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Kirsch A, Gindlhuber J, Zabini D, Osto E. Bile acids and incretins as modulators of obesity-associated atherosclerosis. Front Cardiovasc Med 2025; 11:1510148. [PMID: 39834741 PMCID: PMC11743266 DOI: 10.3389/fcvm.2024.1510148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/12/2024] [Accepted: 12/17/2024] [Indexed: 01/22/2025] Open
Abstract
Obesity is one of the major global health concerns of the 21st century, associated with many comorbidities such as type 2 diabetes mellitus (T2DM), metabolic dysfunction-associated steatotic liver disease, and early and aggressive atherosclerotic cardiovascular disease, which is the leading cause of death worldwide. Bile acids (BAs) and incretins are gut hormones involved in digestion and absorption of fatty acids, and insulin secretion, respectively. In recent years BAs and incretins are increasingly recognized as key signaling molecules, which target multiple tissues and organs, beyond the gastro-intestinal system. Moreover, incretin-based therapy has revolutionized the treatment of T2DM and obesity. This mini review highlights the current knowledge about dysregulations in BA homeostasis in obesity with a special focus on atherosclerosis as well as athero-modulating roles of incretins and currently available incretin-based therapies.
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Affiliation(s)
- Andrijana Kirsch
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Juergen Gindlhuber
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Diana Zabini
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
| | - Elena Osto
- Division of Physiology and Pathophysiology, Otto Loewi Research Center for Vascular Biology, Immunology and Inflammation, Medical University of Graz, Graz, Austria
- Vetsuisse Faculty, University of Zurich, Zurich, Switzerland
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Xie J, Zhang X, Cheng L, Deng Y, Ren H, Mu M, Zhao L, Mu C, Chen J, Liu K, Ma R. Integrated multi-omics analysis of the microbial profile characteristics associated with pulmonary arterial hypertension in congenital heart disease. Microbiol Spectr 2024; 12:e0180824. [PMID: 39470277 PMCID: PMC11619245 DOI: 10.1128/spectrum.01808-24] [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: 07/22/2024] [Accepted: 10/09/2024] [Indexed: 10/30/2024] Open
Abstract
Dysregulation of immune and inflammatory cells around blood vessels and metabolic dysfunction are key mechanisms in the development of pulmonary arterial hypertension (PAH). The homeostasis of the human microbiome plays a crucial role in regulating immune responses and the progression of diseases. For pulmonary arterial hypertension associated with congenital heart disease involving body-lung shunt (PAH-CHD), the potential impact of the microbiome on the "gut-lung axis" remains underexplored. This study recruited 15 healthy individuals and 15 patients with pulmonary arterial hypertension due to congenital heart disease from Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences, and Kunming Children's Hospital. We performed differential analyses of metabolites and microbiota from both the gut and lower respiratory tract for these two groups. The goal was to investigate the "gut-lung axis" microbiome and metabolome profiles in children with PAH-CHD and to analyze the interrelationships between these profiles. Ultimately, we aim to propose the potential value of these profiles in aiding diagnosis. The results indicated that the gut and pulmonary microbiota of children with PAH-CHD are characterized by an increased abundance of beneficial symbionts, which are closely linked to changes in the metabolome. Metabolite functional enrichment analysis revealed energy metabolism reprogramming in the PAH-CHD group, with active metabolic pathways associated with bile acid secretion and carnitine homeostasis. Moreover, the differential expression of metabolites was correlated with right heart function and growth development.IMPORTANCEPrevious studies have primarily focused on the relationship between the gut microbiome and PAH. However, the impact of microbial homeostasis on the progression of PAH-CHD from the perspective of the gut-lung axis has not been adequately elucidated. Our study utilizes an integrated multi-omics approach to report on the differential characteristics of gut and lung microbiota between children with PAH-CHD and reference subjects. We found that microbiota influence the pathological changes and disease manifestations of PAH-CHD through their metabolic activity. Additionally, alterations in metabolites impact the microbial ecological structure. Our findings suggest that modulating the microbiome composition may have positive implications for maintaining and regulating the immune environment and pathological progression of PAH-CHD.
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Affiliation(s)
- Jiahui Xie
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Xiaoyu Zhang
- Department of Cardiothoracic Surgery, The first hospital of Kunming, Kunming, Yunnan Province, China
| | - Liming Cheng
- Department of Anesthesiology and Surgical Intensive Care Unit, Kunming Children’s Hospital, Kunming, Yunnan Province, China
| | - Yao Deng
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Haobo Ren
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Minghua Mu
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Liang Zhao
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Chunjie Mu
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Jiaxiang Chen
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
| | - Kai Liu
- Comprehensive Pediatrics, Kunming Children’s Hospital, Kunming, Yunnan Province, China
| | - Runwei Ma
- Department of Cardiovascular Surgery, Fuwai Yunnan Hospital, Chinese Academy of Medical Sciences/Affiliated Cardiovascular Hospital of Kunming Medical University, Kunming, Yunnan Province, China
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Li XJ, Fang C, Zhao RH, Zou L, Miao H, Zhao YY. Bile acid metabolism in health and ageing-related diseases. Biochem Pharmacol 2024; 225:116313. [PMID: 38788963 DOI: 10.1016/j.bcp.2024.116313] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/18/2024] [Revised: 05/18/2024] [Accepted: 05/21/2024] [Indexed: 05/26/2024]
Abstract
Bile acids (BAs) have surpassed their traditional roles as lipid solubilizers and regulators of BA homeostasis to emerge as important signalling molecules. Recent research has revealed a connection between microbial dysbiosis and metabolism disruption of BAs, which in turn impacts ageing-related diseases. The human BAs pool is primarily composed of primary BAs and their conjugates, with a smaller proportion consisting of secondary BAs. These different BAs exert complex effects on health and ageing-related diseases through several key nuclear receptors, such as farnesoid X receptor and Takeda G protein-coupled receptor 5. However, the underlying molecular mechanisms of these effects are still debated. Therefore, the modulation of signalling pathways by regulating synthesis and composition of BAs represents an interesting and novel direction for potential therapies of ageing-related diseases. This review provides an overview of synthesis and transportion of BAs in the healthy body, emphasizing its dependence on microbial community metabolic capacity. Additionally, the review also explores how ageing and ageing-related diseases affect metabolism and composition of BAs. Understanding BA metabolism network and the impact of their nuclear receptors, such as farnesoid X receptor and G protein-coupled receptor 5 agonists, paves the way for developing therapeutic agents for targeting BA metabolism in various ageing-related diseases, such as metabolic disorder, hepatic injury, cardiovascular disease, renal damage and neurodegenerative disease.
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Affiliation(s)
- Xiao-Jun Li
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; Southern Medical University Hospital of Integrated Traditional Chinese and Western Medicine, Southern Medical University, No.13, Shi Liu Gang Road, Haizhu District, Guangzhou, Guangdong 510315, China
| | - Chu Fang
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Rui-Hua Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China
| | - Liang Zou
- School of Food and Bioengineering, Chengdu University, No. 2025 Chengluo Avenue, Chengdu, Sichuan 610106, China
| | - Hua Miao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China.
| | - Ying-Yong Zhao
- School of Pharmacy, Zhejiang Chinese Medical University, No. 548 Binwen Road, Hangzhou, Zhejiang 310053, China; National Key Laboratory of Kidney Diseases, First Medical Center of Chinese PLA General Hospital, No. 28 Fuxing Road, Beijing 100853, China.
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Longtine AG, Greenberg NT, Bernaldo de Quirós Y, Brunt VE. The gut microbiome as a modulator of arterial function and age-related arterial dysfunction. Am J Physiol Heart Circ Physiol 2024; 326:H986-H1005. [PMID: 38363212 PMCID: PMC11279790 DOI: 10.1152/ajpheart.00764.2023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2023] [Revised: 01/26/2024] [Accepted: 02/13/2024] [Indexed: 02/17/2024]
Abstract
The arterial system is integral to the proper function of all other organs and tissues. Arterial function is impaired with aging, and arterial dysfunction contributes to the development of numerous age-related diseases, including cardiovascular diseases. The gut microbiome has emerged as an important regulator of both normal host physiological function and impairments in function with aging. The purpose of this review is to summarize more recently published literature demonstrating the role of the gut microbiome in supporting normal arterial development and function and in modulating arterial dysfunction with aging in the absence of overt disease. The gut microbiome can be altered due to a variety of exposures, including physiological aging processes. We explore mechanisms by which the gut microbiome may contribute to age-related arterial dysfunction, with a focus on changes in various gut microbiome-related compounds in circulation. In addition, we discuss how modulating circulating levels of these compounds may be a viable therapeutic approach for improving artery function with aging. Finally, we identify and discuss various experimental considerations and research gaps/areas of future research.
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Affiliation(s)
- Abigail G Longtine
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Nathan T Greenberg
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
| | - Yara Bernaldo de Quirós
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Instituto Universitario de Sanidad Animal y Seguridad Alimentaria, Universidad de las Palmas de Gran Canaria, Las Palmas, Spain
| | - Vienna E Brunt
- Department of Integrative Physiology, University of Colorado Boulder, Boulder, Colorado, United States
- Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
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5
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Zhao S, Zhang L, Zhao J, Kota VG, Venkat KM, Tasnim F, Yu H. Characteristics of contemporary drug clinical trials regarding the treatment of non-alcoholic steatohepatitis. Diabetes Metab Syndr 2024; 18:102921. [PMID: 38128261 DOI: 10.1016/j.dsx.2023.102921] [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: 01/29/2023] [Revised: 12/04/2023] [Accepted: 12/09/2023] [Indexed: 12/23/2023]
Abstract
BACKGROUND Non-alcoholic steatohepatitis (NASH), a chronic liver disease, has no United States Food and Drug Administration (FDA) approved drugs for treatment. OBJECTIVES To examine fundamental characteristics of drug clinical trials for NASH treatment on the global clinical trials registry platform. METHODS Cross-sectional analysis of clinical trials with NASH as medical condition that are registered on ClinicalTrials.gov. Relevant trial entries registered before and on October 7th, 2022, were downloaded, deduplicated, and reviewed. NCT numbers, titles, locations, funder types, statuses, durations, study designs, subject information, conditions, interventions, outcome measures were extracted and analyzed. RESULTS Overall, 268 drug clinical trials were included in this study. Majority of the trials are conducted in United States (42.2 %). Most of the trials are funded by industry (67.9 %). The earliest initiated trials date back to 2001. Most trials are phase 2 (56.3 %), randomized (84.0 %), parallel assignment (78.7 %), and quadruple blind (40.3 %). The most concerned combined medical conditions are non-alcoholic fatty liver disease (NAFLD, 20.9 %). The most involved mechanisms of action drug categories are farnesoid X receptor (FXR) agonists and peroxisome proliferator-activated receptor (PPAR) agonists, with the most tested drugs being the FXR agonist EDP-305 and the Glucagon-like peptide-1 (GLP-1) agonist semaglutide. CONCLUSION Old drugs are further repurposed for testing in NASH treatment, novel drugs are developed to try to cure NASH. We expect that the drug clinical trials will accelerate the frontier of therapeutic development in NASH, bring an innovative and efficacious medication therapeutic approach to prevent the development and progression of NASH, or even reverse NASH.
