|
1
|
Shi WG, Yao Y, Liang YJ, Lei J, Feng SY, Zhang ZX, Tian Y, Cai J, Xing GG, Fu KY. Activation of TGR5 in the injured nerve site according to a prevention protocol mitigates partial sciatic nerve ligation-induced neuropathic pain by alleviating neuroinflammation. Pain 2025; 166:1296-1313. [PMID: 39450924 PMCID: PMC12067609 DOI: 10.1097/j.pain.0000000000003460] [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: 07/09/2024] [Revised: 09/18/2024] [Accepted: 09/22/2024] [Indexed: 10/26/2024]
Abstract
ABSTRACT Neuropathic pain is a pervasive medical challenge currently lacking effective treatment options. Molecular changes at the site of peripheral nerve injury contribute to both peripheral and central sensitization, critical components of neuropathic pain. This study explores the role of the G-protein-coupled bile acid receptor (GPBAR1 or TGR5) in the peripheral mechanisms underlying neuropathic pain induced by partial sciatic nerve ligation in male mice. TGR5 was upregulated in the injured nerve site and predominantly colocalized with macrophages. Perisciatic nerve administration of the TGR5 agonist, INT-777 according to a prevention protocol (50 μg/μL daily from postoperative day [POD] 0 to POD6) provided sustained relief from mechanical allodynia and spontaneous pain, whereas the TGR5 antagonist, SBI-115 worsened neuropathic pain. Transcriptome sequencing linked the pain relief induced by TGR5 activation to reduced neuroinflammation, which was further evidenced by a decrease in myeloid cells and pro-inflammatory mediators (eg, CCL3, CXCL9, interleukin [IL]-6, and tumor necrosis factor [TNF] α) and an increase in CD86-CD206+ anti-inflammatory macrophages at POD7. Besides, myeloid-cell-specific TGR5 knockdown in the injured nerve site exacerbated both neuropathic pain and neuroinflammation, which was substantiated by bulk RNA-sequencing and upregulated expression levels of inflammatory mediators (including CCL3, CCL2, IL-6, TNF α, and IL-1β) and the increased number of monocytes/macrophages at POD7. Furthermore, the activation of microglia in the spinal cord on POD7 and POD14 was altered when TGR5 in the sciatic nerve was manipulated. Collectively, TGR5 activation in the injured nerve site mitigates neuropathic pain by reducing neuroinflammation, while TGR5 knockdown in myeloid cells worsens pain by enhancing neuroinflammation.
Collapse
Affiliation(s)
- Wen-Ge Shi
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Yao Yao
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Ya-Jing Liang
- Department of General Dentistry and Integrated Emergency Dental Care, Beijing Stomatological Hospital, Capital Medical University, Beijing, China
| | - Jie Lei
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Shi-Yang Feng
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| | - Zi-Xian Zhang
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Yue Tian
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Jie Cai
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Guo-Gang Xing
- Neuroscience Research Institute, Peking University, Department of Neurobiology, School of Basic Medical Sciences, Peking University Health Science Center, Key Laboratory for Neuroscience, Ministry of Education of China & National Health, Beijing, China
| | - Kai-Yuan Fu
- Center for TMD and Orofacial Pain, Peking University School and Hospital of Stomatology, Beijing, China
- National Center for Stomatology & National Clinical Research Center for Oral Diseases, Beijing, China
| |
Collapse
|
|
2
|
Liu Z, You C. The bile acid profile. Clin Chim Acta 2025; 565:120004. [PMID: 39419312 DOI: 10.1016/j.cca.2024.120004] [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: 07/22/2024] [Revised: 10/13/2024] [Accepted: 10/14/2024] [Indexed: 10/19/2024]
Abstract
As a large and structurally diverse family of small molecules, bile acids play a crucial role in regulating lipid, glucose, and energy metabolism. In the human body, bile acids share a similar chemical structure with many isomers, exhibit little difference in polarity, and possess various physiological activities. The types and contents of bile acids present in different diseases vary significantly. Therefore, comprehensive and accurate detection of the content of various types of bile acids in different biological samples can not only provide new insights into the pathogenesis of diseases but also facilitate the exploration of novel strategies for disease diagnosis, treatment, and prognosis. The detection of disease-induced changes in bile acid profiles has emerged as a prominent research focus in recent years. Concurrently, targeted metabolomics methods utilizing high-performance liquid chromatography-mass spectrometry (HPLC-MS) have progressively established themselves as the predominant technology for the separation and detection of bile acids. Bile acid profiles will increasingly play an important role in diagnosis and guidance in the future as the relationship between disease and changes in bile acid profiles becomes clearer. This highlights the growing diagnostic value of bile acid profiles and their potential to guide clinical decision-making. This review aims to explore the significance of bile acid profiles in clinical diagnosis from four perspectives: the synthesis and metabolism of bile acids, techniques for detecting bile acid profiles, changes in bile acid profiles associated with diseases, and the challenges and future prospects of applying bile acid profiles in clinical settings.
Collapse
Affiliation(s)
- Zhenhua Liu
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China
| | - Chongge You
- Laboratory Medicine Center, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou 730030, China.
| |
Collapse
|
|
3
|
Lee MH, Nuccio SP, Mohanty I, Hagey LR, Dorrestein PC, Chu H, Raffatellu M. How bile acids and the microbiota interact to shape host immunity. Nat Rev Immunol 2024; 24:798-809. [PMID: 39009868 DOI: 10.1038/s41577-024-01057-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
Collapse
Affiliation(s)
- Michael H Lee
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Hiutung Chu
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA.
| |
Collapse
|
|
4
|
Gu S, Hu S, Wang S, Shi C, Qi C, Wan R, Fan G. Altered biliary microbial and metabolic profile reveals the crosstalk between NAFLD and cholelithiasis. Clin Res Hepatol Gastroenterol 2024; 48:102431. [PMID: 39094784 DOI: 10.1016/j.clinre.2024.102431] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2024] [Revised: 07/17/2024] [Accepted: 07/26/2024] [Indexed: 08/04/2024]
Abstract
BACKGROUND The relationship between non-alcoholic fatty liver disease (NAFLD) and cholelithiasis is intricate, with alterations in the microenvironment potentially mediating this interplay. Thus, this study aimed to explore the biliary microbiota and metabolites of patients with cholelithiasis and detect changes induced by comorbid NAFLD. METHODS In this study, 16S rRNA gene sequencing and metabolome analysis were performed on biliary samples collected from 35 subjects. Then, patients were stratified into two groups: the comorbidity group (n = 18), consisting of cholelithiasis patients with NAFLD, and the non-comorbidity group (n = 17), comprising cholelithiasis patients without NAFLD. RESULTS Comorbid NAFLD did not significantly increase α-diversity but affected β-diversity. A statistically significant difference was observed in the abundance of biliary metabolites between the two groups. Specifically, differences in the abundance of 4 phyla, 19 genera, and 28 metabolites were significant between the two groups. Correlation analysis demonstrated positive associations among 12α-hydroxylated bile acid levels, Pyramidobacter and Fusobacterium abundance, AST levels, and the fibrosis-4 index (p < 0.05, r > 0.3), all of which were increased in patients with cholelithiasis and comorbid NAFLD. CONCLUSIONS The relationship between cholelithiasis and NAFLD influences the biliary microbial and metabolic profile, creating a detrimental microenvironment that promotes the disease progression.
Collapse
Affiliation(s)
- Shengying Gu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shanshan Hu
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Shuowen Wang
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chenyang Shi
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Chendong Qi
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
| | - Rong Wan
- Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| | - Guorong Fan
- Department of Clinical Pharmacy, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China.
| |
Collapse
|
|
5
|
Bhimanwar RS, Mittal A, Chaudhari S, Sharma V. Recent advancements in the structural exploration of TGR5 agonists for diabetes treatment. RSC Med Chem 2024; 15:3026-3037. [PMID: 39309359 PMCID: PMC11411620 DOI: 10.1039/d4md00473f] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2024] [Accepted: 07/16/2024] [Indexed: 09/25/2024] Open
Abstract
TGR5, a receptor that interacts with bile acids on cell surfaces, has become a promising therapeutic target for type II diabetes due to its ability to regulate energy expenditure and blood sugar levels. While several TGR5 agonists have been identified, only a few are currently in clinical trials. This article reviews the promising TGR5 agonists discovered in recent years, highlighting the chemical structure and pharmacological profile of the most effective compounds. With the limited number of effective drugs available for treating type II diabetes, the search for a potent TGR5 agonist with high efficacy and fewer side effects continues. The goal of this article is to provide an overview of the latest advancements in TGR5 agonists and offer insights for the future development of novel, potent TGR5 agonists for diabetes treatment. A noteworthy aspect addressed in the discussion is the common side effect associated with TGR5 agonist treatment - gallbladder filling. The review also explores potential strategies to mitigate this side effect, with the goal of improving the overall safety and tolerability of TGR5-targeted therapies.
Collapse
Affiliation(s)
- Rachana S Bhimanwar
- Department of Pharmaceutical Chemistry, Dr. D. Y. Patil Institute of Pharmaceutical Sciences and Research Pimpri Pune Maharashtra-411018 India
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
| | - Amit Mittal
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
| | - Snehal Chaudhari
- Department of Biochemistry, University of Wisconsin-Madison Madison WI-53706 USA
| | - Vikas Sharma
- Department of Pharmaceutical Chemistry, School of Pharmaceutical Sciences, Lovely Professional University Jalandhar-Delhi G.T. Road (NH-1) Phagwara Punjab-144411 India
| |
Collapse
|
|
6
|
Peiper AM, Morales Aparicio J, Hu Z, Phophi L, Helm EW, Rubinstein RJ, Phillips M, Williams CG, Subramanian S, Cross M, Iyer N, Nguyen Q, Newsome R, Jobin C, Langel SN, Bucardo F, Becker-Dreps S, Tan XD, Dawson PA, Karst SM. Metabolic immaturity and breastmilk bile acid metabolites are central determinants of heightened newborn vulnerability to norovirus diarrhea. Cell Host Microbe 2024; 32:1488-1501.e5. [PMID: 39214086 PMCID: PMC11392616 DOI: 10.1016/j.chom.2024.08.003] [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: 07/06/2024] [Revised: 07/17/2024] [Accepted: 08/01/2024] [Indexed: 09/04/2024]
Abstract
The pathogenic outcome of enteric virus infections is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors, with metabolites serving as a key mediator. Noroviruses bind bile acid metabolites, which are produced by the host and then modified by commensal bacteria. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Working in an infant mouse model of norovirus infection, we demonstrate that microbiota and their bile acid metabolites protect from norovirus diarrhea, whereas host bile acids promote disease. We also find that maternal bile acid metabolism determines the susceptibility of newborn mice to norovirus diarrhea during breastfeeding. Finally, targeting maternal and neonatal bile acid metabolism can protect newborn mice from norovirus disease. In summary, neonatal metabolic immaturity and breastmilk bile acids are central determinants of heightened newborn vulnerability to norovirus disease.
Collapse
Affiliation(s)
- Amy M Peiper
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Joyce Morales Aparicio
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Zhengzheng Hu
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Lufuno Phophi
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Emily W Helm
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rebecca J Rubinstein
- Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Matthew Phillips
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Caroline G Williams
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Saravanan Subramanian
- Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA
| | - Michael Cross
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Neha Iyer
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Quyen Nguyen
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Rachel Newsome
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Christian Jobin
- Department of Medicine, College of Medicine, University of Florida, Gainesville, FL 32610, USA
| | - Stephanie N Langel
- Department of Pathology, Center for Global Health and Diseases, Case Western Reserve University School of Medicine, Cleveland, OH 44106, USA
| | - Filemon Bucardo
- Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Microbiology and Immunology, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Sylvia Becker-Dreps
- Department of Family Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA; Department of Epidemiology, Gillings School of Public Health, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
| | - Xiao-Di Tan
- Pediatric Mucosal Inflammation and Regeneration Research Program, Center for Pediatric Translational Research and Education, Department of Pediatrics, College of Medicine, University of Illinois at Chicago, Chicago, IL 60612, USA; Department of Research & Development, Jesse Brown Veterans Affairs Medical Center, Chicago, IL 60612, USA
| | - Paul A Dawson
- Department of Pediatrics, Division of Gastroenterology, Hepatology and Nutrition, Emory School of Medicine, Atlanta, GA 30329, USA
| | - Stephanie M Karst
- Department of Molecular Genetics & Microbiology, College of Medicine, University of Florida, Gainesville, FL 32610, USA.
| |
Collapse
|
|
7
|
Romero-Ramírez L, Mey J. Emerging Roles of Bile Acids and TGR5 in the Central Nervous System: Molecular Functions and Therapeutic Implications. Int J Mol Sci 2024; 25:9279. [PMID: 39273226 PMCID: PMC11395147 DOI: 10.3390/ijms25179279] [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: 07/31/2024] [Revised: 08/15/2024] [Accepted: 08/17/2024] [Indexed: 09/15/2024] Open
Abstract
Bile acids (BAs) are cholesterol derivatives synthesized in the liver and released into the digestive tract to facilitate lipid uptake during the digestion process. Most of these BAs are reabsorbed and recycled back to the liver. Some of these BAs progress to other tissues through the bloodstream. The presence of BAs in the central nervous system (CNS) has been related to their capacity to cross the blood-brain barrier (BBB) from the systemic circulation. However, the expression of enzymes and receptors involved in their synthesis and signaling, respectively, support the hypothesis that there is an endogenous source of BAs with a specific function in the CNS. Over the last decades, BAs have been tested as treatments for many CNS pathologies, with beneficial effects. Although they were initially reported as neuroprotective substances, they are also known to reduce inflammatory processes. Most of these effects have been related to the activation of the Takeda G protein-coupled receptor 5 (TGR5). This review addresses the new challenges that face BA research for neuroscience, focusing on their molecular functions. We discuss their endogenous and exogenous sources in the CNS, their signaling through the TGR5 receptor, and their mechanisms of action as potential therapeutics for neuropathologies.
