases in plasma insulin and serotonin levels in food-deprived mice. These findings suggest the potential of liraglutide as a novel inhibitor of primary BAs and serotonin in the colon.
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Affiliation(s)
- Katsunori Nonogaki
- Division of Diabetes and Nutrition, RARiS, Tohoku University, 6-6-11 Aramakiaza-Aoba, Aoba-ku, Sendai 980-8579, Miyagi, Japan;
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11
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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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12
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [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: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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13
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Sugiyama K, Shimano H, Takahashi M, Shimura Y, Shimura A, Furuya T, Tomabechi R, Shirasaka Y, Higuchi K, Kishimoto H, Inoue K. The Use of Carboxyfluorescein Reveals the Transport Function of MCT6/SLC16A5 Associated with CD147 as a Chloride-Sensitive Organic Anion Transporter in Mammalian Cells. J Pharm Sci 2024; 113:1113-1120. [PMID: 38160712 DOI: 10.1016/j.xphs.2023.12.023] [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: 10/07/2023] [Revised: 12/25/2023] [Accepted: 12/25/2023] [Indexed: 01/03/2024]
Abstract
Oral drug absorption involves drug permeation across the apical and basolateral membranes of enterocytes. Although transporters mediating the influx of anionic drugs in the apical membranes have been identified, transporters responsible for efflux in the basolateral membranes remain unclear. Monocarboxylate transporter 6 (MCT6/SLC16A5) has been reported to localize to the apical and basolateral membranes of human enterocytes and to transport organic anions such as bumetanide and nateglinide in the Xenopus oocyte expression system; however, its transport functions have not been elucidated in detail. In this study, we characterized the function of MCT6 expressed in HEK293T cells and explored fluorescent probes to more easily evaluate MCT6 function. The results illustrated that MCT6 interacts with CD147 to localize at the plasma membrane. When the uptake of various fluorescein derivatives was examined in NaCl-free uptake buffer (pH 5.5), the uptake of 5-carboxyfluorescein (5-CF) was significantly greater in MCT6 and CD147-expressing cells. MCT6-mediated 5-CF uptake was saturable with a Km of 1.07 mM and inhibited by several substrates/inhibitors of organic anion transporters and extracellular Cl ion with an IC50 of 53.7 mM. These results suggest that MCT6 is a chloride-sensitive organic anion transporter that can be characterized using 5-CF as a fluorescent probe.
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Affiliation(s)
- Koki Sugiyama
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Hiroe Shimano
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Masaki Takahashi
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Yuta Shimura
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Asuka Shimura
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Takahito Furuya
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Ryuto Tomabechi
- Laboratory of Pharmaceutics, Kitasato University School of Pharmacy, Tokyo, Japan
| | - Yoshiyuki Shirasaka
- Institute of Medical, Pharmaceutical and Health Sciences, Kanazawa University, Kanazawa, Japan
| | - Kei Higuchi
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Hisanao Kishimoto
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan
| | - Katsuhisa Inoue
- Department of Biopharmaceutics, School of Pharmacy, Tokyo University of Pharmacy and Life Sciences, Tokyo, Japan.
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14
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Kharve K, Engley AS, Paine MF, Sprowl JA. Impact of Drug-Mediated Inhibition of Intestinal Transporters on Nutrient and Endogenous Substrate Disposition…an Afterthought? Pharmaceutics 2024; 16:447. [PMID: 38675109 PMCID: PMC11053474 DOI: 10.3390/pharmaceutics16040447] [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: 02/07/2024] [Revised: 03/06/2024] [Accepted: 03/14/2024] [Indexed: 04/28/2024] Open
Abstract
A large percentage (~60%) of prescription drugs and new molecular entities are designed for oral delivery, which requires passage through a semi-impervious membrane bilayer in the gastrointestinal wall. Passage through this bilayer can be dependent on membrane transporters that regulate the absorption of nutrients or endogenous substrates. Several investigations have provided links between nutrient, endogenous substrate, or drug absorption and the activity of certain membrane transporters. This knowledge has been key in the development of new therapeutics that can alleviate various symptoms of select diseases, such as cholestasis and diabetes. Despite this progress, recent studies revealed potential clinical dangers of unintended altered nutrient or endogenous substrate disposition due to the drug-mediated disruption of intestinal transport activity. This review outlines reports of glucose, folate, thiamine, lactate, and bile acid (re)absorption changes and consequent adverse events as examples. Finally, the need to comprehensively expand research on intestinal transporter-mediated drug interactions to avoid the unwanted disruption of homeostasis and diminish therapeutic adverse events is highlighted.
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Affiliation(s)
- Kshitee Kharve
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA;
| | - Andrew S. Engley
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA; (A.S.E.); (M.F.P.)
| | - Mary F. Paine
- Department of Pharmaceutical Sciences, College of Pharmacy and Pharmaceutical Sciences, Washington State University, Spokane, WA 99202, USA; (A.S.E.); (M.F.P.)
| | - Jason A. Sprowl
- Department of Pharmaceutical Sciences, School of Pharmacy and Pharmaceutical Sciences, University at Buffalo, State University of New York, Buffalo, NY 14214, USA;
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15
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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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16
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Zhang P, Fang Z, Zhao M, Yi B, Huang Y, Yang H, Guo N, Zhao C. Ethanol extract of Pueraria lobata improve acute myocardial infarction in rats via regulating gut microbiota and bile acid metabolism. Phytother Res 2023; 37:5932-5946. [PMID: 37697496 DOI: 10.1002/ptr.8005] [Citation(s) in RCA: 6] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/13/2023] [Revised: 06/15/2023] [Accepted: 08/20/2023] [Indexed: 09/13/2023]
Abstract
BACKGROUND AND AIM Acute myocardial infarction (AMI) is a multifactorial disease with high mortality rate worldwide. Ethanol extract of Pueraria lobata (EEPL) has been widely used in treating cardiovascular diseases in China. This study aimed to explore the underlying therapeutic mechanism of EEPL in AMI rats. EXPERIMENTAL PROCEDURE We first evaluated the anti-AMI efficacy of EEPL through immunohistochemistry staining and biochemical indexes. Then, UPLC-MS/MS, 16S rDNA, and shotgun metagenomic sequencing were used to analyze the alterations in bile acid metabolism and intestinal flora. Finally, the influence of EEPL on ilem bile acid metabolism, related enzymes expression, and transporter proteins expression in rats were verified by mass spectrometry image and ELISA. KEY RESULTS The results showed that EEPL can reduce cardiac impairment in AMI rats. Besides, EEPL effectively increased bile acid levels and regulated gut microbiota disturbance in AMI rats via increasing CYP7A1 expression and restoring intestinal microbiota diversity, separately. Moreover, it can increase bile acids reabsorption and fecal excretion through inhibiting FXR-FGF15 signaling pathway and increasing OST-α expression, which associated with Lachnoclostridium. CONCLUSIONS AND IMPLICATIONS Our findings demonstrated that EEPL alleviated AMI partially by remediating intestinal dysbiosis and promoting bile acid biosynthesis, which provided new targets for AMI treatment.
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Affiliation(s)
- Pin Zhang
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Zhengyu Fang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Min Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
| | - Bojiao Yi
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Yihe Huang
- School of Public Health, Shenyang Medical College, Shenyang, China
| | - Hongjun Yang
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Na Guo
- Experimental Research Center, China Academy of Chinese Medical Sciences, Beijing, China
| | - Chunjie Zhao
- School of Pharmacy, Shenyang Pharmaceutical University, Shenyang, China
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17
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Tveter KM, Mezhibovsky E, Wu Y, Roopchand DE. Bile acid metabolism and signaling: Emerging pharmacological targets of dietary polyphenols. Pharmacol Ther 2023; 248:108457. [PMID: 37268113 PMCID: PMC10528343 DOI: 10.1016/j.pharmthera.2023.108457] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2022] [Revised: 04/03/2023] [Accepted: 05/22/2023] [Indexed: 06/04/2023]
Abstract
Beyond their role as emulsifiers of lipophilic compounds, bile acids (BAs) are signaling endocrine molecules that show differential affinity and specificity for a variety of canonical and non-canonical BA receptors. Primary BAs (PBAs) are synthesized in the liver while secondary BAs (SBAs) are gut microbial metabolites of PBA species. PBAs and SBAs signal to BA receptors that regulate downstream pathways of inflammation and energy metabolism. Dysregulation of BA metabolism or signaling has emerged as a feature of chronic disease. Dietary polyphenols are non-nutritive plant-derived compounds associated with decreased risk of metabolic syndrome, type-2 diabetes, hepatobiliary and cardiovascular disease. Evidence suggests that the health promoting effects of dietary polyphenols are linked to their ability to alter the gut microbial community, the BA pool, and BA signaling. In this review we provide an overview of BA metabolism and summarize studies that link the cardiometabolic improvements of dietary polyphenols to their modulation of BA metabolism and signaling pathways, and the gut microbiota. Finally, we discuss approaches and challenges in deciphering cause-effect relationships between dietary polyphenols, BAs, and gut microbes.