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Affiliation(s)
- Shanshan Zhao
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nerve System Drugs, Beijing Municipal Geriatric Medical Research Center, Beijing, 100053, China; Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore, 117593, Singapore; Drug and medical device clinical trial institution/Department of pharmacy, China Emergency General Hospital, Beijing, 100028, China
| | - Lan Zhang
- Department of Pharmacy, Xuanwu Hospital of Capital Medical University, National Clinical Research Center for Geriatric Diseases, Beijing Engineering Research Center for Nerve System Drugs, Beijing Municipal Geriatric Medical Research Center, Beijing, 100053, China.
| | - Junzhe Zhao
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore, 117593, Singapore; Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore
| | - Vishnu Goutham Kota
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore, 117593, Singapore
| | - Kartik Mitra Venkat
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore, 117593, Singapore
| | - Farah Tasnim
- Biomedical Sciences Industry Partnership Office (BMSIPO), A*STAR, 31 Biopolis Way, 138669, Singapore
| | - Hanry Yu
- Department of Physiology, The Institute for Digital Medicine (WisDM), Yong Loo Lin School of Medicine, MD9-04-11, 2 Medical Drive, Singapore, 117593, Singapore; CAMP, Singapore-MIT Alliance for Research and Technology, 1 CREATE Way, Level 4 Enterprise Wing, Singapore, 138602, Singapore; Mechanobiology Institute, National University of Singapore, T-Lab, #05-01, 5A Engineering Drive 1, Singapore, 117411, Singapore.
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6
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Ralli T, Saifi Z, Tyagi N, Vidyadhari A, Aeri V, Kohli K. Deciphering the role of gut metabolites in non-alcoholic fatty liver disease. Crit Rev Microbiol 2023; 49:815-833. [PMID: 36394607 DOI: 10.1080/1040841x.2022.2142091] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2022] [Revised: 09/30/2022] [Accepted: 10/26/2022] [Indexed: 11/18/2022]
Abstract
Perturbations in microbial abundance or diversity in the intestinal lumen leads to intestinal inflammation and disruption of intestinal membrane which eventually facilitates the translocation of microbial metabolites or whole microbes to the liver and other organs through portal vein. This process of translocation finally leads to multitude of health disorders. In this review, we are going to focus on the mechanisms by which gut metabolites like SCFAs, tryptophan (Trp) metabolites, bile acids (BAs), ethanol, and choline can either cause the development/progression of non-alcoholic fatty liver disease (NAFLD) or serves as a therapeutic treatment for the disease. Alterations in some metabolites like SCFAs, Trp metabolites, etc., can serve as biomarker molecules whereas presence of specific metabolites like ethanol definitely leads to disease progression. Thus, proper understanding of these mechanisms will subsequently help in designing of microbiome-based therapeutic approaches. Furthermore, we have also focussed on the role of dysbiosis on the mucosal immune system. In addition, we would also compile up the microbiome-based clinical trials which are currently undergoing for the treatment of NAFLD and non-alcoholic steatohepatitis (NASH). It has been observed that the use of microbiome-based approaches like prebiotics, probiotics, symbiotics, etc., can act as a beneficial treatment option but more research needs to be done to know how to manipulate the composition of gut microbes.
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Affiliation(s)
- Tanya Ralli
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
| | - Zoya Saifi
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
| | - Neha Tyagi
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
| | - Arya Vidyadhari
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
| | - Vidhu Aeri
- Department of Pharmacognosy, School of Pharmaceutical Education and Research, New Delhi, India
| | - Kanchan Kohli
- Department of Pharmaceutics, School of Pharmaceutical Education and Research, New Delhi, India
- Research and Publications, Llyod Institute of Management and Technology, Greater Noida, India
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Yntema T, Koonen DPY, Kuipers F. Emerging Roles of Gut Microbial Modulation of Bile Acid Composition in the Etiology of Cardiovascular Diseases. Nutrients 2023; 15:nu15081850. [PMID: 37111068 PMCID: PMC10141989 DOI: 10.3390/nu15081850] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2023] [Revised: 04/04/2023] [Accepted: 04/06/2023] [Indexed: 04/29/2023] Open
Abstract
Despite advances in preventive measures and treatment options, cardiovascular disease (CVD) remains the number one cause of death globally. Recent research has challenged the traditional risk factor profile and highlights the potential contribution of non-traditional factors in CVD, such as the gut microbiota and its metabolites. Disturbances in the gut microbiota have been repeatedly associated with CVD, including atherosclerosis and hypertension. Mechanistic studies support a causal role of microbiota-derived metabolites in disease development, such as short-chain fatty acids, trimethylamine-N-oxide, and bile acids, with the latter being elaborately discussed in this review. Bile acids represent a class of cholesterol derivatives that is essential for intestinal absorption of lipids and fat-soluble vitamins, plays an important role in cholesterol turnover and, as more recently discovered, acts as a group of signaling molecules that exerts hormonal functions throughout the body. Studies have shown mediating roles of bile acids in the control of lipid metabolism, immunity, and heart function. Consequently, a picture has emerged of bile acids acting as integrators and modulators of cardiometabolic pathways, highlighting their potential as therapeutic targets in CVD. In this review, we provide an overview of alterations in the gut microbiota and bile acid metabolism found in CVD patients, describe the molecular mechanisms through which bile acids may modulate CVD risk, and discuss potential bile-acid-based treatment strategies in relation to CVD.
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Affiliation(s)
- Tess Yntema
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Debby P Y Koonen
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
| | - Folkert Kuipers
- Department of Pediatrics, University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
- European Research Institute for the Biology of Ageing (ERIBA), University of Groningen, University Medical Center Groningen, 9713 GZ Groningen, The Netherlands
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Moutsoglou DM, Tatah J, Prisco SZ, Prins KW, Staley C, Lopez S, Blake M, Teigen L, Kazmirczak F, Weir EK, Kabage AJ, Guan W, Khoruts A, Thenappan T. Pulmonary Arterial Hypertension Patients Have a Proinflammatory Gut Microbiome and Altered Circulating Microbial Metabolites. Am J Respir Crit Care Med 2023; 207:740-756. [PMID: 36343281 PMCID: PMC10037487 DOI: 10.1164/rccm.202203-0490oc] [Citation(s) in RCA: 30] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/11/2022] [Accepted: 11/07/2022] [Indexed: 11/09/2022] Open
Abstract
Rationale: Inflammation drives pulmonary arterial hypertension (PAH). Gut dysbiosis causes immune dysregulation and systemic inflammation by altering circulating microbial metabolites; however, little is known about gut dysbiosis and microbial metabolites in PAH. Objectives: To characterize the gut microbiome and microbial metabolites in patients with PAH. Methods: We performed 16S ribosomal RNA gene and shotgun metagenomics sequencing on stool from patients with PAH, family control subjects, and healthy control subjects. We measured markers of inflammation, gut permeability, and microbial metabolites in plasma from patients with PAH, family control subjects, and healthy control subjects. Measurements and Main Results: The gut microbiome was less diverse in patients with PAH. Shannon diversity index correlated with measures of pulmonary vascular disease but not with right ventricular function. Patients with PAH had a distinct gut microbial signature at the phylogenetic level, with fewer copies of gut microbial genes that produce antiinflammatory short-chain fatty acids (SCFAs) and secondary bile acids and lower relative abundances of species encoding these genes. Consistent with the gut microbial changes, patients with PAH had relatively lower plasma concentrations of SCFAs and secondary bile acids. Patients with PAH also had enrichment of species with the microbial genes that encoded the proinflammatory microbial metabolite trimethylamine. The changes in the gut microbiome and circulating microbial metabolites between patients with PAH and family control subjects were not as substantial as the differences between patients with PAH and healthy control subjects. Conclusions: Patients with PAH have proinflammatory gut dysbiosis, in which lower circulating SCFAs and secondary bile acids may facilitate pulmonary vascular disease. These findings support investigating modulation of the gut microbiome as a potential treatment for PAH.
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Affiliation(s)
| | - Jasmine Tatah
- Division of Cardiovascular Medicine, Department of Medicine
| | | | - Kurt W. Prins
- Division of Cardiovascular Medicine, Department of Medicine
| | - Christopher Staley
- Division of Basic and Translational Research, Department of Surgery, and
| | - Sharon Lopez
- Division of Gastroenterology, Hepatology, and Nutrition
| | - Madelyn Blake
- Division of Cardiovascular Medicine, Department of Medicine
| | - Levi Teigen
- Division of Gastroenterology, Hepatology, and Nutrition
| | | | | | | | - Weihua Guan
- Division of Biostatistics, School of Public Health, University of Minnesota, Minneapolis, Minnesota
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Kim DH, Park JS, Choi HI, Kim CS, Bae EH, Ma SK, Kim SW. The role of the farnesoid X receptor in kidney health and disease: a potential therapeutic target in kidney diseases. Exp Mol Med 2023; 55:304-312. [PMID: 36737665 PMCID: PMC9981614 DOI: 10.1038/s12276-023-00932-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/22/2022] [Accepted: 12/01/2022] [Indexed: 02/05/2023] Open
Abstract
The prevalence of kidney diseases has been increasing worldwide due to the aging population and has results in an increased socioeconomic burden as well as increased morbidity and mortality. A deep understanding of the mechanisms underlying the physiological regulation of the kidney and the pathogenesis of related diseases can help identify potential therapeutic targets. The farnesoid X receptor (FXR, NR1H4) is a primary nuclear bile acid receptor that transcriptionally regulates bile acid homeostasis as well as glucose and lipid metabolism in multiple tissues. The roles of FXR in tissues other than hepatic and intestinal tissues are poorly understood. In studies over the past decade, FXR has been demonstrated to have a protective effect against kidney diseases through its anti-inflammatory and antifibrotic effects; it also plays roles in glucose and lipid metabolism in the kidney. In this review, we discuss the physiological role of FXR in the kidney and its pathophysiological roles in various kidney diseases, including acute kidney injury and chronic kidney diseases, diabetic nephropathy, and kidney fibrosis. Therefore, the regulatory mechanisms involving nuclear receptors, such as FXR, in the physiology and pathophysiology of the kidney and the development of agonists and antagonists for modulating FXR expression and activation should be elucidated to identify therapeutic targets for the treatment of kidney diseases.