Collapse
Affiliation(s)
- Lorenzo Romero-Ramírez
- Laboratorio de Regeneración Neuronal, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla-La Mancha, 45071 Toledo, Spain
| | - Jörg Mey
- Laboratorio de Regeneración Neuronal, Hospital Nacional de Parapléjicos, Servicio de Salud de Castilla-La Mancha, 45071 Toledo, Spain
- EURON Graduate School of Neuroscience, Maastricht University, 6229 ER Maastricht, The Netherlands;
| |
Collapse
|
|
8
|
Zhang C, Wang G, Yin X, Gou L, Guo M, Suo F, Zhuang T, Yuan Z, Liu Y, Gu M, Yao R. Hepatic protein phosphatase 1 regulatory subunit 3G alleviates obesity and liver steatosis by regulating the gut microbiota and bile acid metabolism. J Pharm Anal 2024; 14:100976. [PMID: 39263354 PMCID: PMC11388703 DOI: 10.1016/j.jpha.2024.100976] [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: 11/12/2023] [Revised: 03/05/2024] [Accepted: 04/08/2024] [Indexed: 09/13/2024] Open
Abstract
Intestinal dysbiosis and disrupted bile acid (BA) homeostasis are associated with obesity, but the precise mechanisms remain insufficiently explored. Hepatic protein phosphatase 1 regulatory subunit 3G (PPP1R3G) plays a pivotal role in regulating glycolipid metabolism; nevertheless, its obesity-combatting potency remains unclear. In this study, a substantial reduction was observed in serum PPP1R3G levels in high-body mass index (BMI) and high-fat diet (HFD)-exposed mice, establishing a positive correlation between PPP1R3G and non-12α-hydroxylated (non-12-OH) BA content. Additionally, hepatocyte-specific overexpression of Ppp1r3g (PPP1R3G HOE) mitigated HFD-induced obesity as evidenced by reduced weight, fat mass, and an improved serum lipid profile; hepatic steatosis alleviation was confirmed by normalized liver enzymes and histology. PPP1R3G HOE considerably impacted systemic BA homeostasis, which notably increased the non-12-OH BAs ratio, particularly lithocholic acid (LCA). 16S ribosomal DNA (16S rDNA) sequencing assay indicated that PPP1R3G HOE reversed HFD-induced gut dysbiosis by reducing the Firmicutes/Bacteroidetes ratio and Lactobacillus population, and elevating the relative abundance of Blautia, which exhibited a positive correlation with serum LCA levels. A fecal microbiome transplantation test confirmed that the anti-obesity effect of hepatic PPP1R3G was gut microbiota-dependent. Mechanistically, PPP1R3G HOE markedly suppressed hepatic cholesterol 7α-hydroxylase (CYP7A1) and sterol-12α-hydroxylase (CYP8B1), and concurrently upregulated oxysterol 7-α hydroxylase and G protein-coupled BA receptor 5 (TGR5) expression under HFD conditions. Furthermore, LCA administration significantly mitigated the HFD-induced obesity phenotype and elevated non-12-OH BA levels. These findings emphasize the significance of hepatic PPP1R3G in ameliorating diet-induced adiposity and hepatic steatosis through the gut microbiota-BA axis, which may serve as potential therapeutic targets for obesity-related disorders.
Collapse
Affiliation(s)
- Chu Zhang
- Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Gui Wang
- Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Xin Yin
- Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China
| | - Lingshan Gou
- Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China
| | - Mengyuan Guo
- Department of Geriatrics, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, Jiangsu, 221006, China
| | - Feng Suo
- Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China
| | - Tao Zhuang
- Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Zhenya Yuan
- Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China
| | - Yanan Liu
- Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| | - Maosheng Gu
- Department of Genetic Medicine, Xuzhou Maternity and Child Health Care Hospital Affiliated to Xuzhou Medical University, Xuzhou, Jiangsu, 221009, China
| | - Ruiqin Yao
- Xuzhou Key Laboratory of Neurobiology, Department of Cell Biology and Neurobiology, Xuzhou Medical University, Xuzhou, Jiangsu, 221004, China
| |
Collapse
|
|
9
|
Fiorucci S, Marchianò S, Urbani G, Di Giorgio C, Distrutti E, Zampella A, Biagioli M. Immunology of bile acids regulated receptors. Prog Lipid Res 2024; 95:101291. [PMID: 39122016 DOI: 10.1016/j.plipres.2024.101291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/30/2024] [Accepted: 08/02/2024] [Indexed: 08/12/2024]
Abstract
Bile acids are steroids formed at the interface of host metabolism and intestinal microbiota. While primary bile acids are generated in the liver from cholesterol metabolism, secondary bile acids represent the products of microbial enzymes. Close to 100 different enzymatic modifications of bile acids structures occur in the human intestine and clinically guided metagenomic and metabolomic analyses have led to the identification of an extraordinary number of novel metabolites. These chemical mediators make an essential contribution to the composition and function of the postbiota, participating to the bidirectional communications of the intestinal microbiota with the host and contributing to the architecture of intestinal-liver and -brain and -endocrine axes. Bile acids exert their function by binding to a group of cell membrane and nuclear receptors collectively known as bile acid-regulated receptors (BARRs), expressed in monocytes, tissue-resident macrophages, CD4+ T effector cells, including Th17, T regulatory cells, dendritic cells and type 3 of intestinal lymphoid cells and NKT cells, highlighting their role in immune regulation. In this review we report on how bile acids and their metabolitesmodulate the immune system in inflammations and cancers and could be exploiting for developing novel therapeutic approaches in these disorders.
Collapse
Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Silvia Marchianò
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Ginevra Urbani
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | | | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| |
Collapse
|
|
10
|
Huang X, Liu X, Li Z. Bile acids and coronavirus disease 2019. Acta Pharm Sin B 2024; 14:1939-1950. [PMID: 38799626 PMCID: PMC11119507 DOI: 10.1016/j.apsb.2024.02.011] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2023] [Revised: 12/08/2023] [Accepted: 01/28/2024] [Indexed: 05/29/2024] Open
Abstract
The coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has been significantly alleviated. However, long-term health effects and prevention strategy remain unresolved. Thus, it is essential to explore the pathophysiological mechanisms and intervention for SARS-CoV-2 infection. Emerging research indicates a link between COVID-19 and bile acids, traditionally known for facilitating dietary fat absorption. The bile acid ursodeoxycholic acid potentially protects against SARS-CoV-2 infection by inhibiting the farnesoid X receptor, a bile acid nuclear receptor. The activation of G-protein-coupled bile acid receptor, another membrane receptor for bile acids, has also been found to regulate the expression of angiotensin-converting enzyme 2, the receptor through which the virus enters human cells. Here, we review the latest basic and clinical evidence linking bile acids to SARS-CoV-2, and reveal their complicated pathophysiological mechanisms.
Collapse
Affiliation(s)
- Xiaoru Huang
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing 100191, China
| | - Xuening Liu
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing 100191, China
| | - Zijian Li
- Department of Pharmacy, Peking University Third Hospital, Beijing 100191, China
- Department of Pharmaceutical Management and Clinical Pharmacy, College of Pharmacy, Peking University, Beijing 100191, China
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing Key Laboratory of Cardiovascular Receptors Research, Key Laboratory of Cardiovascular Molecular Biology and Regulatory Peptides, Ministry of Health, State Key Laboratory of Vascular Homeostasis and Remodeling, Peking University, Beijing 100191, China
| |
Collapse
|
|
11
|
Peiper AM, Aparicio JM, Phophi L, Hu Z, Helm EW, Phillips M, Williams CG, Subramanian S, Cross M, Iyer N, Nguyen Q, Newsome R, Jobin C, Langel SN, Bucardo F, Becker-Dreps S, Tan XD, Dawson PA, Karst SM. Metabolic immaturity of newborns and breast milk bile acid metabolites are the central determinants of heightened neonatal vulnerability to norovirus diarrhea. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.01.592031. [PMID: 38746153 PMCID: PMC11092632 DOI: 10.1101/2024.05.01.592031] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/16/2024]
Abstract
Noroviruses are the leading global cause of acute gastroenteritis, responsible for 685 million annual cases. While all age groups are susceptible to noroviruses, children are vulnerable to more severe infections than adults, underscored by 200 million pediatric cases and up to 200,000 deaths in children annually. Understanding the basis for the increased vulnerability of young hosts is critical to developing effective treatments. The pathogenic outcome of any enteric virus infection is governed by a complex interplay between the virus, intestinal microbiota, and host immune factors. A central mediator in these complex relationships are host- and microbiota-derived metabolites. Noroviruses bind a specific class of metabolites, bile acids, which are produced by the host and then modified by commensal bacterial enzymes. Paradoxically, bile acids can have both proviral and antiviral roles during norovirus infections. Considering these opposing effects, the microbiota-regulated balance of the bile acid pool may be a key determinant of the pathogenic outcome of a norovirus infection. The bile acid pool in newborns is unique due to immaturity of host metabolic pathways and developing gut microbiota, which could underlie the vulnerability of these hosts to severe norovirus infections. Supporting this concept, we demonstrate herein that microbiota and their bile acid metabolites protect from severe norovirus diarrhea whereas host-derived bile acids promote disease. Remarkably, we also report that maternal bile acid metabolism determines neonatal susceptibility to norovirus diarrhea during breastfeeding by delivering proviral bile acids to the newborn. Finally, directed targeting of maternal and neonatal bile acid metabolism can protect the neonatal host from norovirus disease. Altogether, these data support the conclusion that metabolic immaturity in newborns and ingestion of proviral maternal metabolites in breast milk are the central determinants of heightened neonatal vulnerability to norovirus disease.
Collapse
|
|
12
|
Jia W, Li Y, Cheung KCP, Zheng X. Bile acid signaling in the regulation of whole body metabolic and immunological homeostasis. SCIENCE CHINA. LIFE SCIENCES 2024; 67:865-878. [PMID: 37515688 DOI: 10.1007/s11427-023-2353-0] [Citation(s) in RCA: 57] [Impact Index Per Article: 57.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/21/2023] [Accepted: 04/23/2023] [Indexed: 07/31/2023]
Abstract
Bile acids (BAs) play a crucial role in nutrient absorption and act as key regulators of lipid and glucose metabolism and immune homeostasis. Through the enterohepatic circulation, BAs are synthesized, metabolized, and reabsorbed, with a portion entering the vascular circulation and distributing systemically. This allows BAs to interact with receptors in all major organs, leading to organ-organ interactions that regulate both local and global metabolic processes, as well as the immune system. This review focuses on the whole-body effects of BA-mediated metabolic and immunological regulation, including in the brain, heart, liver, intestine, eyes, skin, adipose tissue, and muscle. Targeting BA synthesis and receptor signaling is a promising strategy for the development of novel therapies for various diseases throughout the body.
Collapse
Affiliation(s)
- Wei Jia
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China.
| | - Yitao Li
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Kenneth C P Cheung
- School of Chinese Medicine, Hong Kong Baptist University, Hong Kong, China
| | - Xiaojiao Zheng
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai, 200233, China.
| |
Collapse
|
|
13
|
Ye D, He J, He X. The role of bile acid receptor TGR5 in regulating inflammatory signalling. Scand J Immunol 2024; 99:e13361. [PMID: 38307496 DOI: 10.1111/sji.13361] [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: 08/09/2023] [Revised: 10/12/2023] [Accepted: 01/18/2024] [Indexed: 02/04/2024]
Abstract
Takeda G protein-coupled receptor 5 (TGR5) is a bile acid receptor, and its role in regulating metabolism after binding with bile acids has been established. Since the immune response depends on metabolism to provide biomolecules and energy to cope with challenging conditions, emerging evidence reveals the regulatory effects of TGR5 on the immune response. An in-depth understanding of the effect of TGR5 on immune regulation can help us disentangle the interaction of metabolism and immune response, accelerating the development of TGR5 as a therapeutic target. Herein, we reviewed more than 200 articles published in the last 20 years in PubMed, to discuss the roles of TGR5 in regulating inflammatory response, the molecular mechanism, as well as existing problems. Particularly, its anti-inflammation effect is emphasized.