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Affiliation(s)
- Kevin M Tveter
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Esther Mezhibovsky
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Yue Wu
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA
| | - Diana E Roopchand
- Rutgers, The State University of New Jersey, Department of Food Science, Institute for Food Nutrition and Health [Center for Microbiome, Nutrition and Health & Rutgers Center for Lipid Research], 61 Dudley Road, New Brunswick, NJ 08901, USA.
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18
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Shao Y, Chen S, Han L, Liu J. Pharmacotherapies of NAFLD: updated opportunities based on metabolic intervention. Nutr Metab (Lond) 2023; 20:30. [PMID: 37415199 DOI: 10.1186/s12986-023-00748-x] [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: 02/07/2023] [Accepted: 04/22/2023] [Indexed: 07/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a chronic liver disease that is becoming increasingly prevalent, and it ranges from simple steatosis to cirrhosis. However, there is still a lack of pharmacotherapeutic strategies approved by the Food and Drug Administration, which results in a higher risk of death related to carcinoma and cardiovascular complications. Of note, it is well established that the pathogenesis of NAFLD is tightly associated with whole metabolic dysfunction. Thus, targeting interconnected metabolic conditions could present promising benefits to NAFLD, according to a number of clinical studies. Here, we summarize the metabolic characteristics of the development of NAFLD, including glucose metabolism, lipid metabolism and intestinal metabolism, and provide insight into pharmacological targets. In addition, we present updates on the progresses in the development of pharmacotherapeutic strategies based on metabolic intervention globally, which could lead to new opportunities for NAFLD drug development.
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Affiliation(s)
- Yaodi Shao
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Suzhen Chen
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China
| | - Liu Han
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| | - Junli Liu
- Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Diabetes Institute, Department of Endocrinology and Metabolism, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
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19
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Zhang S, Chen A, Jiang L, Liu X, Chai L. Copper-mediated shifts in transcriptomic responses of intestines in Bufo gargarizans tadpoles to lead stress. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2023; 30:50144-50161. [PMID: 36790706 DOI: 10.1007/s11356-023-25801-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/19/2022] [Accepted: 02/04/2023] [Indexed: 04/16/2023]
Abstract
The differential transcriptomic responses of intestines in Bufo gargarizans tadpoles to Pb alone or in the presence of Cu were evaluated. Tadpoles were exposed to 30 μg/L Pb individually and in combination with Cu at 16 or 64 μg/L from Gosner stage (Gs) 26 to Gs 38. After de novo assembly, 105,107 unigenes were generated. Compared to the control group, 7387, 6937, and 11139 differentially expressed genes (DEGs) were identified in the treatment of Pb + Cu0, Pb + Cu16, and Pb + Cu64, respectively. In addition, functional annotation and enrichment analysis of DEGs revealed substantial transcriptional reprogramming of diverse molecular and biological pathways were induced in all heavy metal treatments. The relative expression levels of genes associated with intestinal epithelial barrier and bile acids (BAs) metabolism, such as mucin2, claudin5, ZO-1, Asbt, and Ost-β, were validated by qPCR. This study demonstrated that Pb exposure induced transcriptional responses in tadpoles, and the responses could be modulated by Cu.
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Affiliation(s)
- Siliang Zhang
- School of Water and Environment, Chang'an University, Xi'an, 710054, People's Republic of China
- Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, Xi'an, 710054, People's Republic of China
| | - Aixia Chen
- School of Water and Environment, Chang'an University, Xi'an, 710054, People's Republic of China
- Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, Xi'an, 710054, People's Republic of China
| | - Ling Jiang
- School of Water and Environment, Chang'an University, Xi'an, 710054, People's Republic of China
- Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, Xi'an, 710054, People's Republic of China
| | - Xiaoli Liu
- School of Water and Environment, Chang'an University, Xi'an, 710054, People's Republic of China
- Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, Xi'an, 710054, People's Republic of China
| | - Lihong Chai
- School of Water and Environment, Chang'an University, Xi'an, 710054, People's Republic of China.
- Key Laboratory of Subsurface Hydrology and Ecological Effect in Arid Region of Ministry of Education, Chang'an University, Xi'an, 710054, People's Republic of China.
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Nonogaki K, Kaji T. Ingestion of whey protein and β-conglycinin exerts opposite effects on intestinal FGF15 and serotonin secretion in mice. Front Endocrinol (Lausanne) 2023; 14:1080790. [PMID: 36777350 PMCID: PMC9911684 DOI: 10.3389/fendo.2023.1080790] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/26/2022] [Accepted: 01/09/2023] [Indexed: 01/28/2023] Open
Abstract
Farnesoid X receptor (FXR) and Takeda G protein-coupled Receptor 5 (TGR5), the intestinal bile acid (BA) receptors, regulate the gut-derived hormones including fibroblast growth factor 15/19 (FGF15/19) and serotonin (5-hydrooxytryptamine, 5-HT). Here we show that ingestion of whey protein isolate, a milk protein, significantly decreased expression of heteromeric organic solute transporter Ostα and Ostβ, which is the basolateral BA transporter in the enterocyte, and increased the expression of FXR and FGF15 in C57BL6J mouse ileum and plasma FGF15 levels. In addition, the ingestion of whey protein isolate significantly suppressed expression of hepatic cholesterol-7α hydroxylase (CYP7A1), which induces the primary BA synthesis, bile salt export pump (BSEP) and sodium-taurocholate cotransporting polypeptide (NTCP), which are the key transporters for the BA excretion and uptake in the liver, and genes involved in gluconeogenesis, and decreased the primary BAs including cholic acid, taurocholic acid, glycocholic acid, and taurochenodeoxycholic acid in the liver compared with controls. Moreover, ingestion of whey protein isolate significantly decreased the expression of TGR5, glucagon-like peptide 1 (GLP-1), and tryptophan hydroxylase1 (Tph1) in the small intestine, leading to decreases in plasma 5-HT and insulin levels. On the other hand, ingestion of the soy protein β-conglycinin significantly increased the expression of Ostα and Ostβ, and decreased the expression of FGF15 in the ileum and plasma FGF15 levels, leading to the increases in expression of hepatic CYP7A1, BSEP, NTCP, and genes involved in gluconeogenesis, and the primary BAs in the liver. Moreover, ingestion of β-conglycinin significantly increased the expression of intestinal TGR5, GLP-1, and Tph1, leading to increases in plasma 5-HT and insulin levels. These findings suggest that whey protein and β-conglycinin have opposite effects on intestinal FGF15 and 5-HT secretion in mice.
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Lu ZN, He HW, Zhang N. Advances in understanding the regulatory mechanism of organic solute transporter α-β. Life Sci 2022; 310:121109. [DOI: 10.1016/j.lfs.2022.121109] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/09/2022] [Accepted: 10/17/2022] [Indexed: 11/07/2022]
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Fat Malabsorption and Ursodeoxycholic Acid Treatment in Children With Reduced Organic Solute Transporter-α (SLC51A) Expression. JPGN REPORTS 2022; 3. [PMID: 36148443 PMCID: PMC9491403 DOI: 10.1097/pg9.0000000000000229] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 11/25/2022]
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Deng F, Kim KS, Moon J, Bae YH. Bile Acid Conjugation on Solid Nanoparticles Enhances ASBT-Mediated Endocytosis and Chylomicron Pathway but Weakens the Transcytosis by Inducing Transport Flow in a Cellular Negative Feedback Loop. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2201414. [PMID: 35652273 PMCID: PMC9313510 DOI: 10.1002/advs.202201414] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/08/2022] [Indexed: 05/20/2023]
Abstract
Bile acid-modified nanoparticles provide a convenient strategy to improve oral bioavailability of poorly permeable drugs by exploiting specific interactions with bile acid transporters. However, the underlying mechanisms are unknown, especially considering the different absorption sites of free bile acids (ileum) and digested fat molecules from bile acid-emulsified fat droplets (duodenum). Here, glycocholic acid (GCA)-conjugated polystyrene nanoparticles (GCPNs) are synthesized and their transport in Caco-2 cell models is studied. GCA conjugation enhances the uptake by interactions with apical sodium-dependent bile acid transporter (ASBT). A new pathway correlated with both ASBT and chylomicron pathways is identified. Meanwhile, the higher uptake of GCPNs does not lead to higher transcytosis to the same degree compared with unmodified nanoparticles (CPNs). The pharmacological and genomics study confirm that GCA conjugation changes the endocytosis mechanisms and downregulates the cellular response to the transport at gene levels, which works as a negative feedback loop and explains the higher cellular retention of GCPNs. These findings offer a solid foundation in the bile acid-based nanomedicine design, with utilizing advantages of the ASBT-mediated uptake, as well as inspiration to take comprehensive consideration of the cellular response with more developed technologies.