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Affiliation(s)
- Dong-Hyun Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea.
| | - Jung Sun Park
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea
| | - Hoon-In Choi
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea
| | - Chang Seong Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea
| | - Eun Hui Bae
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea
| | - Seong Kwon Ma
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea
| | - Soo Wan Kim
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, 61469, Korea.
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10
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Panzitt K, Zollner G, Marschall HU, Wagner M. Recent advances on FXR-targeting therapeutics. Mol Cell Endocrinol 2022; 552:111678. [PMID: 35605722 DOI: 10.1016/j.mce.2022.111678] [Citation(s) in RCA: 45] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/20/2022] [Revised: 04/25/2022] [Accepted: 04/27/2022] [Indexed: 12/25/2022]
Abstract
The bile acid receptor FXR has emerged as a bona fide drug target for chronic cholestatic and metabolic liver diseases, ahead of all non-alcoholic fatty liver disease (NAFLD). FXR is highly expressed in the liver and intestine and activation at both sites differentially contributes to its desired metabolic effects. Unrestricted FXR activation, however, also comes along with undesired effects such as a pro-atherogenic lipid profile, pruritus and hepatocellular toxicity under certain conditions. Several pre-clinical studies have confirmed the potency of FXR activation for cholestatic and metabolic liver diseases, but overall it remains still open whether selective activation of intestinal FXR is advantageous over pan-FXR activation and whether restricted or modulated FXR activation can limit some of the side effects. Even more, FXR antagonist also bear the potential as intestinal-selective drugs in NAFLD models. In this review we will discuss the molecular prerequisites for FXR activation, pan-FXR activation and intestinal FXR in/activation from a therapeutic point of view, different steroidal and non-steroidal FXR agonists, ways to restrict FXR activation and finally what we have learned from pre-clinical models and clinical trials with different FXR therapeutics.
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Affiliation(s)
- Katrin Panzitt
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Gernot Zollner
- Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria
| | - Hanns-Ulrich Marschall
- Department of Molecular and Clinical Medicine/Wallenberg Laboratory, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden
| | - Martin Wagner
- Research Unit for Translational Nuclear Receptor Research, Medical University Graz, Graz, Austria; Division of Gastroenterology and Hepatology, Medical University Graz, Graz, Austria.
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11
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Renal Farnesoid X Receptor improves high fructose-induced salt-sensitive hypertension in mice by inhibiting DNM3 to promote nitro oxide production. J Hypertens 2022; 40:1577-1588. [PMID: 35792095 DOI: 10.1097/hjh.0000000000003189] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
OBJECTIVE Farnesoid X Receptor (FXR) is highly expressed in renal tubules, activation of which attenuates renal injury by suppressing inflammation and fibrosis. However, whether renal FXR contributes to the regulation of blood pressure (BP) is poorly understood. This study aimed to investigate the anti-hypertensive effect of renal FXR on high-fructose-induced salt-sensitive hypertension and underlying mechanism. METHODS Hypertension was induced in male C57BL/6 mice by 20% fructose in drinking water with 4% sodium chloride in diet (HFS) for 8 weeks. The effects of FXR on NO production were estimated in vitro and in vivo. RESULTS Compared with control, HFS intake elevated BP, enhanced renal injury and reduced renal NO levels as well as FXR expression in the kidney of mice. In the mouse renal collecting duct cells mIMCD-K2, FXR agonists promoted NO production by enhancing the expression of neuronal nitric oxide synthase (nNOS) and inducible nitric oxide synthase (iNOS), whereas this effect was diminished by fxr knockdown. We further found that Dynamin 3 (DNM3), a binding protein with nNOS in the renal medulla, was inhibited by FXR and its deficiency elevated NO production in mIMCD-K2 cells. In HFS-fed mice, renal fxr overexpression significantly attenuated hypertension and renal fibrosis, regulated the expression of DNM3/nNOS/iNOS, and increased renal NO levels. CONCLUSION Our results demonstrated that renal FXR prevents HFS-induced hypertension by inhibiting DNM3 to promote NO production. These findings provide insights into the role and potential mechanism of renal FXR for the treatment of hypertension.
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Survival Benefit of Statin with Anti-Angiogenesis Efficacy in Lung Cancer-Associated Pleural Fluid through FXR Modulation. Cancers (Basel) 2022; 14:cancers14112765. [PMID: 35681743 PMCID: PMC9179389 DOI: 10.3390/cancers14112765] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/21/2022] [Revised: 05/27/2022] [Accepted: 05/30/2022] [Indexed: 11/19/2022] Open
Abstract
Simple Summary Our previous works showed that pleural fluid from lung cancer significantly induced endothelial proliferation, migration, and angiogenesis. Since endothelial metabolism was a key step in angiogenesis, we investigated the role of bile acid signaling and FXR expression in pleural angiogenesis. Elevated bile acid levels in lung-cancer-associated pleural fluid (LCPF) were characterized with positive FXR staining in pleural microvessels. We then confirmed the inhibitory effect of an FXR antagonist on LCPF-induced endothelial migration and angiogenesis. Due to the elevated protein expression in the cholesterol metabolism caused by LCPF, lipid-lowering agents with the efficacy needed to counteract LCPF-regulated angiogenesis were evaluated. Statin showed the potent efficacy needed to suppress LCPF-induced endothelial proliferation, migration, and angiogenesis through FXR inhibition. Following that, Kaplan–Meier analysis showed the survival benefit of statin exposure in patients with lung adenocarcinoma with LCPF. Our results suggest that targeting endothelial FXR signaling with statin treatment could ameliorate the angiogenesis activity of LCPF. Abstract Lung cancer-related pleural fluid (LCPF) presents as a common complication with limited treatment. Beyond its function in lipid digestion, bile acid was identified as a potent carcinogen to stimulate tumor proliferation. Previous research indicated a correlation between serum bile acid levels and the risk of developing several gastrointestinal cancers. Our study identified elevated bile acid levels in LCPF and increased farnesoid X receptor (FXR) expression as bile acid nuclear receptors in pleural microvessels of lung adenocarcinoma. Additionally, LCPF stimulated the expression of proteins involved in bile acid synthesis and cholesterol metabolism in HUVECs including CYP7A1, StAR, HMGCR, and SREBP2. LCPF-induced endothelial motility and angiogenesis were counteracted by using β-muricholic acid as an FXR antagonist. Moreover, we investigated the efficacy of cholesterol-lowering medications, such as cholestyramine, fenofibrate, and atorvastatin, in regulating LCPF-regulated angiogenesis. Along with suppressing endothelial proliferation and angiogenesis, atorvastatin treatment reversed cholesterol accumulation and endothelial junction disruption caused by LCPF. Statin treatment inhibited LCPF-induced endothelial FXR expression as well as the downstream proteins RXR and SHP. Based on the positive findings of suppressing endothelial angiogenesis, our group further incorporated the effect of statin on clinical patients complicated with LCPF. A Kaplan–Meier analysis revealed the clinical benefit of statin exposure in patients with lung adenocarcinoma with LCPF. Conclusively, our study demonstrated the ability of statin to alleviate LCPF-induced angiogenesis in patients with LCPF via FXR modulation.
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Shulpekova Y, Zharkova M, Tkachenko P, Tikhonov I, Stepanov A, Synitsyna A, Izotov A, Butkova T, Shulpekova N, Lapina N, Nechaev V, Kardasheva S, Okhlobystin A, Ivashkin V. The Role of Bile Acids in the Human Body and in the Development of Diseases. MOLECULES (BASEL, SWITZERLAND) 2022; 27:molecules27113401. [PMID: 35684337 PMCID: PMC9182388 DOI: 10.3390/molecules27113401] [Citation(s) in RCA: 15] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/14/2022] [Revised: 05/13/2022] [Accepted: 05/23/2022] [Indexed: 11/28/2022]
Abstract
Bile acids are specific and quantitatively important organic components of bile, which are synthesized by hepatocytes from cholesterol and are involved in the osmotic process that ensures the outflow of bile. Bile acids include many varieties of amphipathic acid steroids. These are molecules that play a major role in the digestion of fats and the intestinal absorption of hydrophobic compounds and are also involved in the regulation of many functions of the liver, cholangiocytes, and extrahepatic tissues, acting essentially as hormones. The biological effects are realized through variable membrane or nuclear receptors. Hepatic synthesis, intestinal modifications, intestinal peristalsis and permeability, and receptor activity can affect the quantitative and qualitative bile acids composition significantly leading to extrahepatic pathologies. The complexity of bile acids receptors and the effects of cross-activations makes interpretation of the results of the studies rather difficult. In spite, this is a very perspective direction for pharmacology.
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Affiliation(s)
- Yulia Shulpekova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Maria Zharkova
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Pyotr Tkachenko
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Igor Tikhonov
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexander Stepanov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Alexandra Synitsyna
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
- Correspondence: ; Tel.: +7-499-764-98-78
| | - Alexander Izotov
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | - Tatyana Butkova
- Biobanking Group, Branch of Institute of Biomedical Chemistry “Scientific and Education Center”, 119435 Moscow, Russia; (A.S.); (A.I.); (T.B.)
| | | | - Natalia Lapina
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Nechaev
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Svetlana Kardasheva
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Alexey Okhlobystin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
| | - Vladimir Ivashkin
- Sechenov First Moscow State Medical University (Sechenov University), 119435 Moscow, Russia; (Y.S.); (M.Z.); (P.T.); (I.T.); (N.L.); (V.N.); (S.K.); (A.O.); (V.I.)