Collapse
Affiliation(s)
- Daijiao Ye
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Jiayao He
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| | - Xiaofei He
- Medical Research Center, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
- The Key Laboratory of Pediatric Hematology and Oncology Disease of Wenzhou, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, Zhejiang Province, China
| |
Collapse
|
|
14
|
Gether IM, Bahne E, Nerild HH, Rehfeld JF, Hartmann B, Holst JJ, Vilsbøll T, Sonne DP, Knop FK. Colesevelam has no acute effect on postprandial GLP-1 levels but abolishes gallbladder refilling. Eur J Endocrinol 2024; 190:314-326. [PMID: 38551029 DOI: 10.1093/ejendo/lvae033] [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: 11/03/2023] [Revised: 03/04/2024] [Accepted: 03/14/2024] [Indexed: 04/18/2024]
Abstract
OBJECTIVE Colesevelam, a bile acid sequestrant approved for the treatment of hypercholesterolaemia, improves glycaemic control in type 2 diabetes. We hypothesised that single-dose colesevelam increases postprandial GLP-1 secretion, thus, reducing postprandial glucose excursions in individuals with type 2 diabetes. Further, we explored the effects of single-dose colesevelam on ultrasonography-assessed postprandial gallbladder motility, paracetamol absorption (proxy for gastric emptying), and circulating factors known to affect gallbladder motility. METHODS In a randomised, double-blind, placebo-controlled crossover study, 12 individuals with type 2 diabetes (mean ± SD: age 61 ± 8.8 years; body mass index 29.8 ± 3.0 kg/m2) were subjected to 4 mixed meal tests on separate days; 2 with orally administered colesevelam (3.75 g) and 2 with placebo, with intravenous infusion of the GLP-1 receptor antagonist exendin(9-39)NH2 or saline. RESULTS Single-dose colesevelam had no effect on postprandial concentrations of glucose (P = .786), C-peptide (P = .440), or GLP-1 (P = .729), and exendin(9-39)NH2 administration revealed no GLP-1-mediated effects of colesevelam. Colesevelam did not affect gallbladder emptying but abolished gallbladder refilling (P = .001), increased postprandial cholecystokinin (CCK) secretion (P = .010), and decreased postprandial serum concentrations of fibroblast growth factor 19 (FGF19) (P = .035) and bile acids (P = .043). CONCLUSION Single-dose colesevelam had no effect on postprandial GLP-1 responses or glucose tolerance but disrupted postprandial gallbladder refilling by increasing CCK secretion and reducing circulating concentrations of FGF19 and bile acids. These findings leave the antidiabetic actions of colesevelam unresolved but provide mechanistic insights into its effect on gallbladder motility.
Collapse
Affiliation(s)
- Ida M Gether
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Emilie Bahne
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Henriette H Nerild
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Rigshospitalet, University of Copenhagen, DK-2100 Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Novo Nordisk Foundation Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Pharmacology, Bispebjerg Hospital, University of Copenhagen, DK-2400 Copenhagen, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark
- Steno Diabetes Center Copenhagen, DK-2730 Herlev, Denmark
| |
Collapse
|
|
15
|
Zhou W, Lew B, Choi H, Kim K, Anakk S. Chenodeoxycholic Acid-Loaded Nanoparticles Are Sufficient to Decrease Adipocyte Size by Inducing Mitochondrial Function. NANO LETTERS 2024; 24:1642-1649. [PMID: 38278518 PMCID: PMC10854752 DOI: 10.1021/acs.nanolett.3c04352] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/13/2023] [Revised: 12/20/2023] [Accepted: 12/22/2023] [Indexed: 01/28/2024]
Abstract
Excess fat accumulation is not only associated with metabolic diseases but also negatively impacts physical appearance and emotional well-being. Bile acid, the body's natural emulsifier, is one of the few FDA-approved noninvasive therapeutic options for double chin (submental fat) reduction. Synthetic sodium deoxycholic acid (NaDCA) causes adipose cell lysis; however, its side effects include inflammation, bruising, and necrosis. Therefore, we investigated if an endogenous bile acid, chenodeoxycholic acid (CDCA), a well-known signaling molecule, can be beneficial without many of the untoward effects. We first generated CDCA-loaded nanoparticles to achieve sustained and localized delivery. Then, we injected them into the subcutaneous fat depot and monitored adipocyte size and mitochondrial function. Unlike NaDCA, CDCA did not cause cytolysis. Instead, we demonstrate that a single injection of CDCA-loaded nanoparticles into the subcutaneous fat reduced the adipocyte size by promoting fat burning and mitochondrial respiration, highlighting their potential for submental fat reduction.
Collapse
Affiliation(s)
- Weinan Zhou
- Department
of Molecular and Integrative Physiology, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Benjamin Lew
- Department
of Electrical and Computer Engineering, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Hyungsoo Choi
- Department
of Electrical and Computer Engineering, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Kyekyoon Kim
- Department
of Electrical and Computer Engineering, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
- Department
of Bioengineering, University of Illinois
Urbana−Champaign, Urbana, Illinois 61801, United States
- Beckman
Institute for Advanced Science and Technology, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
| | - Sayeepriyadarshini Anakk
- Department
of Molecular and Integrative Physiology, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
- Beckman
Institute for Advanced Science and Technology, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
- Division
of Nutritional Sciences, University of Illinois
Urbana−Champaign, Urbana, Illinois 61801, United States
- Cancer Center
at Illinois, University of Illinois Urbana−Champaign, Urbana, Illinois 61801, United States
| |
Collapse
|
|
16
|
Tao Y, Zhou H, Li Z, Wu H, Wu F, Miao Z, Shi H, Huang F, Wu X. TGR5 deficiency-induced anxiety and depression-like behaviors: The role of gut microbiota dysbiosis. J Affect Disord 2024; 344:219-232. [PMID: 37839469 DOI: 10.1016/j.jad.2023.10.072] [Citation(s) in RCA: 22] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2023] [Revised: 09/28/2023] [Accepted: 10/09/2023] [Indexed: 10/17/2023]
Abstract
BACKGROUND AND PURPOSE Anxiety and depression have been associated with imbalances in the gut microbiota and bile acid metabolism. Takeda G protein-coupled receptor 5 (TGR5), a bile acid receptor involved in metabolism, is influenced by the gut microbiota. This study aimed to investigate the relationship between anxiety, depression, and microbiota using TGR5 knockout mice. METHODS We employed the following methods: (1) Assessment of behavioral changes, (2) Measurement of 5-HT levels and protein expression, (3) Analysis of stool samples, (4) Utilization of gene sequencing and statistical analysis to identify microbial signatures, (5) Examination of correlations between microbial signatures and 5-HT levels, and (6) Fecal microbiota transplantation experiments of TGR5-/- mice. RESULTS The deletion of TGR5 was found to result in increased anxiety- and depression-like behaviors in mice. TGR5 knockout mice exhibited significant reductions in 5-hydroxytryptamine (5-HT) levels in both serum and hippocampus, accompanied by a decrease in the expression of 5-HT1A receptor in the hippocampus. Moreover, TGR5 deficiency was associated with a decrease in the species richness of the gut microbiota. Specifically, the gut microbiota compositions of TGR5 knockout mice displayed distinct differences compared to their littermates, characterized by higher abundances of Anaeroplasma, Prevotella, Staphylococcus, Jeotgalicoccus, and Helicobacter, and a lower abundance of Bifidobacterium. Notably, a strong association between Jeotgalicoccus as well as Staphylococcus and serum 5-HT levels was observed in co-occurrence network. Furthermore, mice that received fecal microbiota transplants from TGR5-/- mice displayed anxiety and depression -like behaviors, accompanied by alterations in 5-HT levels in the hippocampus and serum. LIMITATIONS Study limitations for gut bacteria were analyzed at the genus level only. CONCLUSION TGR5 deletion in mice induces anxiety and depression-like behaviors, linked to reduced 5-HT levels in serum and the hippocampus. Gut microbiota changes play a direct role in these behaviors and serotonin alterations. This implicates TGR5 and gut bacteria in mood regulation, with potential therapeutic implications.
Collapse
Affiliation(s)
- Yanlin Tao
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Houyuan Zhou
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Zikang Li
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Hui Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Fanggeng Wu
- Jiangxi Tumor Hospital, Nanchang 330029, PR China
| | - Zhiguo Miao
- Jiangxi Tumor Hospital, Nanchang 330029, PR China
| | - Hailian Shi
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China
| | - Fei Huang
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
| | - Xiaojun Wu
- Shanghai Key Laboratory of Compound Chinese Medicines, the Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines, the MOE Innovation Centre for Basic Medicine Research on Qi-Blood TCM Theories, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, PR China.
| |
Collapse
|
|
17
|
Zhu L, Fang S, Zhang H, Sun X, Yang P, Wan J, Zhang Y, Lu W, Yu L. Total Sn-2 Palmitic Triacylglycerols and the Ratio of OPL to OPO in Human Milk Fat Substitute Modulated Bile Acid Metabolism and Intestinal Microbiota Composition in Rats. Nutrients 2023; 15:4929. [PMID: 38068787 PMCID: PMC10708361 DOI: 10.3390/nu15234929] [Citation(s) in RCA: 7] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2023] [Revised: 11/22/2023] [Accepted: 11/24/2023] [Indexed: 12/18/2023] Open
Abstract
In this study, the impact of sn-2 palmitic triacyclglycerols (TAGs) in combination with their ratio of two major TAGs (1-oleoyl-2-palmitoyl-3-linoleoylglycerol (OPL) to 1,3-dioleoyl-2-palmitoylglycerol (OPO)) in human milk fat substitute (HMFS) on bile acid (BA) metabolism and intestinal microbiota composition was investigated in newly-weaned Sprague-Dawley rats after four weeks of high-fat feeding. Compared to those of control group rats, HMFS-fed rats had significantly increased contents of six hepatic primary BAs (CDCA, αMCA, βMCA, TCDCA, TαMCA and TβMCA), four ileal primary BAs (UDCA, TCA, TCDCA and TUDCA) and three secondary BAs (DCA, LCA and ωMCA), especially for the HMFS with the highest sn-2 palmitic acid TAGs of 57.9% and OPL to OPO ratio of 1.4. Meanwhile, the inhibition of ileal FXR-FGF15 and activation of TGR5-GLP-1 signaling pathways in HMFS-fed rats were accompanied by the increased levels of enzymes involved in BA synthesis (CYP7A1, CYP27A1 and CYP7B1) in the liver and two key thermogenic proteins (PGC1α and UCP1) in perirenal adipose tissue, respectively. Moreover, increasing sn-2 palmitic TAGs and OPL to OPO ratio in HMFS also altered the microbiota composition both on the phylum and genus level in rats, predominantly microbes associated with bile-salt hydrolase activity, short-chain fatty acid production and reduced obesity risk, which suggested a beneficial effect on host microbial ecosystem. These observations provided important nutritional evidence for developing new HMFS products for infants.
Collapse
Affiliation(s)
- Lin Zhu
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Shuaizhen Fang
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Hong Zhang
- Wilmar (Shanghai) Biotechnology Research & Development Center Co., Ltd., Shanghai 200137, China; (H.Z.); (J.W.)
| | - Xiangjun Sun
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Puyu Yang
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Jianchun Wan
- Wilmar (Shanghai) Biotechnology Research & Development Center Co., Ltd., Shanghai 200137, China; (H.Z.); (J.W.)
| | - Yaqiong Zhang
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Weiying Lu
- Institute of Food and Nutraceutical Science, School of Agriculture and Biology, Shanghai Jiao Tong University, Shanghai 200240, China; (L.Z.); (S.F.); (X.S.); (P.Y.); (W.L.)
| | - Liangli Yu
- Department of Nutrition and Food Science, University of Maryland, College Park, MD 20742, USA;
| |
Collapse
|
|
18
|
Li SX, Guo Y. Gut microbiome: New perspectives for type 2 diabetes prevention and treatment. World J Clin Cases 2023; 11:7508-7520. [DOI: 10.12998/wjcc.v11.i31.7508] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Revised: 09/19/2023] [Accepted: 10/23/2023] [Indexed: 11/06/2023] Open
Abstract
Type 2 diabetes mellitus (T2DM), which is distinguished by increased glucose levels in the bloodstream, is a metabolic disease with a rapidly increasing incidence worldwide. Nevertheless, the etiology and characteristics of the mechanism of T2DM remain unclear. Recently, abundant evidence has indicated that the intestinal microbiota is crucially involved in the initiation and progression of T2DM. The gut microbiome, the largest microecosystem, engages in material and energy metabolism in the human body. In this review, we concentrated on the correlation between the gut flora and T2DM. Meanwhile, we summarized the pathogenesis involving the intestinal flora in T2DM, as well as therapeutic approaches aimed at modulating the gut microbiota for the management of T2DM. Through the analysis presented here, we draw attention to further exploration of these research directions.