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Affiliation(s)
- Feiyang Deng
- Department of Pharmaceutics and Pharmaceutical ChemistryCollege of PharmacyUniversity of Utah30 S 2000 ESalt Lake CityUT84112USA
| | - Kyoung Sub Kim
- Department of Pharmaceutics and Pharmaceutical ChemistryCollege of PharmacyUniversity of Utah30 S 2000 ESalt Lake CityUT84112USA
| | - Jiyoung Moon
- Department of Pharmaceutics and Pharmaceutical ChemistryCollege of PharmacyUniversity of Utah30 S 2000 ESalt Lake CityUT84112USA
| | - You Han Bae
- Department of Pharmaceutics and Pharmaceutical ChemistryCollege of PharmacyUniversity of Utah30 S 2000 ESalt Lake CityUT84112USA
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Li C, Yu S, Li X, Cao Y, Li M, Ji G, Zhang L. Medicinal Formula Huazhi-Rougan Attenuates Non-Alcoholic Steatohepatitis Through Enhancing Fecal Bile Acid Excretion in Mice. Front Pharmacol 2022; 13:833414. [PMID: 35721143 PMCID: PMC9198489 DOI: 10.3389/fphar.2022.833414] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/11/2021] [Accepted: 05/16/2022] [Indexed: 11/13/2022] Open
Abstract
Huazhi-Rougan (HZRG) formula is a Traditional Chinese medicine prescription, and has been widely used to treat non-alcoholic fatty liver disease (NAFLD) and its progressive form non-alcoholic steatohepatitis (NASH). However, the anti-NASH effects and the underlying mechanisms of HZRG have not yet been characterized. Here we showed that 4-week HZRG treatment alleviated methionine-choline-deficiency (MCD) diet-induced NASH in C57BL/6J mice, as evidenced by the improvement of hepatic steatosis and inflammation, as well as the decrease of serum levels of alanine and aspartate transaminases. Fecal 16S rDNA sequencing indicated that HZRG reduced the enrichment of pathogenic bacteria and increased the abundance of bacteria gena that are involved in bile acid (BA) conversation. The alteration of fecal and serum BA profile suggested that HZRG enhanced fecal BA excretion, and reduced the reabsorption of toxic secondary BA species (LCA, DCA, HCA). We further analyzed the BA receptors and transporters, and found that HZRG inhibited the expression of ileal bile acid transporter, and organic solute transporter subunit β, and increased the expression of intestinal tight junction proteins (ZO-1, Occludin, Claudin-2). The modulation of gut dysbiosis and BA profile, as well as the improvement of the intestinal environment, may contribute to the decrease of the p-65 subunit of NF-κB phosphorylation, liver F4/80 positive macrophages, inflammatory cytokine IL-1β and TNF-α expression. In conclusion, HZRG treatment enhances fecal BA excretion via inhibiting BA transporters, modulates BA profiles, gut dysbiosis as well as the intestinal environment, thus contributing to the beneficial effect of HZRG on NASH mice.
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Affiliation(s)
| | | | | | | | | | - Guang Ji
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Li Zhang
- Institute of Digestive Diseases, Longhua Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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Durník R, Šindlerová L, Babica P, Jurček O. Bile Acids Transporters of Enterohepatic Circulation for Targeted Drug Delivery. Molecules 2022; 27:molecules27092961. [PMID: 35566302 PMCID: PMC9103499 DOI: 10.3390/molecules27092961] [Citation(s) in RCA: 34] [Impact Index Per Article: 11.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2022] [Revised: 04/24/2022] [Accepted: 05/02/2022] [Indexed: 12/29/2022] Open
Abstract
Bile acids (BAs) are important steroidal molecules with a rapidly growing span of applications across a variety of fields such as supramolecular chemistry, pharmacy, and biomedicine. This work provides a systematic review on their transport processes within the enterohepatic circulation and related processes. The focus is laid on the description of specific or less-specific BA transport proteins and their localization. Initially, the reader is provided with essential information about BAs′ properties, their systemic flow, metabolism, and functions. Later, the transport processes are described in detail and schematically illustrated, moving step by step from the liver via bile ducts to the gallbladder, small intestine, and colon; this description is accompanied by descriptions of major proteins known to be involved in BA transport. Spillage of BAs into systemic circulation and urine excretion are also discussed. Finally, the review also points out some of the less-studied areas of the enterohepatic circulation, which can be crucial for the development of BA-related drugs, prodrugs, and drug carrier systems.
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Affiliation(s)
- Robin Durník
- Department of Biochemistry, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic;
| | - Lenka Šindlerová
- Department of Biophysics of Immune System, Institute of Biophysics, Czech Academy of Sciences, Královopolská 135, 61265 Brno, Czech Republic;
| | - Pavel Babica
- RECETOX, Faculty of Science, Masaryk University, Kotlářská 2, 61137 Brno, Czech Republic;
| | - Ondřej Jurček
- Department of Chemistry, Faculty of Science, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
- CEITEC—Central European Institute of Technology, Masaryk University, Kamenice 5, 62500 Brno, Czech Republic
- Department of Natural Drugs, Faculty of Pharmacy, Masaryk University, Palackého 1946/1, 61200 Brno, Czech Republic
- Correspondence:
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Jiao TY, Ma YD, Guo XZ, Ye YF, Xie C. Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease. Acta Pharmacol Sin 2022; 43:1103-1119. [PMID: 35217817 PMCID: PMC9061718 DOI: 10.1038/s41401-022-00880-z] [Citation(s) in RCA: 67] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/25/2022] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.
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Affiliation(s)
- Ting-Ying Jiao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yuan-di Ma
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao-Zhen Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yun-Fei Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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Choudhuri S, Klaassen CD. Molecular Regulation of Bile Acid Homeostasis. Drug Metab Dispos 2022; 50:425-455. [PMID: 34686523 DOI: 10.1124/dmd.121.000643] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2021] [Accepted: 10/20/2021] [Indexed: 11/22/2022] Open
Abstract
Bile acids have been known for decades to aid in the digestion and absorption of dietary fats and fat-soluble vitamins in the intestine. The development of gene knockout mice models and transgenic humanized mouse models have helped us understand other functions of bile acids, such as their role in modulating fat, glucose, and energy metabolism, and in the molecular regulation of the synthesis, transport, and homeostasis of bile acids. The G-protein coupled receptor TGR5 regulates the bile acid induced alterations of intermediary metabolism, whereas the nuclear receptor FXR regulates bile acid synthesis and homeostasis. However, this review indicates that unidentified factors in addition to FXR must exist to aid in the regulation of bile acid synthesis and homeostasis. SIGNIFICANCE STATEMENT: This review captures the present understanding of bile acid synthesis, the role of bile acid transporters in the enterohepatic circulation of bile acids, the role of the nuclear receptor FXR on the regulation of bile acid synthesis and bile acid transporters, and the importance of bile acids in activating GPCR signaling via TGR5 to modify intermediary metabolism. This information is useful for developing drugs for the treatment of various hepatic and intestinal diseases, as well as the metabolic syndrome.
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Affiliation(s)
- Supratim Choudhuri
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
| | - Curtis D Klaassen
- Office of Food Additive Safety, Center for Food Safety and Applied Nutrition, U.S. Food and Drug Administration, College Park, Maryland (S.C.) and Department of Pharmacology, Toxicology, and Therapeutics, School of Medicine, University of Kansas, Kansas City, Kansas (C.D.K.)