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Jovanovich A, Cai X, Frazier R, Bundy JD, He J, Rao P, Lora C, Dobre M, Go A, Shafi T, Feldman HI, Rhee EP, Miyazaki M, Isakova T, Chonchol M. Deoxycholic Acid and Coronary Artery Calcification in the Chronic Renal Insufficiency Cohort. J Am Heart Assoc 2022; 11:e022891. [PMID: 35322682 PMCID: PMC9075491 DOI: 10.1161/jaha.121.022891] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 02/17/2022] [Indexed: 11/16/2022]
Abstract
Background Deoxycholic acid (DCA) is a secondary bile acid that may promote vascular calcification in experimental settings. Higher DCA levels were associated with prevalent coronary artery calcification (CAC) in a small group of individuals with advanced chronic kidney disease. Whether DCA levels are associated with CAC prevalence, incidence, and progression in a large and diverse population of individuals with chronic kidney disease stages 2 to 4 is unknown. Methods and Results In the CRIC (Chronic Renal Insufficiency Cohort) study, we evaluated cross-sectional (n=1057) and longitudinal (n=672) associations between fasting serum DCA levels and computed tomographic CAC using multivariable-adjusted regression models. The mean age was 57±12 years, 47% were women, and 41% were Black. At baseline, 64% had CAC (CAC score >0 Agatston units). In cross-sectional analyses, models adjusted for demographics and clinical factors showed no association between DCA levels and CAC >0 compared with no CAC (prevalence ratio per 1-SD higher log DCA, 1.08 [95% CI, 0.91-1.26). DCA was not associated with incident CAC (incidence per 1-SD greater log DCA, 1.08 [95% CI, 0.85-1.39]) or CAC progression (risk for increase in ≥100 and ≥200 Agatston units per year per 1-SD greater log DCA, 1.05 [95% CI, 0.84-1.31] and 1.26 [95% CI, 0.77-2.06], respectively). Conclusions Among CRIC study participants, DCA was not associated with prevalent, incident, or progression of CAC.
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Affiliation(s)
- Anna Jovanovich
- Renal SectionVA Eastern Colorado Healthcare SystemAuroraCO
- Division of Renal Diseases and HypertensionUniversity of Colorado Anschutz Medical CampusAuroraCO
| | - Xuan Cai
- Division of Nephrology/HypertensionNorthwestern UniversityChicagoIL
| | - Rebecca Frazier
- Division of Nephrology/HypertensionNorthwestern UniversityChicagoIL
| | - Josh D. Bundy
- Nephrology and HypertensionTulane UniversityNew OrleansLA
| | - Jiang He
- Nephrology and HypertensionTulane UniversityNew OrleansLA
| | | | - Claudia Lora
- Division of NephrologyUniversity of Illinois at ChicagoChicagoIL
| | - Mirela Dobre
- Division of NephrologyCase Western Reserve UniversityClevelandOH
| | - Alan Go
- Division of ResearchKaiser Permanente Northern CaliforniaOaklandCA
| | - Tariq Shafi
- Division of NephrologyUniversity of MississippiJacksonMI
| | - Harold I. Feldman
- Division of Renal Electrolyte and HypertensionUniversity of PennsylvaniaPhiladelphiaPA
| | - Eugene P. Rhee
- Nephrology DivisionMassachusetts General HospitalHarvard Medical SchoolBostonMA
| | - Makoto Miyazaki
- Division of Renal Diseases and HypertensionUniversity of Colorado Anschutz Medical CampusAuroraCO
| | - Tamara Isakova
- Division of Nephrology/HypertensionNorthwestern UniversityChicagoIL
| | - Michel Chonchol
- Division of Renal Diseases and HypertensionUniversity of Colorado Anschutz Medical CampusAuroraCO
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Ishimwe JA, Dola T, Ertuglu LA, Kirabo A. Bile acids and salt-sensitive hypertension: a role of the gut-liver axis. Am J Physiol Heart Circ Physiol 2022; 322:H636-H646. [PMID: 35245132 PMCID: PMC8957326 DOI: 10.1152/ajpheart.00027.2022] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 03/01/2022] [Accepted: 03/02/2022] [Indexed: 12/22/2022]
Abstract
Salt-sensitivity of blood pressure (SSBP) affects 50% of the hypertensive and 25% of the normotensive populations. Importantly, SSBP is associated with increased risk for mortality in both populations independent of blood pressure. Despite its deleterious effects, the pathogenesis of SSBP is not fully understood. Emerging evidence suggests a novel role of bile acids in salt-sensitive hypertension and that they may play a crucial role in regulating inflammation and fluid volume homeostasis. Mechanistic evidence implicates alterations in the gut microbiome, the epithelial sodium channel (ENaC), the farnesoid X receptor, and the G protein-coupled bile acid receptor TGR5 in bile acid-mediated effects on cardiovascular function. The mechanistic interplay between excess dietary sodium-induced alterations in the gut microbiome and immune cell activation, bile acid signaling, and whether such interplay may contribute to the etiology of SSBP is still yet to be defined. The main goal of this review is to discuss the potential role of bile acids in the pathogenesis of cardiovascular disease with a focus on salt-sensitive hypertension.
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Affiliation(s)
- Jeanne A Ishimwe
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Thanvi Dola
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
| | - Lale A Ertuglu
- Division of Nephrology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
| | - Annet Kirabo
- Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Nashville, Tennessee
- Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, Tennessee
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Khotimchenko M, Brunk NE, Hixon MS, Walden DM, Hou H, Chakravarty K, Varshney J. In Silico Development of Combinatorial Therapeutic Approaches Targeting Key Signaling Pathways in Metabolic Syndrome. Pharm Res 2022; 39:2937-2950. [PMID: 35313359 DOI: 10.1007/s11095-022-03231-z] [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: 01/03/2022] [Accepted: 03/10/2022] [Indexed: 11/30/2022]
Abstract
PURPOSE Dysregulations of key signaling pathways in metabolic syndrome are multifactorial, eventually leading to cardiovascular events. Hyperglycemia in conjunction with dyslipidemia induces insulin resistance and provokes release of proinflammatory cytokines resulting in chronic inflammation, accelerated lipid peroxidation with further development of atherosclerotic alterations and diabetes. We have proposed a novel combinatorial approach using FDA approved compounds targeting IL-17a and DPP4 to ameliorate a significant portion of the clustered clinical risks in patients with metabolic syndrome. In our current research we have modeled the outcomes of metabolic syndrome treatment using two distinct drug classes. METHODS Targets were chosen based on the clustered clinical risks in metabolic syndrome: dyslipidemia, insulin resistance, impaired glucose control, and chronic inflammation. Drug development platform, BIOiSIM™, was used to narrow down two different drug classes with distinct modes of action and modalities. Pharmacokinetic and pharmacodynamic profiles of the most promising drugs were modeling showing predicted outcomes of combinatorial therapeutic interventions. RESULTS Preliminary studies demonstrated that the most promising drugs belong to DPP-4 inhibitors and IL-17A inhibitors. Evogliptin was chosen to be a candidate for regulating glucose control with long term collateral benefit of weight loss and improved lipid profiles. Secukinumab, an IL-17A sequestering agent used in treating psoriasis, was selected as a repurposed candidate to address the sequential inflammatory disorders that follow the first metabolic insult. CONCLUSIONS Our analysis suggests this novel combinatorial therapeutic approach inducing DPP4 and Il-17a suppression has a high likelihood of ameliorating a significant portion of the clustered clinical risk in metabolic syndrome.
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Affiliation(s)
- Maksim Khotimchenko
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Nicholas E Brunk
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Mark S Hixon
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Daniel M Walden
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Hypatia Hou
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA
| | - Kaushik Chakravarty
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA.
| | - Jyotika Varshney
- VeriSIM Life, 1 Sansome Street, Suite 3500, San Francisco, California, 94104, USA.
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Rojas Á, Lara-Romero C, Muñoz-Hernández R, Gato S, Ampuero J, Romero-Gómez M. Emerging pharmacological treatment options for MAFLD. Ther Adv Endocrinol Metab 2022; 13:20420188221142452. [PMID: 36533188 PMCID: PMC9747889 DOI: 10.1177/20420188221142452] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/28/2022] [Accepted: 11/13/2022] [Indexed: 12/14/2022] Open
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) prevalence and incidence is rising globally. It is associated with metabolic comorbidities, obesity, overweight, type 2 diabetes mellitus, and at least two metabolic risk factors, such as hypertension, hypertriglyceridemia, hypercholesterolemia, insulin resistance, and cardiovascular risk, increasing the risk of mortality. The excessive accumulation of fat comprises apoptosis, necrosis, inflammation and ballooning degeneration progressing to fibrosis, cirrhosis, and liver decompensations including hepatocellular carcinoma development. The limitation of approved drugs to prevent MAFLD progression is a paradigm. This review focuses on recent pathways and targets with evidence results in phase II/III clinical trials.
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Affiliation(s)
- Ángela Rojas
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Calle Antonio Maura Montaner s/n, 41013 Sevilla, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Av. Monforte de Lemos, 3-5. Pabellón 11, Planta 0 28029 Madrid, Madrid, Spain
| | - Carmen Lara-Romero
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
| | - Rocío Muñoz-Hernández
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain
| | - Sheila Gato
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain
| | - Javier Ampuero
- SeLiver Group, Instituto de Biomedicina de Sevilla (IBiS), Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, Sevilla, Spain
- Hepatic and Digestive Diseases Networking Biomedical Research Centre (CIBERehd), Madrid, Spain
- Digestive Diseases Unit, Hospital Universitario Virgen del Rocío, Sevilla, Spain
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Zhang S, Zhou J, Wu W, Zhu Y, Liu X. The Role of Bile Acids in Cardiovascular Diseases: from Mechanisms to Clinical Implications. Aging Dis 2022; 14:261-282. [PMID: 37008052 PMCID: PMC10017164 DOI: 10.14336/ad.2022.0817] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2022] [Accepted: 08/17/2022] [Indexed: 11/18/2022] Open
Abstract
Bile acids (BAs), key regulators in the metabolic network, are not only involved in lipid digestion and absorption but also serve as potential therapeutic targets for metabolic disorders. Studies have shown that cardiac dysfunction is associated with abnormal BA metabolic pathways. As ligands for several nuclear receptors and membrane receptors, BAs systematically regulate the homeostasis of metabolism and participate in cardiovascular diseases (CVDs), such as myocardial infarction, diabetic cardiomyopathy, atherosclerosis, arrhythmia, and heart failure. However, the molecular mechanism by which BAs trigger CVDs remains controversial. Therefore, the regulation of BA signal transduction by modulating the synthesis and composition of BAs is an interesting and novel direction for potential therapies for CVDs. Here, we mainly summarized the metabolism of BAs and their role in cardiomyocytes and noncardiomyocytes in CVDs. Moreover, we comprehensively discussed the clinical prospects of BAs in CVDs and analyzed the clinical diagnostic and application value of BAs. The latest development prospects of BAs in the field of new drug development are also prospected. We aimed to elucidate the underlying mechanism of BAs treatment in CVDs, and the relationship between BAs and CVDs may provide new avenues for the prevention and treatment of these diseases.