Collapse
Affiliation(s)
- Shu-Xiao Li
- School of Clinical Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130000, Jilin Province, China
| | - Yan Guo
- School of Clinical Medicine, Changchun University of Traditional Chinese Medicine, Changchun 130000, Jilin Province, China
| |
Collapse
|
|
19
|
Li W, Zhuang T, Wang Z, Wang X, Liu L, Luo Y, Wang R, Li L, Huang W, Wang Z, Yang L, Ding L. Red ginseng extracts ameliorate high-fat diet-induced obesity and insulin resistance by activating the intestinal TGR5-mediated bile acids signaling pathway. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2023; 119:154982. [PMID: 37531904 DOI: 10.1016/j.phymed.2023.154982] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/03/2023] [Revised: 06/23/2023] [Accepted: 07/15/2023] [Indexed: 08/04/2023]
Abstract
BACKGROUND Obesity has emerged as a worldwide metabolic disease, given its rapid growth in global prevalence. Red ginseng extracts (RGS), one of the traditional processed products of ginseng, show the potential to improve the metabolic phenotype of obesity. However, the RGS mechanism for regulating obesity and late insulin resistance remains to be clarified. PURPOSE This study aimed to emphasize the potential use of RGS in treatment of obesity and insulin resistance (IR) and explore the underlying mechanism affecting glucose and lipid metabolism improvements. METHODS The role of RGS was evaluated in a high-fat diet (HFD) rodent model. Glucose tolerance test (GTT) and insulin tolerance test (ITT) were performed to characterize the glucose metabolism level. The expression of lipolysis proteins and uncoupling protein-1 (UCP-1) were investigated by western blot. Glucagon-like peptide-1 (GLP-1) and apical sodium-dependent bile acid transporter (ASBT) protein expression in the intestine were determined via immunofluorescence. UPLC-Q-TOF-MS were used to detect the alterations in bile acids (BAs) levels in serum, ileum, and inguinal white adipose tissue (iWAT). In addition, intestine-specific Tgr5 knockout mice were employed to verify the efficacy of RGS in improving obesity. RESULTS RGS treatment alleviated dietary-induced dyslipidemia and IR in obese mice in a dose-dependent manner and improved glucose and insulin tolerance, and energy expenditure. RGS treatment significantly reduced lipid deposition and induced GLP-1 secretion in the intestine of wild-type mice but not in Tgr5ΔIN obese mice. Furthermore, RGS intervention increased BA levels in serum, ileum, and iWAT. The increase of circulating BAs in mice was related to the activation of ileal TGR5 and the promotion of ASBT translocation to the plasma membrane, thus affecting BA transport. Next, the increased level of circulating BAs entered the periphery, which might facilitate lipolysis and energy consumption by activating TGR5 in iWAT. CONCLUSION Our results demonstrated that RGS significantly alleviated HFD-induced obesity and insulin resistance in mice. RGS intervention improved glucose metabolism, promoted lipolysis, and energy metabolism by activating TGR5 in the intestine. In addition, we found that activating intestinal TGR5 facilitated the localization of ASBT to the plasma membrane, which ultimately promoted the transport of BAs to regulate metabolic phenotype.
Collapse
Affiliation(s)
- Wei Li
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Tongxi Zhuang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China; Department of Diabetes Complications and Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zixuan Wang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Longchan Liu
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Yixuan Luo
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Rufeng Wang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Linnan Li
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Institute of Diabetes Center, Beckman Research Institute, City of Hope National Medical Center, 1500 E. Duarte Road, Duarte, CA 91010, USA
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription, MOE Key Laboratory for Standardization of Chinese Medicines and SATCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicines, Shanghai 201203, China.
| |
Collapse
|
|
20
|
Gou X, Qin L, Wu D, Xie J, Lu Y, Zhang Q, He Y. Research Progress of Takeda G Protein-Coupled Receptor 5 in Metabolic Syndrome. Molecules 2023; 28:5870. [PMID: 37570840 PMCID: PMC10421342 DOI: 10.3390/molecules28155870] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2023] [Revised: 07/28/2023] [Accepted: 08/01/2023] [Indexed: 08/13/2023] Open
Abstract
Bile acids are acknowledged as signaling molecules involved in metabolic syndrome. The Takeda G protein-coupled receptor 5 (TGR5) functions as a significant bile acid receptor. The accumulated evidence suggests that TGR5 involves lipid homeostasis, glucose metabolism, and inflammation regulation. In line with this, recent preclinical studies also demonstrate that TGR5 plays a significant role in the generation and progression of metabolic syndrome, encompassing type 2 diabetes mellitus, obesity, atherosclerosis, and non-alcoholic fatty liver disease (NAFLD). In this review, we discuss the role of TGR5 in metabolic syndrome, illustrating the underlying mechanisms and therapeutic targets.
Collapse
Affiliation(s)
- Xianmei Gou
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Lin Qin
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Di Wu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Jian Xie
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Yanliu Lu
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
- Joint International Research Laboratory of Ethnomedicine of Ministry of Education, Zunyi Medical University, Zunyi 563000, China
| | - Qianru Zhang
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| | - Yuqi He
- Guizhou Engineering Research Center of Industrial Key-Technology for Dendrobium Nobile, Zunyi Medical University, Zunyi 563000, China
| |
Collapse
|
|
21
|
Pokhrel S, Dilts M, Stahl Z, Boehme S, Frame G, Chiang JY, Ferrell JM. Tgr5-/- mice are protected from ethanol-induced metabolic alterations through enhanced leptin and Fgf21 signaling. Hepatol Commun 2023; 7:e0138. [PMID: 37185802 PMCID: PMC10145946 DOI: 10.1097/hc9.0000000000000138] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2022] [Accepted: 02/23/2023] [Indexed: 05/17/2023] Open
Abstract
BACKGROUND Alcohol-associated liver disease (ALD) is caused by chronic use of alcohol and ranges from hepatic steatosis to fibrosis and cirrhosis. Bile acids are physiological detergents that also regulate hepatic glucose and lipid homeostasis by binding to several receptors. One such receptor, Takeda G protein-coupled receptor 5 (TGR5), may represent a therapeutic target for ALD. Here, we used a chronic 10-day + binge ethanol-feeding model in mice to study the role of TGR5 in alcohol-induced liver injury. METHODS Female C57BL/6J wild-type mice and Tgr5-/- mice were pair-fed Lieber-DeCarli liquid diet with ethanol (5% v/v) or isocaloric control diet for 10 days followed by a gavage of 5% ethanol or isocaloric maltose control, respectively, to represent a binge-drinking episode. Tissues were harvested 9 hours following the binge, and metabolic phenotypes were characterized through examination of liver, adipose, and brain mechanistic pathways. RESULTS Tgr5-/- mice were protected from alcohol-induced accumulation of hepatic triglycerides. Interestingly, liver and serum levels of Fgf21 were significantly increased during ethanol feeding in Tgr5-/- mice, as was phosphorylation of Stat3. Parallel to Fgf21 levels, increased leptin gene expression in white adipose tissue and increased leptin receptor in liver were detected in Tgr5-/- mice fed ethanol diet. Adipocyte lipase gene expression was significantly increased in Tgr5-/- mice regardless of diet, whereas adipose browning markers were also increased in ethanol-fed Tgr5-/- mice, indicating potential for enhanced white adipose metabolism. Lastly, hypothalamic mRNA targets of leptin, involved in the regulation of food intake, were significantly increased in Tgr5-/- mice fed ethanol diet. CONCLUSIONS Tgr5-/- mice are protected from ethanol-induced liver damage and lipid accumulation. Alterations in lipid uptake and Fgf21 signaling, and enhanced metabolic activity of white adipose tissue, may mediate these effects.
Collapse
Affiliation(s)
- Sabita Pokhrel
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Matthew Dilts
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Zachary Stahl
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Shannon Boehme
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Gabrielle Frame
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - John Y.L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| | - Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, USA
| |
Collapse
|
|
22
|
Chen N, Wang J, Zhou L, Hu B, Chen Y, Zhu Z. GPBAR1 is associated with asynchronous bone metastasis and poor prognosis of hepatocellular carcinoma. Front Oncol 2023; 12:1113785. [PMID: 36755861 PMCID: PMC9899898 DOI: 10.3389/fonc.2022.1113785] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2022] [Accepted: 12/30/2022] [Indexed: 01/24/2023] Open
Abstract
Background Hepatocellular carcinoma (HCC) is the second leading cause of cancer-related death in China. Asynchronous metastasis is the main reason for HCC recurrence, but the current assessment of HCC metastasis and prognosis is far from clinically satisfactory. Materials In our study, we investigated the expression of G-protein-coupled bile acid receptor (GPBAR1) in HCC tissues and tumor-adjacent tissues by qRT-PCR and immunohistochemistry. The associations between GPBAR1 expression, clinicopathological factors, and asynchronous metastases were assessed by the Chi-square test. The overall survival curves of different variables were plotted with the Kaplan-Meier method, and the statistical significance between different subgroups was analyzed with the log-rank test. The independent prognostic factors were identified by the Cox regression hazard model. Results GPBAR1 was more highly expressed in HCC tissues than in tumor-adjacent tissues. GPBAR1 expression in HCC was significantly higher than that in liver cirrhosis, followed by normal liver tissues. GPBAR1 was significantly associated with poor prognosis in HCC and can be regarded as an independent prognostic biomarker. Interestingly, GPBAR1 expression in HCC was significantly correlated with asynchronous metastasis to the bone but not to the liver or lung. Conclusions GPBAR1 was found to be an independent, unfavorable prognostic factor of HCC, as well as an indicator of asynchronous bone metastasis but not liver or lung metastases. Our results could provide a new aspect for HCC metastasis studies and help identify high-risk HCC patients, which helps ameliorate the prognostic assessment of HCC.
Collapse
Affiliation(s)
- Nan Chen
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong, China
| | - Jieqing Wang
- Department of Pharmacy, The Affiliated Taian City Central Hospital of Qingdao University, Tai'an, Shandong, China
| | - Lei Zhou
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong, China
| | - Baiqiang Hu
- Department of Orthopaedic Surgery, Yantai Yuhuangding Hospital, Yantai, Shandong, China
| | - Yinzhong Chen
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong, China
| | - Zhuangchen Zhu
- Department of Orthopaedic Surgery, The Second Affiliated Hospital of Shandong First Medical University, Tai'an, Shandong, China,*Correspondence: Zhuangchen Zhu,
| |
Collapse
|
|
23
|
Shi T, Malik A, Yang vom Hofe A, Matuschek L, Mullen M, Lages CS, Kudira R, Singh R, Zhang W, Setchell KD, Hildeman D, Pasare C, Wagner B, Miethke AG. Farnesoid X receptor antagonizes macrophage-dependent licensing of effector T lymphocytes and progression of sclerosing cholangitis. Sci Transl Med 2022; 14:eabi4354. [PMID: 36516265 PMCID: PMC9999117 DOI: 10.1126/scitranslmed.abi4354] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Immune-mediated bile duct epithelial injury and toxicity of retained hydrophobic bile acids drive disease progression in fibrosing cholangiopathies such as biliary atresia or primary sclerosing cholangitis. Emerging therapies include pharmacological agonists to farnesoid X receptor (FXR), the master regulator of hepatic synthesis, excretion, and intestinal reuptake of bile acids. Unraveling the mechanisms of action of pharmacological FXR agonists in the treatment of sclerosing cholangitis (SC), we found that intestinally restricted FXR activation effectively reduced bile acid pool size but did not improve the SC phenotype in MDR2-/- mice. In contrast, systemic FXR activation not only lowered bile acid synthesis but also suppressed proinflammatory cytokine production by liver-infiltrating inflammatory cells and blocked progression of hepatobiliary injury. The hepatoprotective activity was linked to suppressed production of IL1β and TNFα by hepatic macrophages and inhibition of TH1/TH17 lymphocyte polarization. Deletion of FXR in myeloid cells caused aberrant TH1 and TH17 lymphocyte responses in diethoxycarbonyl-1,4-dihydrocollidine-induced SC and rendered these mice resistant to the anti-inflammatory and liver protective effects of systemic FXR agonist treatment. Pharmacological FXR activation reduced IL1β and IFNγ production by liver- and blood-derived mononuclear cells from patients with fibrosing cholangiopathies. In conclusion, we demonstrate FXR to control the macrophage-TH1/17 axis, which is critically important for the progression of SC. Hepatic macrophages are cellular targets of systemic FXR agonist therapy for cholestatic liver disease.