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van de Wiel SM, Porteiro B, Belt SC, Vogels EW, Bolt I, Vermeulen JL, de Waart DR, Verheij J, Muncan V, Oude Elferink RP, van de Graaf SF. Differential and organ-specific functions of organic solute transporter alpha and beta in experimental cholestasis. JHEP Rep 2022; 4:100463. [PMID: 35462858 PMCID: PMC9019253 DOI: 10.1016/j.jhepr.2022.100463] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2020] [Revised: 02/15/2022] [Accepted: 02/17/2022] [Indexed: 02/07/2023] Open
Abstract
Background & Aims Organic solute transporter (OST) subunits OSTα and OSTβ facilitate bile acid efflux from the enterocyte into the portal circulation. Patients with deficiency of OSTα or OSTβ display considerable variation in the level of bile acid malabsorption, chronic diarrhea, and signs of cholestasis. Herein, we generated and characterized a mouse model of OSTβ deficiency. Methods Ostβ-/- mice were generated using CRISR/Cas9 and compared to wild-type and Ostα-/- mice. OSTβ was re-expressed in livers of Ostβ-/- mice using adeno-associated virus serotype 8 vectors. Cholestasis was induced in both models by bile duct ligation (BDL) or 3.5-diethoxycarbonyl-1.4-dihydrocollidine (DDC) feeding. Results Similar to Ostα-/- mice, Ostβ-/- mice exhibited elongated small intestines with blunted villi and increased crypt depth. Increased expression levels of ileal Fgf15, and decreased Asbt expression in Ostβ-/- mice indicate the accumulation of bile acids in the enterocyte. In contrast to Ostα-/- mice, induction of cholestasis in Ostβ-/- mice by BDL or DDC diet led to lower survival rates and severe body weight loss, but an improved liver phenotype. Restoration of hepatic Ostβ expression via adeno-associated virus-mediated overexpression did not rescue the phenotype of Ostβ-/- mice. Conclusions OSTβ is pivotal for bile acid transport in the ileum and its deficiency leads to an intestinal phenotype similar to Ostα-/- mice, but it exerts distinct effects on survival and the liver phenotype, independent of its expression in the liver. Our findings provide insights into the variable clinical presentation of patients with OSTα and OSTβ deficiencies. Lay summary Organic solute transporter (OST) subunits OSTα and OSTβ together facilitate the efflux of conjugated bile acids into the portal circulation. Ostα knockout mice have longer and thicker small intestines and are largely protected against experimental cholestatic liver injury. Herein, we generated and characterized Ostβ knockout mice for the first time. Ostα and Ostβ knockout mice shared a similar phenotype under normal conditions. However, in cholestasis, Ostβ knockout mice had a worsened overall phenotype which indicates a separate and specific role of OSTβ, possibly as an interacting partner of other intestinal proteins.
This manuscript describes the first mouse model of OSTβ deficiency. Ostβ-/- mice are viable and fertile, but show increased length and weight of the small intestine, blunted villi and deeper crypts. Ostβ deficiency leads to an altered microbiome compared to both wild-type and Ostα-/- mice. Cholestasis led to lower survival and worse body weight loss, but an improved liver phenotype, in Ostβ-/- mice compared to Ostα-/- mice.
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Affiliation(s)
- Sandra M.W. van de Wiel
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Begoña Porteiro
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- CIMUS, Universidade de Santiago de Compostela-Instituto de Investigación Sanitaria, Santiago de Compostela, 15782, Spain
| | - Saskia C. Belt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Esther W.M. Vogels
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Isabelle Bolt
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Jacqueline L.M. Vermeulen
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - D. Rudi de Waart
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
| | - Joanne Verheij
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Pathology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Vanesa Muncan
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam UMC, University of Amsterdam, the Netherlands
- Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam, the Netherlands
- Department of Gastroenterology and Hepatology, Amsterdam UMC, University of Amsterdam, the Netherlands
- Corresponding author. Address: Meibergdreef 69-71, 1105 BK Amsterdam, the Netherlands; Tel.: 020-5668832, fax: 020-5669190
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Jia L, Ma Y, Haywood J, Jiang L, Xue B, Shi H, Dawson PA, Yu L. NPC1L1 Deficiency Suppresses Ileal Fibroblast Growth Factor 15 Expression and Increases Bile Acid Pool Size in High-Fat-Diet-Fed Mice. Cells 2021; 10:3468. [PMID: 34943976 PMCID: PMC8700447 DOI: 10.3390/cells10123468] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2021] [Revised: 12/06/2021] [Accepted: 12/07/2021] [Indexed: 02/04/2023] Open
Abstract
Niemann-Pick C1-like 1 (NPC1L1) mediates intestinal uptake of dietary and biliary cholesterol and is the target of ezetimibe, a cholesterol absorption inhibitor used to treat hypercholesterolemia. Genetic deletion of NPC1L1 or ezetimibe treatment protects mice from high-fat diet (HFD)-induced obesity; however, the molecular mechanisms responsible for this therapeutic benefit remain unknown. A major metabolic fate of cholesterol is its conversion to bile acids. We found that NPC1L1 knockout (L1-KO) mice fed an HFD had increased energy expenditure, bile acid pool size, and fecal bile acid excretion rates. The elevated bile acid pool in the HFD-fed L1-KO mice was enriched with tauro-β-muricholic acid. These changes in the L1-KO mice were associated with reduced ileal mRNA expression of fibroblast growth factor 15 (FGF15) and increased hepatic mRNA expression of cholesterol 7α-hydroxylase (Cyp7A1) and mitochondrial sterol 27-hydroxylase (Cyp27A1). In addition, mRNA expression of the membrane bile acid receptor Takeda G protein-coupled receptor 5 (TGR5) and type 2 iodothyronine deiodinase (Dio2) were elevated in brown adipose tissue of L1-KO mice, which is known to promote energy expenditure. Thus, altered bile acid homeostasis and signaling may play a role in protecting L1-KO mice against HFD-induced obesity.
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Affiliation(s)
- Lin Jia
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Department of Biological Sciences, The University of Texas at Dallas, 800 W, Campbell Road, Richardson, TX 75080, USA
| | - Yinyan Ma
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Jamie Haywood
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
| | - Long Jiang
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
| | - Bingzhong Xue
- Department of Endocrinology and Metabolism, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
| | - Hang Shi
- Department of Biology, Georgia State University, Atlanta, GA 30303, USA;
- Internal Medicine Section on Gerontology and Geriatric Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
| | - Paul A. Dawson
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Pediatrics, Division of Gastroenterology, Hepatology, and Nutrition, Emory University, Atlanta, GA 30322, USA
| | - Liqing Yu
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA; (L.J.); (Y.M.); (J.H.); (P.A.D.)
- Department of Biochemistry, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA
- Division of Endocrinology, Diabetes and Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD 21201, USA;
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Functional characterization of Clonorchis sinensis sodium-bile acid co-transporter (CsSBAT) as a steroid sulfate transporter. Parasitol Res 2021; 121:217-224. [PMID: 34825261 DOI: 10.1007/s00436-021-07393-4] [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: 08/26/2021] [Accepted: 11/19/2021] [Indexed: 10/19/2022]
Abstract
Clonorchis sinensis (Cs) is a common trematode in Asian countries. Infection by Cs can result in many clinical symptoms. Here, a cDNA encoding a Cs apical sodium-dependent bile acid transporter (CsSBAT) was isolated from a Cs cDNA library, and functional characterization was performed using Xenopus laevis oocyte expression system. When expressed in Xenopus laevis oocytes, CsSBAT mediated the transport of radiolabeled estrone sulfate and dehydroepiandrosterone sulfate. No trans-uptake of carnitine, estradiol 17 β-D glucuronide, prostaglandin E2, p-aminohippuric acid, α-ketoglutaric acid, and tetraethylammonium was observed. CsSBAT-mediated estrone sulfate uptake was in a time- and sodium-dependent manner. CsSBAT showed no exchange properties in efflux experiments. Concentration-dependent results showed saturable kinetics consistent with the Michaelis-Menten equation. Nonlinear regression analyses yielded a Km value of 0.3 ± 0.04 μM for [3H]estrone sulfate. CsSBAT-mediated estrone sulfate uptake was strongly inhibited by sulfate conjugates but not glucuronide conjugates. These findings contribute to our understanding of CsSBAT transport properties and the cascade of estrogen metabolite movement in Cs.
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Zhou E, Hoeke G, Li Z, Eibergen AC, Schonk AW, Koehorst M, Boverhof R, Havinga R, Kuipers F, Coskun T, Boon MR, Groen AK, Rensen PCN, Berbée JFP, Wang Y. Colesevelam enhances the beneficial effects of brown fat activation on hyperlipidaemia and atherosclerosis development. Cardiovasc Res 2021; 116:1710-1720. [PMID: 31589318 PMCID: PMC7643538 DOI: 10.1093/cvr/cvz253] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/10/2019] [Revised: 08/28/2019] [Accepted: 09/30/2019] [Indexed: 12/12/2022] Open
Abstract
Aims Brown fat activation accelerates the uptake of cholesterol-enriched remnants by the liver and thereby lowers plasma cholesterol, consequently protecting against atherosclerosis development. Hepatic cholesterol is then converted into bile acids (BAs) that are secreted into the intestine and largely maintained within the enterohepatic circulation. We now aimed to evaluate the effects of prolonged brown fat activation combined with inhibition of intestinal BA reabsorption on plasma cholesterol metabolism and atherosclerosis development. Methods and results APOE*3-Leiden.CETP mice with humanized lipoprotein metabolism were treated for 9 weeks with the selective β3-adrenergic receptor (AR) agonist CL316,243 to substantially activate brown fat. Prolonged β3-AR agonism reduced faecal BA excretion (−31%), while markedly increasing plasma levels of total BAs (+258%), cholic acid-derived BAs (+295%), and chenodeoxycholic acid-derived BAs (+217%), and decreasing the expression of hepatic genes involved in BA production. In subsequent experiments, mice were additionally treated with the BA sequestrant Colesevelam to inhibit BA reabsorption. Concomitant intestinal BA sequestration increased faecal BA excretion, normalized plasma BA levels, and reduced hepatic cholesterol. Moreover, concomitant BA sequestration further reduced plasma total cholesterol (−49%) and non-high-density lipoprotein cholesterol (−56%), tended to further attenuate atherosclerotic lesion area (−54%). Concomitant BA sequestration further increased the proportion of lesion-free valves (+34%) and decreased the relative macrophage area within the lesion (−26%), thereby further increasing the plaque stability index (+44%). Conclusion BA sequestration prevents the marked accumulation of plasma BAs as induced by prolonged brown fat activation, thereby further improving cholesterol metabolism and reducing atherosclerosis development. These data suggest that combining brown fat activation with BA sequestration is a promising new therapeutic strategy to reduce hyperlipidaemia and cardiovascular diseases.