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Affiliation(s)
- Shuwen Zhang
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Junteng Zhou
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
- Health Management Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Wenchao Wu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
| | - Ye Zhu
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
- Correspondence should be addressed to: Prof. Xiaojing Liu (), and Prof. Ye Zhu (), West China Hospital, Sichuan University, Chengdu, Sichuan, China
| | - Xiaojing Liu
- Laboratory of Cardiovascular Diseases, Regenerative Medicine Research Center, West China Hospital, Sichuan University, Chengdu, China.
- Department of Cardiology, West China Hospital, Sichuan University, Chengdu, China.
- Correspondence should be addressed to: Prof. Xiaojing Liu (), and Prof. Ye Zhu (), West China Hospital, Sichuan University, Chengdu, Sichuan, China
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Lee Y, Kim BR, Kang GH, Lee GJ, Park YJ, Kim H, Jang HC, Choi SH. The Effects of PPAR Agonists on Atherosclerosis and Nonalcoholic Fatty Liver Disease in ApoE-/-FXR-/- Mice. Endocrinol Metab (Seoul) 2021; 36:1243-1253. [PMID: 34986301 PMCID: PMC8743579 DOI: 10.3803/enm.2021.1100] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/07/2021] [Accepted: 09/07/2021] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Farnesoid X receptor (FXR), a bile acid-activated nuclear receptor, is a potent regulator of glucose and lipid metabolism as well as of bile acid metabolism. Previous studies have demonstrated that FXR deficiency is associated with metabolic derangements, including atherosclerosis and nonalcoholic fatty liver disease (NAFLD), but its mechanism remains unclear. In this study, we investigated the role of FXR in atherosclerosis and NAFLD and the effect of peroxisome proliferator-activated receptor (PPAR) agonists in mouse models with FXR deficiency. METHODS En face lipid accumulation analysis, liver histology, serum levels of glucose and lipids, and mRNA expression of genes related to lipid metabolism were compared between apolipoprotein E (ApoE)-/- and ApoE-/-FXR-/- mice. The effects of PPARα and PPARγ agonists were also compared in both groups of mice. RESULTS Compared with ApoE-/- mice, ApoE-/-FXR-/- mice showed more severe atherosclerosis, hepatic steatosis, and higher levels of serum cholesterol, low-density lipoprotein cholesterol, and triglycerides, accompanied by increased mRNA expression of FAS, ApoC2, TNFα, IL-6 (liver), ATGL, TGH, HSL, and MGL (adipocytes), and decreased mRNA expressions of CPT2 (liver) and Tfam (skeletal muscle). Treatment with a PPARα agonist, but not with a PPARγ agonist, partly reversed atherosclerosis and hepatic steatosis, and decreased plasma triglyceride levels in the ApoE-/-FXR-/- mice, in association with increased mRNA expression of CD36 and FATP and decreased expression of ApoC2 and ApoC3 (liver). CONCLUSION Loss of FXR is associated with aggravation of atherosclerosis and hepatic steatosis in ApoE-deficient mice, which could be reversed by a PPARα agonist through induction of fatty acid uptake, β-oxidation, and triglyceride hydrolysis.
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Affiliation(s)
- Yenna Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Bo-Rahm Kim
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Geun-Hyung Kang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Gwan Jae Lee
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
| | - Young Joo Park
- Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Haeryoung Kim
- Department of Pathology, Seoul National University Hospital, Seoul National University College of Medicine, Seoul, Korea
| | - Hak Chul Jang
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
| | - Sung Hee Choi
- Department of Internal Medicine, Seoul National University Bundang Hospital, Seongnam, Korea
- Department of Internal Medicine, Seoul National University College of Medicine, Seoul, Korea
- Corresponding author: Sung Hee Choi Department of Internal Medicine, Seoul National University Bundang Hospital, Seoul National University College of Medicine, 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea Tel: +82-31-787-7029, Fax: +82-31-787-4052, E-mail:
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Liu Y, Croft KD, Caparros-Martin J, O'Gara F, Mori TA, Ward NC. Beneficial effects of inorganic nitrate in non-alcoholic fatty liver disease. Arch Biochem Biophys 2021; 711:109032. [PMID: 34520731 DOI: 10.1016/j.abb.2021.109032] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2021] [Revised: 09/08/2021] [Accepted: 09/08/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is considered the hepatic representation of the metabolic disorders. Inorganic nitrate/nitrite can be converted to nitric oxide, regulate glucose metabolism, lower lipid levels, and reduce inflammation, thus raising the hypothesis that inorganic nitrate/nitrite could be beneficial for improving NAFLD. This study assessed the therapeutic effects of chronic dietary nitrate on NAFLD in a mouse model. 60 ApoE-/- mice were fed a high-fat diet (HFD) for 12 weeks to allow for the development of atherosclerosis with associated NAFLD. The mice were then randomly assigned to different groups (20/group) for a further 12 weeks: (i) HFD + NaCl (1 mmol/kg/day), (ii) HFD + NaNO3 (1 mmol/kg/day), and (iii) HFD + NaNO3 (10 mmol/kg/day). A fourth group of ApoE-/- mice consumed a normal chow diet for the duration of the study. At the end of the treatment, caecum contents, serum, and liver were collected. Consumption of the HFD resulted in significantly greater lipid accumulation in the liver compared to mice on the normal chow diet. Mice whose HFD was supplemented with dietary nitrate for the second half of the study, showed an attenuation in hepatic lipid accumulation. This was also associated with an increase in hepatic AMPK activity compared to mice on the HFD. In addition, a significant difference in bile acid profile was detected between mice on the HFD and those receiving the high dose nitrate supplemented HFD. In conclusion, dietary nitrate attenuates the progression of liver steatosis in ApoE-/- mice fed a HFD.
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Affiliation(s)
- Yang Liu
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Kevin D Croft
- School of Biomedical Sciences, University of Western Australia, Perth, WA, Australia
| | - Jose Caparros-Martin
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia
| | - Fergal O'Gara
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA, Australia; BIOMERIT Research Centre, School of Microbiology, University College Cork, T12 YN60, Cork, Ireland
| | - Trevor A Mori
- Medical School, University of Western Australia, Perth, WA, Australia
| | - Natalie C Ward
- Medical School, University of Western Australia, Perth, WA, Australia; Dobney Hypertension Centre, Medical School, University of Western Australia, Perth, WA, Australia.
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21
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Kaur I, Tiwari R, Naidu VGM, Ramakrishna S, Tripathi DM, Kaur S. Bile Acids as Metabolic Inducers of Hepatocyte Proliferation and Liver Regeneration. REGENERATIVE ENGINEERING AND TRANSLATIONAL MEDICINE 2021. [DOI: 10.1007/s40883-021-00221-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/20/2022]
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22
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Sauerbruch T, Hennenberg M, Trebicka J, Beuers U. Bile Acids, Liver Cirrhosis, and Extrahepatic Vascular Dysfunction. Front Physiol 2021; 12:718783. [PMID: 34393832 PMCID: PMC8358446 DOI: 10.3389/fphys.2021.718783] [Citation(s) in RCA: 25] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Accepted: 06/29/2021] [Indexed: 12/12/2022] Open
Abstract
The bile acid pool with its individual bile acids (BA) is modulated in the enterohepatic circulation by the liver as the primary site of synthesis, the motility of the gallbladder and of the intestinal tract, as well as by bacterial enzymes in the intestine. The nuclear receptor farnesoid X receptor (FXR) and Gpbar1 (TGR5) are important set screws in this process. Bile acids have a vasodilatory effect, at least according to in vitro studies. The present review examines the question of the extent to which the increase in bile acids in plasma could be responsible for the hyperdynamic circulatory disturbance of liver cirrhosis and whether modulation of the bile acid pool, for example, via administration of ursodeoxycholic acid (UDCA) or via modulation of the dysbiosis present in liver cirrhosis could influence the hemodynamic disorder of liver cirrhosis. According to our analysis, the evidence for this is limited. Long-term studies on this question are lacking.
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Affiliation(s)
- Tilman Sauerbruch
- Department of Internal Medicine I, University of Bonn, Bonn, Germany
| | - Martin Hennenberg
- Department of Urology I, University Hospital, LMU Munich, Munich, Germany
| | - Jonel Trebicka
- Translational Hepatology, Medical Department, University of Frankfurt, Frankfurt, Germany
| | - Ulrich Beuers
- Department of Gastroenterology and Hepatology, Amsterdam University Medical Centers, location AMC, Amsterdam, Netherlands
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23
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Petrescu AD, DeMorrow S. Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. Cells 2021; 10:cells10081846. [PMID: 34440614 PMCID: PMC8392259 DOI: 10.3390/cells10081846] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023] Open
Abstract
Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.