Collapse
Affiliation(s)
- Tiffany Shi
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Astha Malik
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Annika Yang vom Hofe
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Louis Matuschek
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Mary Mullen
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Celine S. Lages
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Ramesh Kudira
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Ruchi Singh
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Wujuan Zhang
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Kenneth D.R. Setchell
- Department of Pathology and Laboratory Medicine, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| | - David Hildeman
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | - Chandrashekhar Pasare
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
- Division of Immunobiology, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
| | | | - Alexander G. Miethke
- Division of Gastroenterology, Hepatology, and Nutrition, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH 45229, USA
- Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH 45229, USA
| |
Collapse
|
|
24
|
Ferrell JM, Dilts M, Stahl Z, Boehme S, Pokhrel S, Wang X, Chiang JY. Altered serotonin metabolism in Takeda G protein-coupled receptor 5 knockout mice protects against diet-induced hepatic fibrosis. LIVER RESEARCH 2022; 6:214-226. [PMID: 39957909 PMCID: PMC11791863 DOI: 10.1016/j.livres.2022.11.009] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 06/15/2022] [Revised: 09/09/2022] [Accepted: 11/24/2022] [Indexed: 12/03/2022]
Abstract
Background and aims Diet-induced obesity and metabolic syndrome can trigger the progression of fatty liver disease to non-alcoholic steatohepatitis and fibrosis, which is a major public health concern. Bile acids regulate metabolic homeostasis and inflammation in the liver and gut via the activation of nuclear farnesoid X receptor (Fxr) and the membrane receptor Takeda G protein-coupled receptor 5 (Tgr5). Tgr5 is highly expressed in the gut and skeletal muscle, and in cholangiocytes and Kupffer cells of the liver. Tgr5 is implicated in the mediation of liver and gut inflammation, as well as the maintenance of energy homeostasis. Here, we used a high fat, high fructose, and high sucrose (HFS) diet to determine how bile acid signaling through Tgr5 may regulate metabolism during the progression from fatty liver to non-alcoholic steatohepatitis and fibrosis. Materials and methods Female C57BL/6J control wild type (WT) and Tgr5 knockout (Tgr5 -/-) mice were fed HFS (high fat (40% kcal), high fructose, and 20% sucrose water) diet for 20 weeks. Metabolic phenotypes were characterized through examination of bile acid synthesis pathways, lipid and cholesterol metabolism pathways, and fibrosis and inflammation pathways. Results Tgr5 -/- mice were more glucose intolerant when fed HFS diet, despite gaining the same amount of weight as WT mice. Tgr5 -/- mice accumulated significantly more hepatic cholesterol and triglycerides on HFS diet compared to WT mice, and gene expression of lipogenic genes was significantly upregulated. Hepatic cholesterol 7alpha-hydroxylase (Cyp7a1) gene expression was consistently elevated in Tgr5 -/- mice, while oxysterol 7alpha-hydroxylase (Cyp7b1), sterol 27-hydroxylase (Cyp27a1), Fxr, and small heterodimer partner (Shp) were downregulated by HFS diet. Surprisingly, hepatic inflammation and fibrosis were also significantly reduced in Tgr5 -/- mice fed HFS diet, which may be due to altered serotonin signaling in the liver. Conclusions Tgr5 -/- mice may be protected from high fat, high sugar-induced hepatic inflammation and injury due to altered serotonin metabolism.
Collapse
Affiliation(s)
- Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Matthew Dilts
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Zachary Stahl
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Shannon Boehme
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Sabita Pokhrel
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Xinwen Wang
- Department of Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - John Y.L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| |
Collapse
|
|
25
|
Bile acids and neurological disease. Pharmacol Ther 2022; 240:108311. [PMID: 36400238 DOI: 10.1016/j.pharmthera.2022.108311] [Citation(s) in RCA: 32] [Impact Index Per Article: 10.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2022] [Revised: 10/29/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022]
Abstract
This review will focus on how bile acids are being used in clinical trials to treat neurological diseases due to their central involvement with the gut-liver-brain axis and their physiological and pathophysiological roles in both normal brain function and multiple neurological diseases. The synthesis of primary and secondary bile acids species and how the regulation of the bile acid pool may differ between the gut and brain is discussed. The expression of several bile acid receptors in brain and their currently known functions along with the tools available to manipulate them pharmacologically are examined, together with discussion of the interaction of bile acids with the gut microbiome and their lesser-known effects upon brain glucose and lipid metabolism. How dysregulation of the gut microbiome, aging and sex differences may lead to disruption of bile acid signalling and possible causal roles in a number of neurological disorders are also considered. Finally, we discuss how pharmacological treatments targeting bile acid receptors are currently being tested in an array of clinical trials for several different neurodegenerative diseases.
Collapse
|
|
26
|
Abstract
Bile acids wear many hats, including those of an emulsifier to facilitate nutrient absorption, a cholesterol metabolite, and a signaling molecule in various tissues modulating itching to metabolism and cellular functions. Bile acids are synthesized in the liver but exhibit wide-ranging effects indicating their ability to mediate organ-organ crosstalk. So, how does a steroid metabolite orchestrate such diverse functions? Despite the inherent chemical similarity, the side chain decorations alter the chemistry and biology of the different bile acid species and their preferences to bind downstream receptors distinctly. Identification of new modifications in bile acids is burgeoning, and some of it is associated with the microbiota within the intestine. Here, we provide a brief overview of the history and the various receptors that mediate bile acid signaling in addition to its crosstalk with the gut microbiota.
Collapse
Affiliation(s)
| | | | - Sayeepriyadarshini Anakk
- Correspondence: Sayeepriyadarshini Anakk, PhD, Department of Molecular & Integrative Physiology, University of Illinois at Urbana-Champaign, 506 S Mathews Ave, 453 Medical Sciences Bldg, Urbana, IL 61801, USA.
| |
Collapse
|
|
27
|
Sun C, Wang Z, Hu L, Zhang X, Chen J, Yu Z, Liu L, Wu M. Targets of statins intervention in LDL-C metabolism: Gut microbiota. Front Cardiovasc Med 2022; 9:972603. [PMID: 36158845 PMCID: PMC9492915 DOI: 10.3389/fcvm.2022.972603] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2022] [Accepted: 08/08/2022] [Indexed: 11/13/2022] Open
Abstract
Increasing researches have considered gut microbiota as a new “metabolic organ,” which mediates the occurrence and development of metabolic diseases. In addition, the liver is an important organ of lipid metabolism, and abnormal lipid metabolism can cause the elevation of blood lipids. Among them, elevated low-density lipoprotein cholesterol (LDL-C) is related with ectopic lipid deposition and metabolic diseases, and statins are widely used to lower LDL-C. In recent years, the gut microbiota has been shown to mediate statins efficacy, both in animals and humans. The effect of statins on microbiota abundance has been deeply explored, and the pathways through which statins reduce the LDL-C levels by affecting the abundance of microbiota have gradually been explored. In this review, we discussed the interaction between gut microbiota and cholesterol metabolism, especially the cholesterol-lowering effect of statins mediated by gut microbiota, via AMPK-PPARγ-SREBP1C/2, FXR and PXR-related, and LPS-TLR4-Myd88 pathways, which may help to explain the individual differences in statins efficacy.
Collapse
Affiliation(s)
- ChangXin Sun
- Beijing University of Chinese Medicine, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - ZePing Wang
- Beijing University of Chinese Medicine, Beijing, China
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - LanQing Hu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - XiaoNan Zhang
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - JiYe Chen
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - ZongLiang Yu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
| | - LongTao Liu
- Xiyuan Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- *Correspondence: LongTao Liu
| | - Min Wu
- Guang'anmen Hospital, China Academy of Chinese Medical Sciences, Beijing, China
- Min Wu
| |
Collapse
|
|
28
|
Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 184] [Impact Index Per Article: 61.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
Collapse
Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
| |
Collapse
|
|
29
|
Duszka K. Versatile Triad Alliance: Bile Acid, Taurine and Microbiota. Cells 2022; 11:2337. [PMID: 35954180 PMCID: PMC9367564 DOI: 10.3390/cells11152337] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2022] [Revised: 07/21/2022] [Accepted: 07/24/2022] [Indexed: 11/21/2022] Open
Abstract
Taurine is the most abundant free amino acid in the body, and is mainly derived from the diet, but can also be produced endogenously from cysteine. It plays multiple essential roles in the body, including development, energy production, osmoregulation, prevention of oxidative stress, and inflammation. Taurine is also crucial as a molecule used to conjugate bile acids (BAs). In the gastrointestinal tract, BAs deconjugation by enteric bacteria results in high levels of unconjugated BAs and free taurine. Depending on conjugation status and other bacterial modifications, BAs constitute a pool of related but highly diverse molecules, each with different properties concerning solubility and toxicity, capacity to activate or inhibit receptors of BAs, and direct and indirect impact on microbiota and the host, whereas free taurine has a largely protective impact on the host, serves as a source of energy for microbiota, regulates bacterial colonization and defends from pathogens. Several remarkable examples of the interaction between taurine and gut microbiota have recently been described. This review will introduce the necessary background information and lay out the latest discoveries in the interaction of the co-reliant triad of BAs, taurine, and microbiota.
Collapse
Affiliation(s)
- Kalina Duszka
- Department of Nutritional Sciences, University of Vienna, 1090 Vienna, Austria
| |
Collapse
|
|
30
|
Chemometric Study, Homology Modeling of G Protein-Coupled Bile Acids Receptor (GPBAR_HUMAN) of Type-2 Diabetes Mellitus, Virtual Screening Evaluation, Drug-Likeness and ADME Prediction for Newly Designed Compounds. Macromol Res 2022. [DOI: 10.1007/s13233-022-0071-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/17/2022]
|
|
31
|
Thirouard L, Holota H, Monrose M, Garcia M, de Haze A, Damon‐Soubeyrand C, Renaud Y, Saru J, Perino A, Schoonjans K, Beaudoin C, Volle DH. Identification of a Crosstalk among TGR5, GLIS2, and TP53 Signaling Pathways in the Control of Undifferentiated Germ Cell Homeostasis and Chemoresistance. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2022; 9:e2200626. [PMID: 35435331 PMCID: PMC9189661 DOI: 10.1002/advs.202200626] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 02/01/2022] [Revised: 03/09/2022] [Indexed: 06/14/2023]
Abstract
Spermatogonial stem cells regenerate and maintain spermatogenesis throughout life, making testis a good model for studying stem cell biology. The effects of chemotherapy on fertility have been well-documented previously. This study investigates how busulfan, an alkylating agent that is often used for chemotherapeutic purposes, affects male fertility. Specifically, the role of the TGR5 pathway is investigated on spermatogonia homeostasis using in vivo, in vitro, and pharmacological methods. In vivo studies are performed using wild-type and Tgr5-deficient mouse models. The results clearly show that Tgr5 deficiency can facilitate restoration of the spermatogonia homeostasis and allow faster resurgence of germ cell lineage after exposure to busulfan. TGR5 modulates the expression of key genes of undifferentiated spermatogonia such as Gfra1 and Fgfr2. At the molecular level, the present data highlight molecular mechanisms underlying the interactions among the TGR5, GLIS2, and TP53 pathways in spermatogonia associated with germ cell apoptosis following busulfan exposure. This study makes a significant contribution to the literature because it shows that TGR5 plays key role on undifferentiated germ cell homeostasis and that modulating the TGR5 signaling pathway could be used as a potential therapeutic tool for fertility disorders.