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Affiliation(s)
- Enchen Zhou
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Geerte Hoeke
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Zhuang Li
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Arthur C Eibergen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Amber W Schonk
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Martijn Koehorst
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Renze Boverhof
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Rick Havinga
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
| | - Tamer Coskun
- Department of Diabetes/Endocrine, Lilly Research Laboratories, Lilly Corporate Center, Indianapolis, IN, USA
| | - Mariëtte R Boon
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Albert K Groen
- Department of Laboratory Medicine, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.,Department of Vascular Medicine, Academic Medical Center, Amsterdam, The Netherlands
| | - Patrick C N Rensen
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Jimmy F P Berbée
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
| | - Yanan Wang
- Division of Endocrinology, Department of Medicine, Leiden University Medical Center, PO Box 9600, 2300 RC Leiden, The Netherlands.,Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden, The Netherlands
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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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Ocvirk S, O'Keefe SJD. Dietary fat, bile acid metabolism and colorectal cancer. Semin Cancer Biol 2021; 73:347-355. [PMID: 33069873 DOI: 10.1016/j.semcancer.2020.10.003] [Citation(s) in RCA: 144] [Impact Index Per Article: 36.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2020] [Revised: 10/04/2020] [Accepted: 10/05/2020] [Indexed: 12/12/2022]
Abstract
Colorectal cancer (CRC) risk is predominantly driven by environmental factors, in particular diet. A high intake of dietary fat has been implicated as a risk factor inducing the formation of pre-neoplastic lesions (e.g., adenomatous polyps) and/or exacerbating colonic tumorigenesis. Recent data attributed the tumor-promoting activity of high-fat diets to their effects on gut microbiota composition and metabolism, in particular with regard to bile acids. Bile acids are synthesized in the liver in response to dietary fat and facilitate lipid absorption in the small intestine. The majority of bile acids is re-absorbed during small intestinal transit and subjected to enterohepatic circulation. Bile acids entering the colon undergo complex biotransformation performed by gut bacteria, resulting in secondary bile acids that show tumor-promoting activity. Excessive dietary fat leads to high levels of secondary bile acids in feces and primes the gut microbiota to bile acid metabolism. This promotes an altered overall bile acid pool, which activates or restricts intestinal and hepatic cross-signaling of the bile acid receptor, farnesoid X receptor (FXR). Recent studies provided evidence that FXR is a main regulator of bile acid-mediated effects on intestinal tumorigenesis integrating dietary, microbial and genetic risk factors for CRC. Selective FXR agonist or antagonist activity by specific bile acids depends on additional factors (e.g., bile acid concentration, composition of bile acid pool, genetic instability of cells) and, thus, may differ in healthy and tumorigenic conditions in the intestine. In conclusion, fat-mediated alterations of the gut microbiota link bile acid metabolism to CRC risk and colonic tumorigenesis, exemplifying how gut microbial co-metabolism affects colon health.
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Affiliation(s)
- Soeren Ocvirk
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA; Intestinal Microbiology Research Group, Department of Molecular Toxicology, German Institute of Human Nutrition, Potsdam-Rehbruecke, Nuthetal, Germany
| | - Stephen J D O'Keefe
- Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA.
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Ileal Bile Acid Transporter Inhibitor Improves Hepatic Steatosis by Ameliorating Gut Microbiota Dysbiosis in NAFLD Model Mice. mBio 2021; 12:e0115521. [PMID: 34225483 PMCID: PMC8406289 DOI: 10.1128/mbio.01155-21] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
Nonalcoholic fatty liver disease (NAFLD), characterized by excessive fat deposition in the liver unrelated to alcohol consumption, is highly prevalent worldwide. However, effective therapeutic agents approved for NAFLD treatment are lacking. An ileal bile acid transporter inhibitor (IBATi), which represents a new mode of treatment of chronic idiopathic constipation, leads to increased delivery of bile acids to the colon. We investigated the effect of IBATi against NAFLD through modification of the gut microbiota in mice. IBATi treatment significantly suppressed body weight gain, liver dysfunction, and serum low-density lipoprotein levels and significantly decreased NAFLD activity scores in high-fat diet (HFD) mice. Treatment with IBATi ameliorated the decreased hepatic cholesterol 7-a-monooxygenase (Cyp7a1) and increased ileal fibroblast growth factor 15 (Fgf15) mRNA expression in HFD mice. Further, IBATi treatment changed the α-diversity in the gut microbiota reduced by HFD, which was analyzed in feces using 16S rRNA sequencing. To establish the mechanism underlying improvement in NAFLD induced by IBATi, we recolonized antibiotic solution-treated mice by fecal microbiome transplantation (FMT) using stool from HFD or HFD plus IBATi mice. This is the first report that fecally transplanted gut microbiota from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. In conclusion, IBATi improved hepatic steatosis by ameliorating gut microbiota dysbiosis in NAFLD model mice, suggesting a potential therapeutic agent for NAFLD treatment. IMPORTANCE NAFLD is an increasingly recognized condition that may progress to liver cirrhosis and hepatocellular carcinoma, and community surveys have assessed that the prevalence is 14 to 32% worldwide. The first line of treatment for NAFLD is lifestyle modification to achieve weight reduction, particularly through diet and exercise. However, weight reduction is difficult to achieve and maintain, and pharmacological agents approved for the treatment of NAFLD are lacking. This study investigated the influence of the gut microbiota and the effect of an IBATi on NAFLD using a murine model. Treatment with IBATi significantly improved NAFLD in HFD mice. Further, fecal microbiome transplantation using stool from HFD plus IBATi mice prevented hepatic steatosis caused by HFD. Our study makes a significant contribution to the literature because the study findings suggest a potential treatment strategy for NAFLD patients by ameliorating gut microbiota dysbiosis.
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Matye DJ, Li Y, Chen C, Chao X, Wang H, Ni H, Ding WX, Li T. Gut-restricted apical sodium-dependent bile acid transporter inhibitor attenuates alcohol-induced liver steatosis and injury in mice. Alcohol Clin Exp Res 2021; 45:1188-1199. [PMID: 33885179 PMCID: PMC8717856 DOI: 10.1111/acer.14619] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2021] [Revised: 04/05/2021] [Accepted: 04/13/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Recent studies have shown that human and experimental alcohol-related liver disease (ALD) is robustly associated with dysregulation of bile acid homeostasis, which may in turn modulate disease severity. Pharmacological agents targeting bile acid metabolism and signaling may be potential therapeutics for ALD. METHODS The potential beneficial effects of a gut-restricted apical sodium-dependent bile acid transporter (ASBT) inhibitor were studied in a chronic-plus-binge ALD mouse model. RESULTS Blocking intestinal bile acid reabsorption by the gut-restricted ASBT inhibitor GSK2330672 attenuated hepatic steatosis and liver injury in a chronic-plus-binge ALD mouse model. Alcohol feeding is associated with intestinal bile acid accumulation but paradoxically impaired ileal farnesoid × receptor (FXR) function, and repressed hepatic cholesterol 7α-hydrolase (CYP7A1) expression despite decreased hepatic small heterodimer partner (SHP) and ileal fibroblast growth factor 15 (FGF15) expression. ASBT inhibitor treatment decreased intestinal bile acid accumulation and increased hepatic CYP7A1 expression, but further decreased ileal FXR activity. Alcohol feeding induces serum bile acid concentration that strongly correlates with a liver injury marker. However, alcohol-induced serum bile acid elevation is not due to intrahepatic bile acid accumulation but is strongly and positively associated with hepatic multidrug resistance-associated protein 3 (MRP4) and MRP4 induction but poorly associated with sodium-taurocholate cotransporting peptide (NTCP) expression. ASBT inhibitor treatment decreases serum bile acid concentration without affecting hepatocyte basolateral bile acid uptake and efflux transporters. CONCLUSION ASBT inhibitor treatment corrects alcohol-induced bile acid dysregulation and attenuates liver injury in experimental ALD.