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Affiliation(s)
- Anca D. Petrescu
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Sharon DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
- Central Texas Veterans Health Care System, Temple, TX 78712, USA
- Correspondence: ; Tel.: +1-512-495-5779
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24
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The pathophysiological function of non-gastrointestinal farnesoid X receptor. Pharmacol Ther 2021; 226:107867. [PMID: 33895191 DOI: 10.1016/j.pharmthera.2021.107867] [Citation(s) in RCA: 33] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2021] [Revised: 04/15/2021] [Accepted: 04/19/2021] [Indexed: 02/07/2023]
Abstract
Farnesoid X receptor (FXR) influences bile acid homeostasis and the progression of various diseases. While the roles of hepatic and intestinal FXR in enterohepatic transport of bile acids and metabolic diseases were reviewed previously, the pathophysiological functions of FXR in non-gastrointestinal cells and tissues have received little attention. Thus, the roles of FXR in the liver, immune system, nervous system, cardiovascular system, kidney, and pancreas beyond the gastrointestinal system are reviewed herein. Gain of FXR function studies in non-gastrointestinal tissues reveal that FXR signaling improves various experimentally-induced metabolic and immune diseases, including non-alcoholic fatty liver disease, type 2 diabetes, primary biliary cholangitis, sepsis, autoimmune diseases, multiple sclerosis, and diabetic nephropathy, while loss of FXR promotes regulatory T cells production, protects the brain against ischemic injury, atherosclerosis, and inhibits pancreatic tumor progression. The downstream pathways regulated by FXR are diverse and tissue/cell-specific, and FXR has both ligand-dependent and ligand-independent activities, all of which may explain why activation and inhibition of FXR signaling could produce paradoxical or even opposite effects in some experimental disease models. FXR signaling is frequently compromised by diseases, especially during the progressive stage, and rescuing FXR expression may provide a promising strategy for boosting the therapeutic effect of FXR agonists. Tissue/cell-specific modulation of non-gastrointestinal FXR could influence the treatment of various diseases. This review provides a guide for drug discovery and clinical use of FXR modulators.
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25
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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.
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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
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26
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Zhang R, Ma WQ, Fu MJ, Li J, Hu CH, Chen Y, Zhou MM, Gao ZJ, He YL. Overview of bile acid signaling in the cardiovascular system. World J Clin Cases 2021; 9:308-320. [PMID: 33521099 PMCID: PMC7812903 DOI: 10.12998/wjcc.v9.i2.308] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/06/2020] [Revised: 09/28/2020] [Accepted: 10/20/2020] [Indexed: 02/06/2023] Open
Abstract
Bile acids (BAs) are classically known to play a vital role in the metabolism of lipids and in absorption. It is now well established that BAs act as signaling molecules, activating different receptors (such as farnesoid X receptor, vitamin D receptor, Takeda G-protein-coupled receptor 5, sphingosine-1-phosphate, muscarinic receptors, and big potassium channels) and participating in the regulation of energy homeostasis and lipid and glucose metabolism. In addition, increased BAs can impair cardiovascular function in liver cirrhosis. Approximately 50% of patients with cirrhosis develop cirrhotic cardiomyopathy. Exposure to high concentrations of hydrophobic BAs has been shown to be related to adverse effects with respect to vascular tension, endothelial function, arrhythmias, coronary atherosclerotic heart disease, and heart failure. The BAs in the serum BA pool have relevant through their hydrophobicity, and the lipophilic BAs are more harmful to the heart. Interestingly, ursodeoxycholic acid is a hydrophilic BA, and it is used as a therapeutic drug to reverse and protect the harmful cardiac effects caused by hydrophobic elevated BAs. In order to elucidate the mechanism of BAs and cardiovascular function, abundant experiments have been conducted in vitro and in vivo. The aim of this review was to explore the mechanism of BAs in the cardiovascular system.
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Affiliation(s)
- Rou Zhang
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Wen-Qi Ma
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Meng-Jun Fu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Juan Li
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Chun-Hua Hu
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Yi Chen
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Mi-Mi Zhou
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Zhi-Jie Gao
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
| | - Ying-Li He
- Department of Infectious Diseases, The First Affiliated Hospital of Xi’an Jiaotong University, Xi’an 710061, Shaanxi Province, China
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27
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Li C, Yang J, Wang Y, Qi Y, Yang W, Li Y. Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases. Front Pharmacol 2020; 11:1247. [PMID: 32982723 PMCID: PMC7479173 DOI: 10.3389/fphar.2020.01247] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.
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Affiliation(s)
- Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Yang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu Wang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingzi Qi
- School of Health, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenqing Yang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunlun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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28
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Zeng C, Tan H. Gut Microbiota and Heart, Vascular Injury. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1238:107-141. [PMID: 32323183 DOI: 10.1007/978-981-15-2385-4_8] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
The gut microbiota plays an important role in maintaining human health. Accumulating evidence has indicated an intimate relationship between gut microbiota and cardiovascular diseases (CVD) which has become the leading cause of death worldwide. The alteration of gut microbial composition (gut dysbiosis) has been proven to contribute to atherosclerosis, the basic pathological process of CVD. In addition, the metabolites of gut microbiota have been found to be closely related to the development of CVD. For example, short-chain fatty acids are widely acclaimed beneficial effect against CVD, whereas trimethylamine-N-oxide is considered as a contributing factor in the development of CVD. In this chapter, we mainly discuss the gut microbial metabolite-involved mechanisms of CVD focusing on atherosclerosis, hypertension, diabetes, obesity, and heart failure. Targeting gut microbiota and related metabolites are novel and promising strategies for the treatment of CVD.
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Affiliation(s)
- Cheng Zeng
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China
| | - Hongmei Tan
- Department of Pathophysiology, Zhongshan School of Medicine, Sun Yat-sen University, Guangzhou, 510080, China.
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29
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Guizoni DM, Vettorazzi JF, Carneiro EM, Davel AP. Modulation of endothelium-derived nitric oxide production and activity by taurine and taurine-conjugated bile acids. Nitric Oxide 2019; 94:48-53. [PMID: 31669041 DOI: 10.1016/j.niox.2019.10.008] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/22/2019] [Revised: 09/20/2019] [Accepted: 10/21/2019] [Indexed: 02/08/2023]
Abstract
Taurine is a semiessential amino acid found at high concentrations in mammalian plasma and cells, where it regulates cellular functions such as ion flux, controls cell volume and serves as a substrate for conjugated bile acids (BAs). Exogenous administration of both taurine and taurine-conjugated BAs have also been implicated in the modulation of cardiovascular functions. This brief review summarizes the role of taurine and taurine-conjugated BAs in vascular relaxation through the modulation of endothelium-derived nitric oxide (NO). The effects of taurine on vascular health are controversial. However, in the presence of cardiometabolic risk factors, it has been proposed that taurine can increase vascular NO levels by increasing eNOS expression, eNOS phosphorylation on Ser1177, NO bioavailability, the level of antioxidative defense, and the l-arginine/NOS inhibitor asymmetric dimethylarginine (ADMA) ratio. The taurine-conjugated BA-mediated activation of Farnesoid X receptor (FXR), G protein-coupled BA receptor (TGR5) and/or muscarinic 3 receptor (M3) was also reported to increase vascular NO production. FXR activation increases eNOS expression and may reduce ADMA formation, while TGR5 increases mobilization of Ca2+ and phosphorylation of eNOS and Akt in endothelial cells. Furthermore, taurine and taurine-conjugated BAs might regulate NO synthesis and activity by enhancing H2S generation. Several studies have demonstrated the beneficial effects of both taurine and taurine-conjugated BAs in reversing the endothelial dysfunction associated with diabetes, atherosclerosis, hypertension, obesity, malnutrition, and smoking. In addition, taurine-conjugated BAs have emerged as a potential treatment for portal hypertension. Despite these favorable findings, there is a need to further explore the mechanisms and signaling pathways underlying the endothelial effects of taurine and taurine-conjugated BAs. Here, we summarize the main findings regarding the effects of taurine and taurine-conjugated BAs on the endothelial dysfunction associated with altered NO metabolism in cardiovascular diseases.
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Affiliation(s)
- Daniele M Guizoni
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil
| | - Jean F Vettorazzi
- Obesity and Comorbidities Research Center, São Paulo Research Foundation (FAPESP), Institute of Biology, Department of Structural and Functional Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil
| | - Everardo M Carneiro
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil; Obesity and Comorbidities Research Center, São Paulo Research Foundation (FAPESP), Institute of Biology, Department of Structural and Functional Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil
| | - Ana Paula Davel
- Department of Structural and Functional Biology, Institute of Biology, University of Campinas/UNICAMP, Campinas, SP, Brazil.
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30
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Masaoutis C, Theocharis S. The farnesoid X receptor: a potential target for expanding the therapeutic arsenal against kidney disease. Expert Opin Ther Targets 2018; 23:107-116. [PMID: 30577722 DOI: 10.1080/14728222.2019.1559825] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
INTRODUCTION Farnesoid X receptor (FXR) is a nuclear bile acid (BA) receptor widely distributed among tissues, a major sensor of BA levels, primary suppressor of hepatic BA synthesis and secondary regulator of lipid metabolism and inflammation. Chronic kidney disease is a common, multifactorial condition with metabolic and inflammatory causes and implications. An array of natural and synthetic FXR agonists has been developed, but not yet studied clinically in kidney disease. Areas covered: Following a summary of FXR's physiological functions in the kidney, we discuss its effects in renal disease with emphasis on chronic and acute kidney disease, chemotherapy-induced nephrotoxicity, and renal neoplasia. Most information is derived from animal models; no relevant clinical study has been conducted to date. Expert opinion: Most available preclinical data indicates a promising outlook for clinical research in this direction. We believe FXR agonism to be an auspicious approach to treating renal disease, considering that multifactorial diseases call for ideally wide-reaching therapies.