Collapse
Affiliation(s)
- Laura Thirouard
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Hélène Holota
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Mélusine Monrose
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Manon Garcia
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Angélique de Haze
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | | | - Yoan Renaud
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteBio‐informatic facilityClermont‐FerrandF‐63037France
| | - Jean‐Paul Saru
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - Alessia Perino
- Laboratory of Metabolic SignalingInstitute of BioengineeringSchool of Life SciencesEcole Polytechnique Fédérale de LausanneLausanneCH‐1015Switzerland
| | - Kristina Schoonjans
- Laboratory of Metabolic SignalingInstitute of BioengineeringSchool of Life SciencesEcole Polytechnique Fédérale de LausanneLausanneCH‐1015Switzerland
| | - Claude Beaudoin
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| | - David H. Volle
- INSERM U1103Université Clermont AuvergneCNRS UMR‐6293GReD InstituteTeam‐VolleClermont‐FerrandF‐63037France
| |
Collapse
|
|
32
|
Ge YP, Chen WL, Sun M, Zhang L, Liu WB, Li XF. Molecular characterization of farnesoid X receptor alpha in Megalobrama amblycephala and its potential roles in high-carbohydrate diet-induced alterations of bile acid metabolism. J Steroid Biochem Mol Biol 2022; 219:106065. [PMID: 35091085 DOI: 10.1016/j.jsbmb.2022.106065] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/10/2021] [Revised: 12/24/2021] [Accepted: 01/23/2022] [Indexed: 11/22/2022]
Abstract
Farnesoid X receptorα (FXRα) plays a central role in maintaining the bile acid homeostasis in mammals, while relevant processes are still poorly interpreted in aquatic species. This study was conducted to characterize the fxrα gene in a cyprinidae species: blunt snout bream (Megalobrama amblycephala), and investigate its potential roles in bile acid metabolism. The Fxrα protein contains one DNA binding domain, one ligand binding domain, one His-Try "switch" and two modifies residues. A high degree of conservation (53.18-100.00 %) was observed in the Fxrα protein among most aquatic species and higher vertebrates. The transcription of fxrα was mainly observed in intestine, liver and kidney. Then fish (35.0 ± 0.15 g) were fed two diets containing 33 % and 45 % carbohydrate levels for 12weeks. High-carbohydrate diet significantly elevated the total cholesterol concentrations in plasma, liver and hindgut as well as the triglyceride concentrations in both liver and hindgut, but decreased the total bile acid concentrations in plasma, liver and hindgut. High dietary carbohydrate levels also significantly enhanced hepatic transcriptions of 3-hydroxy-3-methylglutaryl-CoA reductase (the rate-limiting enzyme in cholesterol synthesis), and those of fxrα (a bile acid receptor) and multidrug resistance associated protein 2 (a bile acid transporter) in hindgut. Furthermore, high dietary carbohydrate levels significantly decreased the transcriptions of cholesterol 7α-hydroxylase (the rate-limiting enzyme in bile acid synthesis) and organic anion-transporting polypeptides (a bile acid transporter) in liver as well as that of takeda G-protein-coupled bile acid receptor in hindgut. The results demonstrated that the fxrα gene of blunt snout bream is highly conserved compared with other vertebrates. Besides, high dietary carbohydrate levels increased total cholesterol concentrations, and up-regulated the transcription of fxrα, thus decreasing the biosynthesis and reabsorption of bile acids by mediating various target genes.
Collapse
Affiliation(s)
- Ya-Ping Ge
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Wei-Liang Chen
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Miao Sun
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Ling Zhang
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Wen-Bin Liu
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China
| | - Xiang-Fei Li
- Key Laboratory of Aquatic Nutrition and Feed Science of Jiangsu Province, College of Animal Science and Technology, Nanjing Agricultural University, No. 1 Weigang Road, Nanjing, 210095, People's Republic of China.
| |
Collapse
|
|
33
|
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.
Collapse
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.
| |
Collapse
|
|
34
|
Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
| |
Collapse
|
|
35
|
Zhang B, Kuipers F, de Boer JF, Kuivenhoven JA. Modulation of Bile Acid Metabolism to Improve Plasma Lipid and Lipoprotein Profiles. J Clin Med 2021; 11:jcm11010004. [PMID: 35011746 PMCID: PMC8745251 DOI: 10.3390/jcm11010004] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 12/15/2021] [Accepted: 12/16/2021] [Indexed: 02/06/2023] Open
Abstract
New drugs targeting bile acid metabolism are currently being evaluated in clinical studies for their potential to treat cholestatic liver diseases, non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH). Changes in bile acid metabolism, however, translate into an alteration of plasma cholesterol and triglyceride concentrations, which may also affect cardiovascular outcomes in such patients. This review attempts to gain insight into this matter and improve our understanding of the interactions between bile acid and lipid metabolism. Bile acid sequestrants (BAS), which bind bile acids in the intestine and promote their faecal excretion, have long been used in the clinic to reduce LDL cholesterol and, thereby, atherosclerotic cardiovascular disease (ASCVD) risk. However, BAS modestly but consistently increase plasma triglycerides, which is considered a causal risk factor for ASCVD. Like BAS, inhibitors of the apical sodium-dependent bile acid transporter (ASBTi’s) reduce intestinal bile acid absorption. ASBTi’s show effects that are quite similar to those obtained with BAS, which is anticipated when considering that accelerated faecal loss of bile acids is compensated by an increased hepatic synthesis of bile acids from cholesterol. Oppositely, treatment with farnesoid X receptor agonists, resulting in inhibition of bile acid synthesis, appears to be associated with increased LDL cholesterol. In conclusion, the increasing efforts to employ drugs that intervene in bile acid metabolism and signalling pathways for the treatment of metabolic diseases such as NAFLD warrants reinforcing interactions between the bile acid and lipid and lipoprotein research fields. This review may be considered as the first step in this process.
Collapse
Affiliation(s)
- Boyan Zhang
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
| | - Folkert Kuipers
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
| | - Jan Freark de Boer
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Department of Laboratory Medicine, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands
- Correspondence: (J.F.d.B.); (J.A.K.)
| | - Jan Albert Kuivenhoven
- Department of Pediatrics, University Medical Centre Groningen, University of Groningen, 9713 AV Groningen, The Netherlands; (B.Z.); (F.K.)
- Correspondence: (J.F.d.B.); (J.A.K.)
| |
Collapse
|
|
36
|
Fan M, Wang Y, Jin L, Fang Z, Peng J, Tu J, Liu Y, Zhang E, Xu S, Liu X, Huo Y, Sun Z, Chao X, Ding WX, Yan Q, Huang W. Bile Acid-Mediated Activation of Brown Fat Protects From Alcohol-Induced Steatosis and Liver Injury in Mice. Cell Mol Gastroenterol Hepatol 2021; 13:809-826. [PMID: 34896286 PMCID: PMC8802063 DOI: 10.1016/j.jcmgh.2021.12.001] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Revised: 11/30/2021] [Accepted: 12/01/2021] [Indexed: 12/11/2022]
Abstract
BACKGROUND & AIMS Alcohol-associated liver disease (AALD) is one of the most common causes of liver injury and failure. Limited knowledge of the mechanisms underlying AALD impedes the development of efficacious therapies. Bile acid (BA) signaling was shown to participate in the progression of AALD. However, the mechanisms remain poorly understood. METHODS C57BL/6J wild-type (WT), Takeda G-protein-coupled bile acid receptor 5 (TGR5) knockout (KO) and brown adipose tissue (BAT)-specific TGR5 knockdown mice were subjected to ethanol feeding-induced AALD. Liver samples from alcoholic hepatitis patients were used to examine the BA circulation signaling. Human Embryonic Kidney Cells 293 were used for the TGR5 reporter assay. 23(S)-methyl-lithocholic acid was used as a molecular tool to confirm the regulatory functions of BAT in the AALD mouse model. RESULTS Ethanol feeding increased the expression of the thermogenesis genes downstream of TGR5 in BAT of WT, but not TGR5 KO, mice. TGR5 deficiency significantly blocked BAT activity and energy expenditure in mice after ethanol feeding. Alcohol increased serum BA levels in mice and human beings through altering BA transportation, and the altered BAs activated TGR5 signaling to regulate metabolism. Compared with ethanol-fed WT mice, ethanol-fed TGR5 KO mice showed less free fatty acid (FFA) β-oxidation in BAT, leading to higher levels of FFA in the circulation, increased liver uptake of FFAs, and exacerbated AALD. BAT-specific TGR5 knockdown mice showed similar results with TGR5 KO mice in AALD. Agonist treatment significantly activated TGR5 signaling in BAT, increased thermogenesis, reduced serum FFA level, and ameliorated hepatic steatosis and injury in AALD mice, while these effects were lost in TGR5 KO mice. CONCLUSIONS BA signaling plays a protective role in AALD by enhancing BAT thermogenesis. Targeting TGR5 in BAT may be a promising approach for the treatment of AALD.
Collapse
Affiliation(s)
- Mingjie Fan
- College of Life Science, Zhejiang University, Hangzhou, Zhejiang, China,Department of Diabetes Complications and Metabolism, Duarte, California
| | - Yangmeng Wang
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Lihua Jin
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Zhipeng Fang
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Jiangling Peng
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Jui Tu
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Yanjun Liu
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Eryun Zhang
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Senlin Xu
- Department of Diabetes Complications and Metabolism, Duarte, California,Graduate School of Biological Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, California
| | - Xiaoqian Liu
- Department of Diabetes Complications and Metabolism, Duarte, California
| | - Yuqing Huo
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Zhaoli Sun
- Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, Maryland
| | - Xiaojuan Chao
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Wen-Xing Ding
- Department of Pharmacology, Toxicology and Therapeutics, University of Kansas Medical Center, Kansas City, Kansas
| | - Qingfeng Yan
- College of Life Science, Zhejiang University, Hangzhou, Zhejiang, China,Qingfeng Yan, PhD, College of Life Science, Zhejiang University, Hangzhou, 310058 Zhejiang, China. fax: 01186-571-88206646.
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Duarte, California,Graduate School of Biological Science, Beckman Research Institute, City of Hope National Medical Center, Duarte, California,Correspondence Address correspondence to: Wendong Huang, PhD, Department of Diabetes Complications and Metabolism, Beckman Research Institute, City of Hope National Medical Center, Duarte, California 91010. fax: (626) 256-8704.
| |
Collapse
|
|
37
|
Strassheim D, Sullivan T, Irwin DC, Gerasimovskaya E, Lahm T, Klemm DJ, Dempsey EC, Stenmark KR, Karoor V. Metabolite G-Protein Coupled Receptors in Cardio-Metabolic Diseases. Cells 2021; 10:3347. [PMID: 34943862 PMCID: PMC8699532 DOI: 10.3390/cells10123347] [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: 10/10/2021] [Revised: 11/10/2021] [Accepted: 11/18/2021] [Indexed: 12/15/2022] Open
Abstract
G protein-coupled receptors (GPCRs) have originally been described as a family of receptors activated by hormones, neurotransmitters, and other mediators. However, in recent years GPCRs have shown to bind endogenous metabolites, which serve functions other than as signaling mediators. These receptors respond to fatty acids, mono- and disaccharides, amino acids, or various intermediates and products of metabolism, including ketone bodies, lactate, succinate, or bile acids. Given that many of these metabolic processes are dysregulated under pathological conditions, including diabetes, dyslipidemia, and obesity, receptors of endogenous metabolites have also been recognized as potential drug targets to prevent and/or treat metabolic and cardiovascular diseases. This review describes G protein-coupled receptors activated by endogenous metabolites and summarizes their physiological, pathophysiological, and potential pharmacological roles.
Collapse
Affiliation(s)
- Derek Strassheim
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Timothy Sullivan
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - David C. Irwin
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Evgenia Gerasimovskaya
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Tim Lahm
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
| | - Dwight J. Klemm
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Edward C. Dempsey
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Rocky Mountain Regional VA Medical Center, Aurora, CO 80045, USA
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| | - Kurt R. Stenmark
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
| | - Vijaya Karoor
- Department of Medicine Cardiovascular and Pulmonary Research Laboratory, University of Colorado Denver, Denver, CO 80204, USA; (D.S.); (T.S.); (D.C.I.); (E.G.); (D.J.K.); (E.C.D.); (K.R.S.)
- Division of Pulmonary, Critical Care and Sleep Medicine, National Jewish Health Denver, Denver, CO 80206, USA;
- Division of Pulmonary Sciences and Critical Care Medicine, School of Medicine, University of Colorado, Anschutz Medical Campus, Aurora, CO 80045, USA
| |
Collapse
|
|
38
|
Simbrunner B, Trauner M, Reiberger T. Review article: therapeutic aspects of bile acid signalling in the gut-liver axis. Aliment Pharmacol Ther 2021; 54:1243-1262. [PMID: 34555862 PMCID: PMC9290708 DOI: 10.1111/apt.16602] [Citation(s) in RCA: 56] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2021] [Revised: 08/29/2021] [Accepted: 08/31/2021] [Indexed: 12/13/2022]
Abstract
BACKGROUND Bile acids are important endocrine modulators of intestinal and hepatic signalling cascades orchestrating critical pathophysiological processes in various liver diseases. Increasing knowledge on bile acid signalling has stimulated the development of synthetic ligands of nuclear bile acid receptors and other bile acid analogues. AIM This review summarises important aspects of bile acid-mediated crosstalk between the gut and the liver ("gut-liver axis") as well as recent findings from experimental and clinical studies. METHODS We performed a literature review on bile acid signalling, and therapeutic applications in chronic liver disease. RESULTS Intestinal and hepatic bile acid signalling pathways maintain bile acid homeostasis. Perturbations of bile acid-mediated gut-liver crosstalk dysregulate transcriptional networks involved in inflammation, fibrosis and endothelial dysfunction. Bile acids induce enterohepatic feedback signalling by the release of intestinal hormones, and regulate enterohepatic circulation. Importantly, bile acid signalling plays a central role in maintaining intestinal barrier integrity and antibacterial defense, which is particularly relevant in cirrhosis, where bacterial translocation has a profound impact on disease progression. The nuclear bile acid farnesoid X receptor (FXR) is a central intersection in bile acid signalling and has emerged as a relevant therapeutic target. CONCLUSIONS Experimental evidence suggests that bile acid signalling improves the intestinal barrier and protects against bacterial translocation in cirrhosis. FXR agonists have displayed efficacy for the treatment of cholestatic and metabolic liver disease in randomised controlled clinical trials. However, similar effects remain to be shown in advanced liver disease, particularly in patients with decompensated cirrhosis.