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Affiliation(s)
- David J. Matye
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Yuan Li
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Cheng Chen
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Huaiwen Wang
- Laboratory For Molecular Biology and Cytometry Research, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
| | - Hongmin Ni
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology, Therapeutics, University of Kansas Medical Center, Kansas City, KS 66160
| | - Tiangang Li
- Harold Hamm Diabetes Center, Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104
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Kunst RF, Verkade HJ, Oude Elferink RP, van de Graaf SF. Targeting the Four Pillars of Enterohepatic Bile Salt Cycling; Lessons From Genetics and Pharmacology. Hepatology 2021; 73:2577-2585. [PMID: 33222321 PMCID: PMC8252069 DOI: 10.1002/hep.31651] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Revised: 10/29/2020] [Accepted: 11/12/2020] [Indexed: 12/14/2022]
Abstract
Bile salts play a pivotal role in lipid homeostasis, are sensed by specialized receptors, and have been implicated in various disorders affecting the gut or liver. They may play a role either as culprit or as potential panacea. Four very efficient transporters mediate most of the hepatic and intestinal bile salt uptake and efflux, and are each essential for the efficient enterohepatic circulation of bile salts. Starting from the intestinal lumen, conjugated bile salts cross the otherwise impermeable lipid bilayer of (primarily terminal ileal) enterocytes through the apical sodium-dependent bile acid transporter (gene SLC10A2) and leave the enterocyte through the basolateral heteromeric organic solute transporter, which consists of an alpha and beta subunit (encoded by SLC51A and SLC51B). The Na+ -taurocholate cotransporting polypeptide (gene SLC10A1) efficiently clears the portal circulation of bile salts, and the apical bile salt export pump (gene ABCB11) pumps the bile salts out of the hepatocyte into primary bile, against a very steep concentration gradient. Recently, individuals lacking either functional Na+ -taurocholate cotransporting polypeptide or organic solute transporter have been described, completing the quartet of bile acid transport deficiencies, as apical sodium-dependent bile acid transporter and bile salt export pump deficiencies were already known for years. Novel pathophysiological insights have been obtained from knockout mice lacking functional expression of these genes and from pharmacological transporter inhibition in mice or humans. Conclusion: We provide a concise overview of the four main bile salt transport pathways and of their status as possible targets of interventions in cholestatic or metabolic disorders.
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MESH Headings
- ATP Binding Cassette Transporter, Subfamily B, Member 11/genetics
- ATP Binding Cassette Transporter, Subfamily B, Member 11/metabolism
- Animals
- Bile Acids and Salts/metabolism
- Biological Transport, Active/drug effects
- Biological Transport, Active/physiology
- Drug Development
- Enterohepatic Circulation/drug effects
- Enterohepatic Circulation/physiology
- Humans
- Membrane Transport Proteins/genetics
- Membrane Transport Proteins/metabolism
- Organic Anion Transporters, Sodium-Dependent/antagonists & inhibitors
- Organic Anion Transporters, Sodium-Dependent/genetics
- Organic Anion Transporters, Sodium-Dependent/metabolism
- Receptors, G-Protein-Coupled/genetics
- Receptors, G-Protein-Coupled/metabolism
- Symporters/antagonists & inhibitors
- Symporters/genetics
- Symporters/metabolism
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Affiliation(s)
- Roni F. Kunst
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
| | - Henkjan J. Verkade
- Pediatric Gastroenterology/HepatologyDepartment of PediatricsUniversity of GroningenUniversity Medical Center GroningenGroningenthe Netherlands
| | - Ronald P.J. Oude Elferink
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
- Department of Gastroenterology and HepatologyAmsterdam UMCUniversity of AmsterdamAmsterdamthe Netherlands
| | - Stan F.J. van de Graaf
- Tytgat Institute for Liver and Intestinal ResearchAmsterdam UMC, University of AmsterdamAmsterdamthe Netherlands
- Amsterdam Gastroenterology Endocrinology MetabolismAmsterdamthe Netherlands
- Department of Gastroenterology and HepatologyAmsterdam UMCUniversity of AmsterdamAmsterdamthe Netherlands
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Fairweather SJ, Shah N, Brӧer S. Heteromeric Solute Carriers: Function, Structure, Pathology and Pharmacology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2021; 21:13-127. [PMID: 33052588 DOI: 10.1007/5584_2020_584] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Solute carriers form one of three major superfamilies of membrane transporters in humans, and include uniporters, exchangers and symporters. Following several decades of molecular characterisation, multiple solute carriers that form obligatory heteromers with unrelated subunits are emerging as a distinctive principle of membrane transporter assembly. Here we comprehensively review experimentally established heteromeric solute carriers: SLC3-SLC7 amino acid exchangers, SLC16 monocarboxylate/H+ symporters and basigin/embigin, SLC4A1 (AE1) and glycophorin A exchanger, SLC51 heteromer Ost α-Ost β uniporter, and SLC6 heteromeric symporters. The review covers the history of the heteromer discovery, transporter physiology, structure, disease associations and pharmacology - all with a focus on the heteromeric assembly. The cellular locations, requirements for complex formation, and the functional role of dimerization are extensively detailed, including analysis of the first complete heteromer structures, the SLC7-SLC3 family transporters LAT1-4F2hc, b0,+AT-rBAT and the SLC6 family heteromer B0AT1-ACE2. We present a systematic analysis of the structural and functional aspects of heteromeric solute carriers and conclude with common principles of their functional roles and structural architecture.
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Affiliation(s)
- Stephen J Fairweather
- Research School of Biology, Australian National University, Canberra, ACT, Australia. .,Resarch School of Chemistry, Australian National University, Canberra, ACT, Australia.
| | - Nishank Shah
- Research School of Biology, Australian National University, Canberra, ACT, Australia
| | - Stefan Brӧer
- Research School of Biology, Australian National University, Canberra, ACT, Australia.
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Habib SM, Zwicker BL, Wykes L, Agellon LB. Sexually dimorphic response of mice to the Western-style diet caused by deficiency of fatty acid binding protein 6 (Fabp6). Physiol Rep 2021; 9:e14733. [PMID: 33527741 PMCID: PMC7851434 DOI: 10.14814/phy2.14733] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2020] [Revised: 12/30/2020] [Accepted: 01/04/2021] [Indexed: 11/24/2022] Open
Abstract
Bile acids are natural detergents that aid in the absorption of dietary lipids. Fatty acid binding protein 6 (Fabp6) is a component of the bile acid recovery system that operates in the small intestine. The aim of this study was to determine if Fabp6 deficiency causes dietary fat malabsorption. Wild-type and Fabp6-deficient mice were fed a Western-style diet (WSD) or a reference low-fat diet (LFD) for 10 weeks. The body weight gain, bile acid excretion, fat excretion, energy metabolism, and major gut microbial phyla of the mice were assessed at the end of the controlled diet period. Fabp6-/- mice exhibited enhanced excretion of both bile acids and fat on the WSD but not on the LFD diet. Paradoxically, male Fabp6-/- mice, but not female Fabp6-/- mice, had greater adiposity despite increased fat excretion. Analysis of energy intake and of expenditure by indirect calorimetry revealed sex differences in physical activity level and respiratory quotient, but these did not account for the enhanced adiposity displayed by male Fabp6-/- mice. Analysis of stool DNA showed sex-specific changes in the abundance of major phyla of bacteria in response to Fabp6 deficiency and WSD feeding. The results obtained indicate that the malabsorption of bile acids that occurs in Fabp6-/- mice is associated with dietary fat malabsorption on the high-fat diet but not on the low-fat diet. The WSD induced a sexually dimorphic increase in adiposity displayed by Fabp6-/- mice and sexually distinct pattern of change in gut microbiota composition.