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Affiliation(s)
- Christos Masaoutis
- a First Department of Pathology, Medical School , National and Kapodistrian University of Athens , Athens , Greece
| | - Stamatios Theocharis
- a First Department of Pathology, Medical School , National and Kapodistrian University of Athens , Athens , Greece
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31
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Ðanić M, Stanimirov B, Pavlović N, Goločorbin-Kon S, Al-Salami H, Stankov K, Mikov M. Pharmacological Applications of Bile Acids and Their Derivatives in the Treatment of Metabolic Syndrome. Front Pharmacol 2018; 9:1382. [PMID: 30559664 PMCID: PMC6287190 DOI: 10.3389/fphar.2018.01382] [Citation(s) in RCA: 76] [Impact Index Per Article: 10.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2018] [Accepted: 11/09/2018] [Indexed: 12/12/2022] Open
Abstract
Apart from well-known functions of bile acids in digestion and solubilization of lipophilic nutrients and drugs in the small intestine, the emerging evidence from the past two decades identified the role of bile acids as signaling, endocrine molecules that regulate the glucose, lipid, and energy metabolism through complex and intertwined pathways that are largely mediated by activation of nuclear receptor farnesoid X receptor (FXR) and cell surface G protein-coupled receptor 1, TGR5 (also known as GPBAR1). Interactions of bile acids with the gut microbiota that result in the altered composition of circulating and intestinal bile acids pool, gut microbiota composition and modified signaling pathways, are further extending the complexity of biological functions of these steroid derivatives. Thus, bile acids signaling pathways have become attractive targets for the treatment of various metabolic diseases and metabolic syndrome opening the new potential avenue in their treatment. In addition, there is a significant effort to unveil some specific properties of bile acids relevant to their intrinsic potency and selectivity for particular receptors and to design novel modulators of these receptors with improved pharmacokinetic and pharmacodynamic profiles. This resulted in synthesis of few semi-synthetic bile acids derivatives such as 6α-ethyl-chenodeoxycholic acid (obeticholic acid, OCA), norursodeoxycholic acid (norUDCA), and 12-monoketocholic acid (12-MKC) that are proven to have positive effect in metabolic and hepato-biliary disorders. This review presents an overview of the current knowledge related to bile acids implications in glucose, lipid and energy metabolism, as well as a potential application of bile acids in metabolic syndrome treatment with future perspectives.
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Affiliation(s)
- Maja Ðanić
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Bojan Stanimirov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Nebojša Pavlović
- Department of Pharmacy, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | | | - Hani Al-Salami
- Biotechnology and Drug Development Research Laboratory, School of Pharmacy and Biomedical Sciences, Biosciences Research Precinct, Curtin Health Innovation Research Institute, Curtin University, Perth, WA, Australia
| | - Karmen Stankov
- Department of Biochemistry, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
| | - Momir Mikov
- Department of Pharmacology, Toxicology and Clinical Pharmacology, Faculty of Medicine, University of Novi Sad, Novi Sad, Serbia
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32
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Gray DW, Welsh MD, Mansoor F, Doherty S, Chevallier OP, Elliott CT, Mooney MH. DIVA metabolomics: Differentiating vaccination status following viral challenge using metabolomic profiles. PLoS One 2018; 13:e0194488. [PMID: 29621258 PMCID: PMC5886402 DOI: 10.1371/journal.pone.0194488] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2017] [Accepted: 03/05/2018] [Indexed: 12/20/2022] Open
Abstract
Bovine Respiratory Disease (BRD) is a major source of economic loss within the agricultural industry. Vaccination against BRD-associated viruses does not offer complete immune protection and vaccine failure animals present potential routes for disease spread. Serological differentiation of infected from vaccinated animals (DIVA) is possible using antigen-deleted vaccines, but during virus outbreaks DIVA responses are masked by wild-type virus preventing accurate serodiagnosis. Previous work by the authors has established the potential for metabolomic profiling to reveal metabolites associated with systemic immune responses to vaccination. The current study builds on this work by demonstrating for the first time the potential to use plasma metabolite profiling to differentiate between vaccinated and non-vaccinated animals following infection-challenge. Male Holstein Friesian calves were intranasally vaccinated (Pfizer RISPOVAL®PI3+RSV) and subsequently challenged with Bovine Parainfluenza Virus type-3 (BPI3V) via nasal inoculation. Metabolomic plasma profiling revealed that viral challenge led to a shift in acquired plasma metabolite profiles from day 2 to 20 p.i., with 26 metabolites identified whose peak intensities were significantly different following viral challenge depending on vaccination status. Elevated levels of biliverdin and bilirubin and decreased 3-indolepropionic acid in non-vaccinated animals at day 6 p.i. may be associated with increased oxidative stress and reactive oxygen scavenging at periods of peak virus titre. During latter stages of infection, increased levels of N-[(3α,5β,12α)-3,12-dihydroxy-7,24-dioxocholan-24-yl]glycine and lysophosphatidycholine and decreased enterolactone in non-vaccinated animals may reflect suppression of innate immune response mechanisms and progression to adaptive immune responses. Levels of hexahydrohippurate were also shown to be significantly elevated in non-vaccinated animals from days 6 to 20 p.i. These findings demonstrate the potential of metabolomic profiling to identify plasma markers that can be employed in disease diagnostic applications to both differentially identify infected non-vaccinated animals during disease outbreaks and provide greater information on the health status of infected animals.
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Affiliation(s)
- Darren W. Gray
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
- * E-mail:
| | - Michael D. Welsh
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Fawad Mansoor
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Simon Doherty
- Veterinary Sciences Division (VSD), Agri-Food and Biosciences Institute (AFBI), Belfast, Northern Ireland, United Kingdom
| | - Olivier P. Chevallier
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
| | - Christopher T. Elliott
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
| | - Mark H. Mooney
- Institute for Global Food Security (IGFS), School of Biological Sciences, Queen’s University Belfast (QUB), Belfast, Northern Ireland, United Kingdom
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Ferrigno A, Di Pasqua LG, Berardo C, Siciliano V, Rizzo V, Adorini L, Richelmi P, Vairetti M. The farnesoid X receptor agonist obeticholic acid upregulates biliary excretion of asymmetric dimethylarginine via MATE-1 during hepatic ischemia/reperfusion injury. PLoS One 2018; 13:e0191430. [PMID: 29346429 PMCID: PMC5773219 DOI: 10.1371/journal.pone.0191430] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2017] [Accepted: 01/04/2018] [Indexed: 12/12/2022] Open
Abstract
Background We previously showed that increased asymmetric dimethylarginine (ADMA) biliary excretion occurs during hepatic ischemia/reperfusion (I/R), prompting us to study the effects of the farnesoid X receptor (FXR) agonist obeticholic acid (OCA) on bile, serum and tissue levels of ADMA after I/R. Material and methods Male Wistar rats were orally administered 10mg/kg/day of OCA or vehicle for 5 days and were subjected to 60 min partial hepatic ischemia or sham-operated. After a 60 min reperfusion, serum, tissue and bile ADMA levels, liver mRNA and protein expression of ADMA transporters (CAT-1, CAT-2A, CAT-2B, OCT-1, MATE-1), and enzymes involved in ADMA synthesis (protein-arginine-N-methyltransferase-1, PRMT-1) and metabolism (dimethylarginine-dimethylaminohydrolase-1, DDAH-1) were measured. Results OCA administration induced a further increase in biliary ADMA levels both in sham and I/R groups, with no significant changes in hepatic ADMA content. A reduction in CAT-1, CAT-2A or CAT-2B transcripts was found in OCA-treated sham-operated rats compared with vehicle. Conversely, OCA administration did not change CAT-1, CAT-2A or CAT-2B expression, already reduced by I/R. However, a marked decrease in OCT-1 and increase in MATE-1 expression was observed. A similar trend occurred with protein expression. Conclusion The reduced mRNA expression of hepatic CAT transporters suggests that the increase in serum ADMA levels is probably due to decreased liver uptake of ADMA from the systemic circulation. Conversely, the mechanism involved in further increasing biliary ADMA levels in sham and I/R groups treated with OCA appears to be MATE-1-dependent.
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Affiliation(s)
- Andrea Ferrigno
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | | | - Clarissa Berardo
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Veronica Siciliano
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Vittoria Rizzo
- Department of Molecular Medicine, IRCCS San Matteo, University of Pavia, Pavia, Italy
| | - Luciano Adorini
- Intercept Pharmaceuticals, San Diego, California, United States of America
| | - Plinio Richelmi
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
| | - Mariapia Vairetti
- Department of Internal Medicine and Therapeutics, University of Pavia, Pavia, Italy
- * E-mail:
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Comeglio P, Morelli A, Adorini L, Maggi M, Vignozzi L. Beneficial effects of bile acid receptor agonists in pulmonary disease models. Expert Opin Investig Drugs 2017; 26:1215-1228. [PMID: 28949776 DOI: 10.1080/13543784.2017.1385760] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Abstract
INTRODUCTION Bile acids act as steroid hormones, controlling lipid, glucose and energy metabolism, as well as inflammation and fibrosis. Their actions are implemented through activation of nuclear (FXR, VDR, PXR) and membrane G protein-coupled (TGR5, S1PR2) receptors. Areas covered: This review discusses the potential of FXR and TGR5 as therapeutic targets in the treatment of pulmonary disorders linked to metabolism and/or inflammation. Obeticholic acid (OCA) is the most clinically advanced bile acid-derived agonist for FXR-mediated anti-inflammatory and anti-fibrotic effects. It therefore represents an attractive pharmacological approach for the treatment of lung conditions characterized by vascular and endothelial dysfunctions. Expert opinion: Inflammation, vascular remodeling and fibrotic processes characterize the progression of pulmonary arterial hypertension (PAH) and idiopathic pulmonary fibrosis (IPF). These processes are only partially targeted by the available therapeutic options and still represent a relevant medical need. The results hereby summarized demonstrate OCA efficacy in preventing experimental lung disorders, i.e. monocrotaline-induced PAH and bleomycin-induced fibrosis, by abating proinflammatory and vascular remodeling progression. TGR5 is also expressed in the lung, and targeting the TGR5 pathway, using the TGR5 agonist INT-777 or the dual FXR/TGR5 agonist INT-767, could also contribute to the treatment of pulmonary disorders mediated by inflammation and fibrosis.
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Affiliation(s)
- Paolo Comeglio
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Annamaria Morelli
- b Department of Experimental and Clinical Medicine , University of Florence , Florence , Italy
| | | | - Mario Maggi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
| | - Linda Vignozzi
- a Department of Biomedical, Experimental and Clinical Sciences , University of Florence , Florence , Italy
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Voiosu A, Wiese S, Voiosu T, Bendtsen F, Møller S. Bile acids and cardiovascular function in cirrhosis. Liver Int 2017; 37:1420-1430. [PMID: 28222247 DOI: 10.1111/liv.13394] [Citation(s) in RCA: 43] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/02/2016] [Accepted: 02/12/2017] [Indexed: 02/13/2023]
Abstract
Cirrhotic cardiomyopathy and the hyperdynamic syndrome are clinically important complications of cirrhosis, but their exact pathogenesis is still partly unknown. Experimental models have proven the cardiotoxic effects of bile acids and recent studies of their varied receptor-mediated functions offer new insight into their involvement in cardiovascular dysfunction in cirrhosis. Bile acid receptors such as farnesoid X-activated receptor and TGR5 are currently under investigation as potential therapeutic targets in a variety of pathological conditions. These receptors have also recently been identified in cardiomyocytes, vascular endothelial cells and smooth muscle cells where they seem to play an important role in cellular metabolism. Chronic cholestasis leading to abnormal levels of circulating bile acids alters the normal signalling pathways and contributes to the development of profound cardiovascular disturbances. This review summarizes the evidence regarding the role of bile acids and their receptors in the generation of cardiovascular dysfunction in cirrhosis.