Collapse
Affiliation(s)
- Benedikt Simbrunner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| | - Michael Trauner
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria
| | - Thomas Reiberger
- Division of Gastroenterology and HepatologyDepartment of Internal Medicine IIIMedical University of ViennaViennaAustria,Vienna Hepatic Hemodynamic LabMedical University of ViennaViennaAustria,Christian‐Doppler Laboratory for Portal Hypertension and Liver FibrosisMedical University of ViennaViennaAustria
| |
Collapse
|
|
39
|
Yun Y, Zhang C, Guo S, Liang X, Lan Y, Wang M, Zhuo N, Yin J, Liu H, Gu M, Li J, Xie X, Nan F. Identification of Betulinic Acid Derivatives as Potent TGR5 Agonists with Antidiabetic Effects via Humanized TGR5 H88Y Mutant Mice. J Med Chem 2021; 64:12181-12199. [PMID: 34406006 DOI: 10.1021/acs.jmedchem.1c00851] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
Takeda G protein-coupled receptor 5 (TGR5) is a promising target for treating metabolic syndrome and inflammatory diseases. Herein, we identified a new series of betulinic acid derivatives as potent TGR5 agonists, which show remarkable activity on human (h) and canine (c) TGR5 but exhibit unpromising activity on murine (m) TGR5. Species difference was also observed with many other reported TGR5 agonists. Therefore, we screened 29 amino acids which were conserved in hTGR5 and cTGR5 but different in mTGR5 and found a key amino acid, H88 in mTGR5 (Y89 in hTGR5), which contributed to the species difference. With the CRISPR/Cas9 system, the mTGR5H88Y mutation was introduced into mice, and the optimized compound 11d-Na displayed a significant glucose-lowering effect and stimulated GLP-1 and insulin secretion in TGR5H88Y mice but not in wild-type animals. Taken together, our study provides a useful tool to bridge the gap of species difference and discovers a potent TGR5 agonist for further investigation.
Collapse
Affiliation(s)
- Ying Yun
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China
| | - Chenlu Zhang
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Shimeng Guo
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Xiaoying Liang
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Yuan Lan
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China
| | - Min Wang
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Ning Zhuo
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jianpeng Yin
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, China
| | - Huanan Liu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Min Gu
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Jing Li
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
| | - Xin Xie
- CAS Key Laboratory of Receptor Research, the National Center for Drug Screening, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China
- School of Chinese Materia Medica, Nanjing University of Chinese Medicine, Nanjing 210046, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
| | - Fajun Nan
- University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, P. R. China
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
- School of Pharmaceutical Science and Technology, Hangzhou Institute for Advanced Study, University of Chinese Academy of Sciences, Hangzhou 310024, China
- Yantai Key Laboratory of Nanomedicine & Advanced Preparations, Yantai Institute of Materia Medica, Shandong 264000, China
| |
Collapse
|
|
40
|
Gertzen CGW, Gohlke H, Häussinger D, Herebian D, Keitel V, Kubitz R, Mayatepek E, Schmitt L. The many facets of bile acids in the physiology and pathophysiology of the human liver. Biol Chem 2021; 402:1047-1062. [PMID: 34049433 DOI: 10.1515/hsz-2021-0156] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2021] [Accepted: 05/14/2021] [Indexed: 12/12/2022]
Abstract
Bile acids perform vital functions in the human liver and are the essential component of bile. It is therefore not surprising that the biology of bile acids is extremely complex, regulated on different levels, and involves soluble and membrane receptors as well as transporters. Hereditary disorders of these proteins manifest in different pathophysiological processes that result in liver diseases of varying severity. In this review, we summarize our current knowledge of the physiology and pathophysiology of bile acids with an emphasis on recently established analytical approaches as well as the molecular mechanisms that underlie signaling and transport of bile acids. In this review, we will focus on ABC transporters of the canalicular membrane and their associated diseases. As the G protein-coupled receptor, TGR5, receives increasing attention, we have included aspects of this receptor and its interaction with bile acids.
Collapse
Affiliation(s)
- Christoph G W Gertzen
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- Center for Structural Studies (CSS), Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Holger Gohlke
- Institute of Pharmaceutical and Medicinal Chemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
- John von Neumann Institute for Computing (NIC), Jülich Supercomputing Centre (JSC), Institute of Biological Information Processing (IBI-7: Structural Biochemistry), Institute of Bio- and Geosciences (IBG-4: Bioinformatics), Forschungszentrum Jülich GmbH, Jülich, Germany
| | - Dieter Häussinger
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Diran Herebian
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Verena Keitel
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ralf Kubitz
- Department of Gastroenterology, Hepatology and Infectious Diseases, University Hospital Düsseldorf, Düsseldorf, Germany
| | - Ertan Mayatepek
- Department of General Pediatrics, Neonatology and Pediatric Cardiology, Medical Faculty, University Hospital Düsseldorf, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| | - Lutz Schmitt
- Institute of Biochemistry, Heinrich Heine University Düsseldorf, Düsseldorf, Germany
| |
Collapse
|
|
41
|
Dicks N, Gutierrez K, Currin L, de Macedo MP, Glanzner WG, Mondadori RG, Michalak M, Agellon LB, Bordignon V. Tauroursodeoxycholic acid/TGR5 signaling promotes survival and early development of glucose-stressed porcine embryos†. Biol Reprod 2021; 105:76-86. [PMID: 33889948 PMCID: PMC8256098 DOI: 10.1093/biolre/ioab072] [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: 11/23/2020] [Revised: 03/24/2021] [Accepted: 04/12/2021] [Indexed: 01/21/2023] Open
Abstract
Conditions of impaired energy and nutrient homeostasis, such as diabetes and obesity, are associated with infertility. Hyperglycemia increases endoplasmic reticulum stress as well as oxidative stress and reduces embryo development and quality. Oxidative stress also causes deoxyribonucleic acid damage, which impairs embryo quality and development. The natural bile acid tauroursodeoxycholic acid reduces endoplasmic reticulum stress and rescues developmentally incompetent late-cleaving embryos, as well as embryos subjected to nuclear stress, suggesting the endoplasmic reticulum stress response, or unfolded protein response, and the genome damage response are linked. Tauroursodeoxycholic acid acts via the Takeda-G-protein-receptor-5 to alleviate nuclear stress in embryos. To evaluate the role of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling in embryo unfolded protein response, we used a model of glucose-induced endoplasmic reticulum stress. Embryo development was impaired by direct injection of tauroursodeoxycholic acid into parthenogenetically activated oocytes, whereas it was improved when tauroursodeoxycholic acid was added to the culture medium. Attenuation of the Takeda-G-protein-receptor-5 precluded the positive effect of tauroursodeoxycholic acid supplementation on development of parthenogenetically activated and fertilized embryos cultured under standard conditions and parthenogenetically activated embryos cultured with excess glucose. Moreover, attenuation of tauroursodeoxycholic acid/Takeda-G-protein-receptor-5 signaling induced endoplasmic reticulum stress, oxidative stress and cell survival genes, but decreased expression of pluripotency genes in parthenogenetically activated embryos cultured under excess glucose conditions. These data suggest that Takeda-G-protein-receptor-5 signaling pathways link the unfolded protein response and genome damage response. Furthermore, this study identifies Takeda-G-protein-receptor-5 signaling as a potential target for mitigating fertility issues caused by nutrient excess-associated blastomere stress and embryo death.
Collapse
Affiliation(s)
- Naomi Dicks
- Department of Animal Science, McGill University, Quebec, Canada
| | | | - Luke Currin
- Department of Animal Science, McGill University, Quebec, Canada
| | | | | | - Rafael G Mondadori
- Department of Animal Science, McGill University, Quebec, Canada
- ReproPel, Federal University of Pelotas, Pelotas, Rio Grande do Sul, Brazil
| | - Marek Michalak
- Department of Biochemistry, University of Alberta, Edmonton, Alberta, Canada
| | - Luis B Agellon
- School of Human Nutrition, McGill University, Quebec, Canada
| | | |
Collapse
|
|
42
|
Abstract
Bile acids (BAs) are a family of hydroxylated steroids secreted by the liver that aid in the breakdown and absorption of dietary fats. BAs also function as nutrient and inflammatory signaling molecules, acting through cognate receptors, to coordinate host metabolism. Commensal bacteria in the gastrointestinal tract are functional modifiers of the BA pool, affecting composition and abundance. Deconjugation of host BAs creates a molecular network that inextricably links gut microtia with their host. In this review we highlight the roles of BAs in mediating this mutualistic relationship with a focus on those events that impact host physiology and metabolism.
Collapse
Affiliation(s)
- James C Poland
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| | - C Robb Flynn
- Department of Surgery, Vanderbilt University Medical Center, Nashville, Tennessee
| |
Collapse
|
|
43
|
Tang S, Zhong R, Yin C, Su D, Xie J, Chen L, Liu L, Zhang H. Exposure to High Aerial Ammonia Causes Hindgut Dysbiotic Microbiota and Alterations of Microbiota-Derived Metabolites in Growing Pigs. Front Nutr 2021; 8:689818. [PMID: 34179063 PMCID: PMC8231926 DOI: 10.3389/fnut.2021.689818] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Accepted: 05/13/2021] [Indexed: 12/12/2022] Open
Abstract
Ammonia, an atmospheric pollutant in the air, jeopardizes immune function, and perturbs metabolism, especially lipid metabolism, in human and animals. The roles of intestinal microbiota and its metabolites in maintaining or regulating immune function and metabolism are irreplaceable. Therefore, this study aimed to investigate how aerial ammonia exposure influences hindgut microbiota and its metabolites in a pig model. Twelve growing pigs were treated with or without aerial ammonia (35 mg/m3) for 25 days, and then microbial diversity and microbiota-derived metabolites were measured. The results demonstrated a decreasing trend in leptin (p = 0.0898) and reduced high-density lipoprotein cholesterol (HDL-C, p = 0.0006) in serum after ammonia exposure. Besides, an upward trend in hyocholic acid (HCA), lithocholic acid (LCA), hyodeoxycholic acid (HDCA) (p < 0.1); a downward trend in tauro-deoxycholic acid (TDCA, p < 0.1); and a reduced tauro-HDCA (THDCA, p < 0.05) level were found in the serum bile acid (BA) profiles after ammonia exposure. Ammonia exposure notably raised microbial alpha-diversity with higher Sobs, Shannon, or ACE index in the cecum or colon and the Chao index in the cecum (p < 0.05) and clearly exhibited a distinct microbial cluster in hindgut indicated by principal coordinate analysis (p < 0.01), indicating that ammonia exposure induced alterations of microbial community structure and composition in the hindgut. Further analysis displayed that ammonia exposure increased the number of potentially harmful bacteria, such as Negativibacillus, Alloprevotella, or Lachnospira, and decreased the number of beneficial bacteria, such as Akkermansia or Clostridium_sensu_stricto_1, in the hindgut (FDR < 0.05). Analysis of microbiota-derived metabolites in the hindgut showed that ammonia exposure increased acetate and decreased isobutyrate or isovalerate in the cecum or colon, respectively (p < 0.05). Unlike the alteration of serum BA profiles, cecal BA data showed that high ammonia exposure had a downward trend in cholic acid (CA), HCA, and LCA (p < 0.1); a downward trend in deoxycholic acid (DCA) and HDCA (p < 0.05); and an upward trend in glycol-chenodeoxycholic acid (GCDCA, p < 0.05). Mantel test and correlation analysis revealed associations between microbiota-derived metabolites and ammonia exposure-responsive cecal bacteria. Collectively, the findings illustrated that high ammonia exposure induced the dysbiotic microbiota in the hindgut, thereby affecting the production of microbiota-derived short-chain fatty acids and BAs, which play a pivotal role in the modulation of host systematic metabolism.