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Affiliation(s)
- Salam M. Habib
- School of Human NutritionMcGill UniversityMontrealQCCanada
| | - Brittnee L. Zwicker
- School of Human NutritionMcGill UniversityMontrealQCCanada
- Present address:
McGill University Health CentreMontrealQCH4A 3J1Canada
| | - Linda Wykes
- School of Human NutritionMcGill UniversityMontrealQCCanada
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Zwitterion-functionalized mesoporous silica nanoparticles for enhancing oral delivery of protein drugs by overcoming multiple gastrointestinal barriers. J Colloid Interface Sci 2021; 582:364-375. [DOI: 10.1016/j.jcis.2020.08.010] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 07/30/2020] [Accepted: 08/03/2020] [Indexed: 01/28/2023]
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40
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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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41
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Ayewoh EN, Czuba LC, Nguyen TT, Swaan PW. S-acylation status of bile acid transporter hASBT regulates its function, metabolic stability, membrane expression, and phosphorylation state. BIOCHIMICA ET BIOPHYSICA ACTA-BIOMEMBRANES 2020; 1863:183510. [PMID: 33189717 DOI: 10.1016/j.bbamem.2020.183510] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 07/09/2020] [Revised: 11/09/2020] [Accepted: 11/10/2020] [Indexed: 10/23/2022]
Abstract
The human apical sodium-dependent bile acid transporter (hASBT, SLC10A2) is the rate-limiting step of intestinal bile acid absorption in the enterohepatic circulation system of bile acids. Therefore, the regulation and stability of hASBT is vital in maintaining bile acid and cholesterol homeostasis and may serve as a potential target for cholesterol-related disorders. We hypothesized that post-translational mechanisms that govern hASBT function and regulation will provide novel insight on intestinal bile acid transport and homeostasis. In this study, we confirm the S-acylation status of hASBT via acyl biotin exchange in COS-1 cells and its impact on hASBT expression, function, kinetics, and protein stability. Using the acylation inhibitor, 2-bromopalmitate, we show that S-acylation is an important modification which modulates the function, surface expression, and maximal transporter flux (Jmax) of hASBT. By means of proteasome inhibitors, S-acylated hASBT was found to be cleared via the proteasome whereas a reduction in the palmitoylation status of hASBT resulted in rapid proteolytic degradation compared to the unmodified transporter. Screening of cysteine mutants in and or near transmembrane domains, some of which are exposed to the cytosol, confirmed Cys314 to be the predominate S-acylated residue. Lastly, we show that S-acylation was reduced in a mutant form of hASBT devoid of cytosolic facing tyrosine residues, suggestive of crosstalk between acylation and phosphorylation post-translational modification mechanisms.
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Affiliation(s)
- Ebehiremen N Ayewoh
- Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
| | - Lindsay C Czuba
- Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
| | - Thao T Nguyen
- Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA
| | - Peter W Swaan
- Department of Pharmaceutical Sciences, University of Maryland, 20 Penn Street, Baltimore, MD 21201, USA.
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Dawson HD, Chen C, Li RW, Bell LN, Shea-Donohue T, Kringel H, Beshah E, Hill DE, Urban JF. Molecular and metabolomic changes in the proximal colon of pigs infected with Trichuris suis. Sci Rep 2020; 10:12853. [PMID: 32732949 PMCID: PMC7393168 DOI: 10.1038/s41598-020-69462-5] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 07/06/2020] [Indexed: 12/14/2022] Open
Abstract
The pig whipworm Trichuris suis is important in swine production because of its negative effects on pig performance and, notably, to some humans with inflammatory bowel disease as a therapeutic agent that modulates inflammation. The proximal colon of T. suis-infected pigs exhibited general inflammation around day 21 after inoculation with infective eggs that is transcriptionally characterized by markers of type-2 immune activation, inflammation, cellular infiltration, tissue repair enzymes, pathways of oxidative stress, and altered intestinal barrier function. Prominent gene pathways involved the Th2-response, de novo cholesterol synthesis, fructose and glucose metabolism, basic amino acid metabolism, and bile acid transport. Upstream regulatory factor analysis implicated the bile acid/farnesoid X receptor in some of these processes. Metabolic analysis indicated changes in fatty acids, antioxidant capacity, biochemicals related to methylation, protein glycosylation, extracellular matrix structure, sugars, Krebs cycle intermediates, microbe-derived metabolites and altered metabolite transport. Close to 1,200 differentially expressed genes were modulated in the proximal colon of pigs with a persistent adult worm infection that was nearly 90% lower in pigs that had expelled worms. The results support a model to test diets that favorably alter the microbiome and improve host intestinal health in both pigs and humans exposed to Trichuris.
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Affiliation(s)
- Harry D Dawson
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Celine Chen
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Robert W Li
- Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA
| | | | | | - Helene Kringel
- Department of Veterinary Disease Biology, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Ethiopia Beshah
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA
| | - Dolores E Hill
- Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA
| | - Joseph F Urban
- United States Department of Agriculture, Agricultural Research Service, Beltsville Human Nutrition Research Center, Diet, Genomics, and Immunology Laboratory, Beltsville, USA. .,Beltsville Agricultural Research Center, Animal Parasitic Diseases Laboratory, Beltsville, MD, USA.
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43
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Kunst RF, Niemeijer M, van der Laan LJW, Spee B, van de Graaf SFJ. From fatty hepatocytes to impaired bile flow: Matching model systems for liver biology and disease. Biochem Pharmacol 2020; 180:114173. [PMID: 32717228 DOI: 10.1016/j.bcp.2020.114173] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 07/21/2020] [Accepted: 07/22/2020] [Indexed: 02/08/2023]
Abstract
A large variety of model systems are used in hepatobiliary research. In this review, we aim to provide an overview of established and emerging models for specific research questions. We specifically discuss the value and limitations of these models for research on metabolic associated fatty liver disease (MAFLD), (previously named non-alcoholic fatty liver diseases/non-alcoholic steatohepatitis (NAFLD/NASH)) and cholestasis-related diseases such as primary biliary cholangitis (PBC) and primary sclerosing cholangitis (PSC). The entire range of models is discussed varying from immortalized cell lines, mature or pluripotent stem cell-based models including organoids/spheroids, to animal models and human ex vivo models such as normothermic machine perfusion of livers and living liver slices. Finally, the pros and cons of each model are discussed as well as the need in the scientific community for continuous innovation in model development to better mimic the human (patho)physiology.
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Affiliation(s)
- Roni F Kunst
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands
| | - Marije Niemeijer
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands; Division of Drug Discovery and Safety, Leiden Academic Centre for Drug Research, Leiden University, Leiden, the Netherlands
| | - Luc J W van der Laan
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands
| | - Bart Spee
- Department of Clinical Sciences, Faculty of Veterinary Medicine, Utrecht University, Utrecht, the Netherlands
| | - Stan F J van de Graaf
- Tytgat Institute for Liver and Intestinal Research, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands; Department of Gastroenterology and Hepatology, Amsterdam Gastroenterology Endocrinology Metabolism, Amsterdam University Medical Centers, University of Amsterdam, Amsterdam, the Netherlands.
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44
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Beaudoin JJ, Brouwer KLR, Malinen MM. Novel insights into the organic solute transporter alpha/beta, OSTα/β: From the bench to the bedside. Pharmacol Ther 2020; 211:107542. [PMID: 32247663 PMCID: PMC7480074 DOI: 10.1016/j.pharmthera.2020.107542] [Citation(s) in RCA: 42] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2020] [Accepted: 03/25/2020] [Indexed: 12/14/2022]
Abstract
Organic solute transporter alpha/beta (OSTα/β) is a heteromeric solute carrier protein that transports bile acids, steroid metabolites and drugs into and out of cells. OSTα/β protein is expressed in various tissues, but its expression is highest in the gastrointestinal tract where it facilitates the recirculation of bile acids from the gut to the liver. Previous studies established that OSTα/β is upregulated in liver tissue of patients with extrahepatic cholestasis, obstructive cholestasis, and primary biliary cholangitis (PBC), conditions that are characterized by elevated bile acid concentrations in the liver and/or systemic circulation. The discovery that OSTα/β is highly upregulated in the liver of patients with nonalcoholic steatohepatitis (NASH) further highlights the clinical relevance of this transporter because the incidence of NASH is increasing at an alarming rate with the obesity epidemic. Since OSTα/β is closely linked to the homeostasis of bile acids, and tightly regulated by the nuclear receptor farnesoid X receptor, OSTα/β is a potential drug target for treatment of cholestatic liver disease, and other bile acid-related metabolic disorders such as obesity and diabetes. Obeticholic acid, a semi-synthetic bile acid used to treat PBC, under review for the treatment of NASH, and in development for the treatment of other metabolic disorders, induces OSTα/β. Some drugs associated with hepatotoxicity inhibit OSTα/β, suggesting a possible role for OSTα/β in drug-induced liver injury (DILI). Furthermore, clinical cases of homozygous genetic defects in both OSTα/β subunits resulting in diarrhea and features of cholestasis have been reported. This review article has been compiled to comprehensively summarize the recent data emerging on OSTα/β, recapitulating the available literature on the structure-function and expression-function relationships of OSTα/β, the regulation of this important transporter, the interaction of drugs and other compounds with OSTα/β, and the comparison of OSTα/β with other solute carrier transporters as well as adenosine triphosphate-binding cassette transporters. Findings from basic to more clinically focused research efforts are described and discussed.