Collapse
Affiliation(s)
- Shanlong Tang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Ruqing Zhong
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Chang Yin
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Dan Su
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China.,College of Animal Science and Technology, Qingdao Agricultural University, Qingdao, China
| | - Jingjing Xie
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Liang Chen
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Lei Liu
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| | - Hongfu Zhang
- State Key Laboratory of Animal Nutrition, Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing, China
| |
Collapse
|
|
44
|
Ding L, Yang Q, Zhang E, Wang Y, Sun S, Yang Y, Tian T, Ju Z, Jiang L, Wang X, Wang Z, Huang W, Yang L. Notoginsenoside Ft1 acts as a TGR5 agonist but FXR antagonist to alleviate high fat diet-induced obesity and insulin resistance in mice. Acta Pharm Sin B 2021; 11:1541-1554. [PMID: 34221867 PMCID: PMC8245856 DOI: 10.1016/j.apsb.2021.03.038] [Citation(s) in RCA: 70] [Impact Index Per Article: 17.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2021] [Revised: 03/07/2021] [Accepted: 03/10/2021] [Indexed: 02/08/2023] Open
Abstract
Obesity and its associated complications are highly related to a current public health crisis around the world. A growing body of evidence has indicated that G-protein coupled bile acid (BA) receptor TGR5 (also known as Gpbar-1) is a potential drug target to treat obesity and associated metabolic disorders. We have identified notoginsenoside Ft1 (Ft1) from Panax notoginseng as an agonist of TGR5 in vitro. However, the pharmacological effects of Ft1 on diet-induced obese (DIO) mice and the underlying mechanisms are still elusive. Here we show that Ft1 (100 mg/100 diet) increased adipose lipolysis, promoted fat browning in inguinal adipose tissue and induced glucagon-like peptide-1 (GLP-1) secretion in the ileum of wild type but not Tgr5 -/- obese mice. In addition, Ft1 elevated serum free and taurine-conjugated bile acids (BAs) by antagonizing Fxr transcriptional activities in the ileum to activate Tgr5 in the adipose tissues. The metabolic benefits of Ft1 were abolished in Cyp27a1 -/- mice which have much lower BA levels. These results identify Ft1 as a single compound with opposite activities on two key BA receptors to alleviate high fat diet-induced obesity and insulin resistance in mice.
Collapse
Key Words
- ANOVA, analysis of variance
- AUC, area under the curve
- BAT, brown adipose tissue
- BAs, bile acids
- Bile acids
- DIO, diet-induced obesity
- FGF, fibroblast growth factor
- FXR
- Ft1, notoginsenoside Ft1
- Fxr, nuclear farnesoid X receptor
- GLP-1
- GLP-1, glucagon-like peptide-1
- GTT, glucose tolerance test
- HFD, high fat diet
- ITT, insulin tolerance test
- Insulin resistance
- KO, knockout
- Metabolic disorders
- Notoginsenoside Ft1
- Obesity
- TGR5
- Tgr5, membrane-bound G protein-coupled receptor
- Ucp, uncoupling protein
- Wt, wild-type
- cAMP, adenosine 3′,5′ cyclic monophosphate
- eWAT, epididymal white adipose tissue
- iWAT, inguinal white adipose tissue
Collapse
Affiliation(s)
- Lili Ding
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Qiaoling Yang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
- Department of Pharmacy, Shanghai Children's Hospital, Shanghai Jiao Tong University, Shanghai 200040, China
| | - Eryun Zhang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yangmeng Wang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Siming Sun
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Yingbo Yang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Tong Tian
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengcai Ju
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Linshan Jiang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Xunjiang Wang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Wendong Huang
- Department of Diabetes Complications and Metabolism, Diabetes and Metabolism Research Institute, Beckman Research Institute, City of Hope National Medical Center, Duarte, CA 91010, USA
- Graduate School of Biological Science, City of Hope National Medical Center, Duarte, CA 91010, USA
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescriptions and MOE Key Laboratory for Standardization of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
- Institute of Interdisciplinary Integrative Medicine Research, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| |
Collapse
|
|
45
|
Wang H, Tan YZ, Mu RH, Tang SS, Liu X, Xing SY, Long Y, Yuan DH, Hong H. Takeda G Protein-Coupled Receptor 5 Modulates Depression-like Behaviors via Hippocampal CA3 Pyramidal Neurons Afferent to Dorsolateral Septum. Biol Psychiatry 2021; 89:1084-1095. [PMID: 33536132 DOI: 10.1016/j.biopsych.2020.11.018] [Citation(s) in RCA: 49] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/07/2020] [Revised: 11/03/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Takeda G protein-coupled receptor 5 (TGR5) is recognized as a promising target for type 2 diabetes and metabolic syndrome; its expression has been demonstrated in the brain and is thought to be neuroprotective. Here, we hypothesize that dysfunction of central TGR5 may contribute to the pathogenesis of depression. METHODS In well-established chronic social defeat stress (CSDS) and chronic restraint stress (CRS) models of depression, we investigated the functional roles of TGR5 in CA3 pyramidal neurons (PyNs) and underlying mechanisms of the neuronal circuit in depression (for in vivo studies, n = 10; for in vitro studies, n = 5-10) using fiber photometry; optogenetic, chemogenetic, pharmacological, and molecular profiling techniques; and behavioral tests. RESULTS Both CSDS and CRS most significantly reduced TGR5 expression of hippocampal CA3 PyNs. Genetic overexpression of TGR5 in CA3 PyNs or intra-CA3 infusion of INT-777, a specific agonist, protected against CSDS and CRS, exerting significant antidepressant-like effects that were mediated via CA3 PyN activation. Conversely, genetic knockout or TGR5 knockdown in CA3 facilitated stress-induced depression-like behaviors. Re-expression of TGR5 in CA3 PyNs rather than infusion of INT-777 significantly improved depression-like behaviors in Tgr5 knockout mice exposed to CSDS or CRS. Silencing and stimulation of CA3 PyNs→somatostatin-GABAergic (gamma-aminobutyric acidergic) neurons of the dorsolateral septum circuit bidirectionally regulated depression-like behaviors, and blockade of this circuit abrogated the antidepressant-like effects from TGR5 activation of CA3 PyNs. CONCLUSIONS These findings indicate that TGR5 can regulate depression via CA3 PyNs→somatostatin-GABAergic neurons of dorsolateral septum transmission, suggesting that TGR5 could be a novel target for developing antidepressants.
Collapse
Affiliation(s)
- Hao Wang
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Yuan-Zhi Tan
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Rong-Hao Mu
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Su-Su Tang
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Xiao Liu
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Shu-Yun Xing
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Yan Long
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Dan-Hua Yuan
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China
| | - Hao Hong
- Department of Pharmacology, Key Laboratory of Neuropsychiatric Diseases, China Pharmaceutical University, Nanjing, China.
| |
Collapse
|
|
46
|
Miyata S, Kawashima Y, Sakai M, Matsubayashi M, Motoki K, Miyajima Y, Watanabe Y, Chikamatsu N, Taniguchi T, Tokuyama R. Discovery, optimization, and evaluation of non-bile acid FXR/TGR5 dual agonists. Sci Rep 2021; 11:9196. [PMID: 33911126 PMCID: PMC8080777 DOI: 10.1038/s41598-021-88493-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2020] [Accepted: 04/13/2021] [Indexed: 02/06/2023] Open
Abstract
Although several potent bile acid Farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1) dual agonists such as INT-767 have been reported, no non-bile acid FXR/TGR5 dual agonist has been investigated to date. Therefore, we attempted to discover potent non-bile acid FXR/TGR5 dual agonists and identified some non-bile acid FXR/TGR5 dual agonists, such as isonicotinamide derivatives in vitro assay. Compound 20p was evaluated in C57BL/6J mice, that were administered a choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) consisting of 60 kcal% fat and 0.1% methionine by weight for one week. Compound 20p dose-dependently induced small heterodimer partner (SHP) mRNA and decreased cytochrome P450 7A1 (CYP7A1) in the liver at 10 and 30 mg/kg, respectively, which were used as FXR agonist markers. Compound 20p significantly increased the plasma levels of GLP-1 as a TGR5 agonist, and a high concentration of GLP-1 lowered blood glucose levels. We confirmed that compound 20p was a non-bile acid FXR/TGR5 dual agonist.
Collapse
Affiliation(s)
- Sachiho Miyata
- Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan.
| | - Yuji Kawashima
- Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan
| | - Miku Sakai
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Masaya Matsubayashi
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Keisuke Motoki
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Yui Miyajima
- Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan
| | - Yousuke Watanabe
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Noriko Chikamatsu
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Tetsuya Taniguchi
- Research Laboratory 2, FUJI YAKUHIN. CO., LTD, Nishi-ku, Iida-Shinden, Saitama City, Saitama, 636-1, Japan
| | - Ryukou Tokuyama
- Research Laboratory 1, FUJI YAKUHIN. CO., LTD, 1-32-3, Nishi-Omiya, Nishi-ku, Saitama City, Saitama, Japan.
| |
Collapse
|
|
47
|
Alterations of gut microbiota and serum bile acids are associated with parenteral nutrition-associated liver disease. J Pediatr Surg 2021; 56:738-744. [PMID: 32732165 DOI: 10.1016/j.jpedsurg.2020.06.035] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2020] [Revised: 06/10/2020] [Accepted: 06/22/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Parenteral nutrition-associated liver disease (PNALD) is a major complication of long-term parenteral nutrition (PN). The pathogenesis of PNALD remains unclear. We investigated the changes in taxonomic and functional composition of gut microbiota and serum bile acid levels in a rat model of PNALD. METHODS Male 4-week-old Sprague Dawley rats received either total parenteral nutrition or standard chow with 0.9% saline for 7 days. The taxonomic composition of cecal microbiota and its functional composition associated with bile acid metabolism were measured. RESULTS There were differences in taxonomic composition between the two groups. The abundance of the secondary bile acid biosynthesis pathway was higher in the TPN group (p < 0.05) with an increase in the percentage of bacteria expressing 7-alpha-hydroxysteroid dehydrogenase (p < 0.05). The abundance of enzymes associated with bile salt hydrolase was also higher (p < 0.05) in the TPN group. The TPN group showed a distinct bile acid profile characterized by a higher ratio of secondary bile acids to primary bile acids. CONCLUSIONS The alteration of bile acid-associated microbiota may lead to increased secondary bile acid production in a rat model of PNALD.
Collapse
|
|
48
|
Zhao S, Li X, Peng W, Wang L, Ye W, Zhao Y, Yin W, Chen WD, Li W, Wang YD. Ligand-based pharmacophore modeling, virtual screening and biological evaluation to identify novel TGR5 agonists. RSC Adv 2021; 11:9403-9409. [PMID: 35423434 PMCID: PMC8695346 DOI: 10.1039/d0ra10168k] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Accepted: 02/19/2021] [Indexed: 12/28/2022] Open
Abstract
Takeda G-protein-coupled receptor 5 (TGR5) is emerging as an important and promising target for the development of anti-diabetic drugs. To understand the structural characteristics of TGR5 agonists, the common feature pharmacophore models were generated and molecular docking was performed. The ligand-based virtual screening combined with pharmacophore mapping and molecular docking was performed to identify novel nonsteroidal TGR5 agonists. Finally, 20 compounds were screened for in vitro TGR5 agonistic activity assay, and results showed most compounds exhibiting TGR5 agonistic activity at 40 μM. Among these compounds, V12 and V14 displayed obvious TGR5 agonist activity, with the EC50 values of 19.5 μM and 7.7 μM, respectively. Compounds V12 and V14 could be considered potential TGR5 agonist candidates and also may be used as initial hits for developing novel TGR5 agonists.
Collapse
Affiliation(s)
- Shizhen Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Xinping Li
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wenjing Peng
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Le Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wenling Ye
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Yang Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wenbo Yin
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
- Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University Hohhot China
| | - Weiguo Li
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing China
| |
Collapse
|
|
49
|
Fiorucci S, Distrutti E, Carino A, Zampella A, Biagioli M. Bile acids and their receptors in metabolic disorders. Prog Lipid Res 2021; 82:101094. [PMID: 33636214 DOI: 10.1016/j.plipres.2021.101094] [Citation(s) in RCA: 153] [Impact Index Per Article: 38.3] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2020] [Revised: 02/03/2021] [Accepted: 02/12/2021] [Indexed: 02/08/2023]
Abstract
Bile acids are a large family of atypical steroids which exert their functions by binding to a family of ubiquitous cell membrane and nuclear receptors. There are two main bile acid activated receptors, FXR and GPBAR1, that are exclusively activated by bile acids, while other receptors CAR, LXRs, PXR, RORγT, S1PR2and VDR are activated by bile acids in addition to other more selective endogenous ligands. In the intestine, activation of FXR and GPBAR1 promotes the release of FGF15/19 and GLP1 which integrate their signaling with direct effects exerted by theother receptors in target tissues. This network is tuned in a time ordered manner by circadian rhythm and is critical for the regulation of metabolic process including autophagy, fast-to-feed transition, lipid and glucose metabolism, energy balance and immune responses. In the last decade FXR ligands have entered clinical trials but development of systemic FXR agonists has been proven challenging because their side effects including increased levels of cholesterol and Low Density Lipoproteins cholesterol (LDL-c) and reduced High-Density Lipoprotein cholesterol (HDL-c). In addition, pruritus has emerged as a common, dose related, side effect of FXR ligands. Intestinal-restricted FXR and GPBAR1 agonists and dual FXR/GPBAR1 agonists have been developed. Here we review the last decade in bile acids physiology and pharmacology.
Collapse
Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Eleonora Distrutti
- SC di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
| | - Adriana Carino
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Napoli, Federico II, Napoli, Italy
| | - Michele Biagioli
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy
| |
Collapse
|
|
50
|
Bariatric surgery works through a novel bile acid. Nat Chem Biol 2021; 17:5-6. [PMID: 32848213 DOI: 10.1038/s41589-020-0648-0] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
|