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Affiliation(s)
- James J Beaudoin
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
| | - Kim L R Brouwer
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA.
| | - Melina M Malinen
- Division of Pharmacotherapy and Experimental Therapeutics, UNC Eshelman School of Pharmacy, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA; School of Pharmacy, Faculty of Health Sciences, University of Eastern Finland, Kuopio, Finland
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45
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Beaudoin JJ, Bezençon J, Sjöstedt N, Fallon JK, Brouwer KLR. Role of Organic Solute Transporter Alpha/Beta in Hepatotoxic Bile Acid Transport and Drug Interactions. Toxicol Sci 2020; 176:34-35. [PMID: 32294204 PMCID: PMC7357176 DOI: 10.1093/toxsci/kfaa052] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Organic solute transporter (OST) α/β is a key bile acid transporter expressed in various organs, including the liver under cholestatic conditions. However, little is known about the involvement of OSTα/β in bile acid-mediated drug-induced liver injury (DILI), a major safety concern in drug development. This study investigated whether OSTα/β preferentially transports more hepatotoxic, conjugated, primary bile acids and to what extent xenobiotics inhibit this transport. Kinetic studies with OSTα/β-overexpressing cells revealed that OSTα/β preferentially transported bile acids in the following order: taurochenodeoxycholate > glycochenodeoxycholate > taurocholate > glycocholate. The apparent half-maximal inhibitory concentrations for OSTα/β-mediated bile acid (5 µM) transport inhibition by fidaxomicin, troglitazone sulfate, and ethinyl estradiol were: 210, 334, and 1050 µM, respectively, for taurochenodeoxycholate; 97.6, 333, and 337 µM, respectively, for glycochenodeoxycholate; 140, 265, and 527 µM, respectively, for taurocholate; 59.8, 102, and 117 µM, respectively, for glycocholate. The potential role of OSTα/β in hepatocellular glycine-conjugated bile acid accumulation and cholestatic DILI was evaluated using sandwich-cultured human hepatocytes (SCHH). Treatment of SCHH with the farnesoid X receptor agonist chenodeoxycholate (100 µM) resulted in substantial OSTα/β induction, among other proteomic alterations, reducing glycochenodeoxycholate and glycocholate accumulation in cells+bile 4.0- and 4.5-fold, respectively. Treatment of SCHH with troglitazone and fidaxomicin together under cholestatic conditions resulted in increased hepatocellular toxicity compared with either compound alone, suggesting that OSTα/β inhibition may accentuate DILI. In conclusion, this study provides insights into the role of OSTα/β in preferential disposition of bile acids associated with hepatotoxicity, the impact of xenobiotics on OSTα/β-mediated bile acid transport, and the role of this transporter in SCHH and cholestatic DILI.
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Affiliation(s)
| | | | - Noora Sjöstedt
- Division of Pharmacotherapy and Experimental Therapeutics
| | - John K Fallon
- Division of Pharmacoengineering and Molecular Pharmaceutics, UNC Eshelman School of Pharmacy, University of North Carolina, Chapel Hill, North Carolina 27599
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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: 63] [Impact Index Per Article: 12.6] [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: 23] [Impact Index Per Article: 4.6] [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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48
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Rao A, van de Peppel IP, Gumber S, Karpen SJ, Dawson PA. Attenuation of the Hepatoprotective Effects of Ileal Apical Sodium Dependent Bile Acid Transporter (ASBT) Inhibition in Choline-Deficient L-Amino Acid-Defined (CDAA) Diet-Fed Mice. Front Med (Lausanne) 2020; 7:60. [PMID: 32158763 PMCID: PMC7052288 DOI: 10.3389/fmed.2020.00060] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2019] [Accepted: 02/10/2020] [Indexed: 12/15/2022] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a major growing worldwide health problem. We previously reported that interruption of the enterohepatic circulation of bile acids using a non-absorbable apical sodium-dependent bile acid transporter inhibitor (ASBTi; SC-435) reduced the development of NAFLD in high fat diet fed mice. However, the ability of ASBTi treatment to impact the progression of NAFLD to non-alcoholic steatohepatitis (NASH) and fibrosis in a diet-induced mouse model remains untested. In the current study, we assessed whether ASBTi treatment is hepatoprotective in the choline-deficient, L-amino acid-defined (CDAA) diet model of NASH-induced fibrosis. Methods: Male C57Bl/6 mice were fed with: (A) choline-sufficient L-amino acid-defined diet (CSAA) (31 kcal% fat), (B) CSAA diet plus ASBTi (SC-435; 60 ppm), (C) CDAA diet, or (D) CDAA diet plus ASBTi. Body weight and food intake were monitored. After 22 weeks on diet, liver histology, cholesterol and triglyceride levels, and gene expression were measured. Fecal bile acid and fat excretion were measured, and intestinal fat absorption was determined using the sucrose polybehenate method. Results: ASBTi treatment reduced bodyweight gain in mice fed either the CSAA or CDAA diet, and prevented the increase in liver to body weight ratio observed in CDAA-fed mice. ASBTi significantly reduced hepatic total cholesterol levels in both CSAA and CDAA-fed mice. ASBTi-associated significant reductions in hepatic triglyceride levels and histological scoring for NAFLD activity were observed in CSAA but not CDAA-fed mice. These changes correlated with measurements of intestinal fat absorption, which was significantly reduced in ASBTi-treated mice fed the CSAA (85 vs. 94%, P < 0.001) but not CDAA diet (93 vs. 93%). As scored by Ishak staging of Sirius red stained liver sections, no hepatic fibrosis was evident in the CSAA diet mice. The CDAA diet-fed mice developed hepatic fibrosis, which was increased by the ASBTi. Conclusions: ASBT inhibition reduced intestinal fat absorption, bodyweight gain and hepatic steatosis in CSAA diet-fed mice. The effects of the ASBTi on steatosis and fat absorption were attenuated in the context of dietary choline-deficiency. Inhibition of intestinal absorption of fatty acids may be involved in the therapeutic effects of ASBTi treatment.
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Affiliation(s)
- Anuradha Rao
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Ivo P van de Peppel
- Section of Molecular Metabolism and Nutrition, Department of Pediatrics, University Medical Center Groningen, University of Groningen, Groningen, Netherlands
| | - Sanjeev Gumber
- Division of Pathology, Yerkes National Primate Research Center, Emory University, Atlanta, GA, United States
| | - Saul J Karpen
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
| | - Paul A Dawson
- Department of Pediatrics, Emory University School of Medicine, Atlanta, GA, United States
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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: 140] [Impact Index Per Article: 23.3] [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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50
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Baier V, Cordes H, Thiel C, Castell JV, Neumann UP, Blank LM, Kuepfer L. A Physiology-Based Model of Human Bile Acid Metabolism for Predicting Bile Acid Tissue Levels After Drug Administration in Healthy Subjects and BRIC Type 2 Patients. Front Physiol 2019; 10:1192. [PMID: 31611804 PMCID: PMC6777137 DOI: 10.3389/fphys.2019.01192] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2019] [Accepted: 09/03/2019] [Indexed: 12/23/2022] Open
Abstract
Drug-induced liver injury (DILI) is a matter of concern in the course of drug development and patient safety, often leading to discontinuation of drug-development programs or early withdrawal of drugs from market. Hepatocellular toxicity or impairment of bile acid (BA) metabolism, known as cholestasis, are the two clinical forms of DILI. Whole-body physiology-based modelling allows a mechanistic investigation of the physiological processes leading to cholestasis in man. Objectives of the present study were: (1) the development of a physiology-based model of the human BA metabolism, (2) population-based model validation and characterisation, and (3) the prediction and quantification of altered BA levels in special genotype subgroups and after drug administration. The developed physiology-based bile acid (PBBA) model describes the systemic BA circulation in humans and includes mechanistically relevant active and passive processes such as the hepatic synthesis, gallbladder emptying, transition through the gastrointestinal tract, reabsorption into the liver, distribution within the whole body, and excretion via urine and faeces. The kinetics of active processes were determined for the exemplary BA glycochenodeoxycholic acid (GCDCA) based on blood plasma concentration-time profiles. The robustness of our PBBA model was verified with population simulations of healthy individuals. In addition to plasma levels, the possibility to estimate BA concentrations in relevant tissues like the intracellular space of the liver enhance the mechanistic understanding of cholestasis. We analysed BA levels in various tissues of Benign Recurrent Intrahepatic Cholestasis type 2 (BRIC2) patients and our simulations suggest a higher susceptibility of BRIC2 patients toward cholestatic DILI due to BA accumulation in the liver. The effect of drugs on systemic BA levels were simulated for cyclosporine A (CsA). Our results confirmed the higher risk of DILI after CsA administration in healthy and BRIC2 patients. The presented PBBA model enhances our mechanistic understanding underlying cholestasis and drug-induced alterations of BA levels in blood and organs. The developed PBBA model might be applied in the future to anticipate potential risk of cholestasis in patients.
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Affiliation(s)
- Vanessa Baier
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany.,Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Henrik Cordes
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Christoph Thiel
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - José V Castell
- Unit of Experimental Hepatology, IIS Hospital La Fe, Faculty of Medicine, University of Valencia and CIBEREHD, Valencia, Spain
| | - Ulf P Neumann
- Department of Surgery, University Hospital Aachen, Aachen, Germany
| | - Lars M Blank
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
| | - Lars Kuepfer
- Institute of Applied Microbiology (iAMB), Aachen Biology and Biotechnology (ABBt), RWTH Aachen University, Aachen, Germany
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