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Affiliation(s)
- Andrei Voiosu
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Gastroenterology and Hepatology Department, Colentina Clinical Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Signe Wiese
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Theodor Voiosu
- Gastroenterology and Hepatology Department, Colentina Clinical Hospital, Bucharest, Romania.,"Carol Davila" University of Medicine and Pharmacy, Bucharest, Romania
| | - Flemming Bendtsen
- Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark.,Gastro Unit, Medical Division, Hvidovre Hospital, Hvidovre, Denmark
| | - Søren Møller
- Department of Clinical Physiology and Nuclear Medicine, Center for Functional and Diagnostic Imaging and Research, Hvidovre Hospital, Hvidovre, Denmark.,Faculty of Health Sciences, University of Copenhagen, Copenhagen, Denmark
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Dopico AM, Bukiya AN. Regulation of Ca 2+-Sensitive K + Channels by Cholesterol and Bile Acids via Distinct Channel Subunits and Sites. CURRENT TOPICS IN MEMBRANES 2017; 80:53-93. [PMID: 28863822 DOI: 10.1016/bs.ctm.2017.07.001] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cholesterol (CLR) conversion into bile acids (BAs) in the liver constitutes the major pathway for CLR elimination from the body. Moreover, these steroids regulate each other's metabolism. While the roles of CLR and BAs in regulating metabolism and tissue function are well known, research of the last two decades revealed the existence of specific protein receptors for CLR or BAs in tissues with minor contribution to lipid metabolism, raising the possibility that these lipids serve as signaling molecules throughout the body. Among other lipids, CLR and BAs regulate ionic current mediated by the activity of voltage- and Ca2+-gated, K+ channels of large conductance (BK channels) and, thus, modulate cell physiology and participate in tissue pathophysiology. Initial work attributed modification of BK channel function by CLR or BAs to the capability of these steroids to directly interact with bilayer lipids and thus alter the physicochemical properties of the bilayer with eventual modification of BK channel function. Based on our own work and that of others, we now review evidence that supports direct interactions between CLR or BA and specific BK protein subunits, and the consequence of such interactions on channel activity and organ function, with a particular emphasis on arterial smooth muscle. For each steroid type, we will also briefly discuss several mechanisms that may underlie modification of channel steady-state activity. Finally, we will present novel computational data that provide a chemical basis for differential recognition of CLR vs lithocholic acid by distinct BK channel subunits and recognition sites.
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Affiliation(s)
- Alex M Dopico
- College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States.
| | - Anna N Bukiya
- College of Medicine, The University of Tennessee Health Science Center, Memphis, TN, United States
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Kang SH, Kim MY, Baik SK. Novelties in the pathophysiology and management of portal hypertension: new treatments on the horizon. Hepatol Int 2017; 12:112-121. [DOI: 10.1007/s12072-017-9806-1] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 06/08/2017] [Indexed: 02/06/2023]
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Ellulu MS, Patimah I, Khaza’ai H, Rahmat A, Abed Y. Obesity and inflammation: the linking mechanism and the complications. Arch Med Sci 2017; 13:851-863. [PMID: 28721154 PMCID: PMC5507106 DOI: 10.5114/aoms.2016.58928] [Citation(s) in RCA: 1180] [Impact Index Per Article: 147.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 12/28/2015] [Indexed: 12/11/2022] Open
Abstract
Obesity is the accumulation of abnormal or excessive fat that may interfere with the maintenance of an optimal state of health. The excess of macronutrients in the adipose tissues stimulates them to release inflammatory mediators such as tumor necrosis factor α and interleukin 6, and reduces production of adiponectin, predisposing to a pro-inflammatory state and oxidative stress. The increased level of interleukin 6 stimulates the liver to synthesize and secrete C-reactive protein. As a risk factor, inflammation is an imbedded mechanism of developed cardiovascular diseases including coagulation, atherosclerosis, metabolic syndrome, insulin resistance, and diabetes mellitus. It is also associated with development of non-cardiovascular diseases such as psoriasis, depression, cancer, and renal diseases. On the other hand, a reduced level of adiponectin, a significant predictor of cardiovascular mortality, is associated with impaired fasting glucose, leading to type-2 diabetes development, metabolic abnormalities, coronary artery calcification, and stroke. Finally, managing obesity can help reduce the risks of cardiovascular diseases and poor outcome via inhibiting inflammatory mechanisms.
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Affiliation(s)
- Mohammed S. Ellulu
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Malaysia
| | - Ismail Patimah
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Malaysia
| | - Huzwah Khaza’ai
- Department of Biomedical Science, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Serdang, Malaysia
| | - Asmah Rahmat
- Cancer Resource and Educational Centre (CARE), Faculty of Medicine and Health Sciences, Universiti Putra Malaysia (UPM), Malaysia
| | - Yehia Abed
- Faculty of Public Health, Al Quds University of Gaza, Palestine
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Schwabl P, Laleman W. Novel treatment options for portal hypertension. Gastroenterol Rep (Oxf) 2017; 5:90-103. [PMID: 28533907 PMCID: PMC5421460 DOI: 10.1093/gastro/gox011] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2017] [Accepted: 03/12/2017] [Indexed: 12/13/2022] Open
Abstract
Portal hypertension is most frequently associated with cirrhosis and is a major driver for associated complications, such as variceal bleeding, ascites or hepatic encephalopathy. As such, clinically significant portal hypertension forms the prelude to decompensation and impacts significantly on the prognosis of patients with liver cirrhosis. At present, non-selective β-blockers, vasopressin analogues and somatostatin analogues are the mainstay of treatment but these strategies are far from satisfactory and only target splanchnic hyperemia. In contrast, safe and reliable strategies to reduce the increased intrahepatic resistance in cirrhotic patients still represent a pending issue. In recent years, several preclinical and clinical trials have focused on this latter component and other therapeutic avenues. In this review, we highlight novel data in this context and address potentially interesting therapeutic options for the future.
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Affiliation(s)
- Philipp Schwabl
- Division of Gastroenterology and Hepatology, Department of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Wim Laleman
- Department of Gastroenterology and Hepatology, University Hospitals Leuven, KU Leuven, Leuven, Belgium
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Schwabl P, Hambruch E, Seeland BA, Hayden H, Wagner M, Garnys L, Strobel B, Schubert TL, Riedl F, Mitteregger D, Burnet M, Starlinger P, Oberhuber G, Deuschle U, Rohr-Udilova N, Podesser BK, Peck-Radosavljevic M, Reiberger T, Kremoser C, Trauner M. The FXR agonist PX20606 ameliorates portal hypertension by targeting vascular remodelling and sinusoidal dysfunction. J Hepatol 2017; 66:724-733. [PMID: 27993716 DOI: 10.1016/j.jhep.2016.12.005] [Citation(s) in RCA: 135] [Impact Index Per Article: 16.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2015] [Revised: 11/27/2016] [Accepted: 12/07/2016] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Steroidal farnesoid X receptor (FXR) agonists demonstrated potent anti-fibrotic activities and lowered portal hypertension in experimental models. The impact of the novel non-steroidal and selective FXR agonist PX20606 on portal hypertension and fibrosis was explored in this study. METHODS In experimental models of non-cirrhotic (partial portal vein ligation, PPVL, 7days) and cirrhotic (carbon tetrachloride, CCl4, 14weeks) portal hypertension, PX20606 (PX,10mg/kg) or the steroidal FXR agonist obeticholic acid (OCA,10mg/kg) were gavaged. We then measured portal pressure, intrahepatic vascular resistance, liver fibrosis and bacterial translocation. RESULTS PX decreased portal pressure in non-cirrhotic PPVL (12.6±1.7 vs. 10.4±1.1mmHg; p=0.020) and cirrhotic CCl4 (15.2±0.5 vs. 11.8±0.4mmHg; p=0.001) rats. In PPVL animals, we observed less bacterial translocation (-36%; p=0.041), a decrease in lipopolysaccharide binding protein (-30%; p=0.024) and splanchnic tumour necrosis factor α levels (-39%; p=0.044) after PX treatment. In CCl4 rats, PX decreased fibrotic Sirius Red area (-43%; p=0.005), hepatic hydroxyproline (-66%; p<0.001), and expression of profibrogenic proteins (Col1a1, α smooth muscle actin, transforming growth factor β). CCl4-PX rats had significantly lower transaminase levels and reduced hepatic macrophage infiltration. Moreover, PX induced sinusoidal vasodilation (upregulation of cystathionase, dimethylaminohydrolase (DDAH)1, endothelial nitric oxide synthase (eNOS), GTP-cyclohydrolase1) and reduced intrahepatic vasoconstriction (downregulation of endothelin-1, p-Moesin). In cirrhosis, PX improved endothelial dysfunction (decreased von-Willebrand factor) and normalized overexpression of vascular endothelial growth factor, platelet-derived growth factor and angiopoietins. While short-term 3-day PX treatment reduced portal pressure (-14%; p=0.041) by restoring endothelial function, 14week PX therapy additionally inhibited sinusoidal remodelling and decreased portal pressure to a greater extent (-22%; p=0.001). In human liver sinusoidal endothelial cells, PX increased eNOS and DDAH expression. CONCLUSIONS The non-steroidal FXR agonist PX20606 ameliorates portal hypertension by reducing liver fibrosis, vascular remodelling and sinusoidal dysfunction. LAY SUMMARY The novel drug PX20606 activates the bile acid receptor FXR and shows beneficial effects in experimental liver cirrhosis: In the liver, it reduces scarring and inflammation, and also widens blood vessels. Thus, PX20606 leads to an improved blood flow through the liver and decreases hypertension of the portal vein. Additionally, PX20606 improves the altered intestinal barrier and decreases bacterial migration from the gut.
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Affiliation(s)
- Philipp Schwabl
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Eva Hambruch
- Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany
| | - Berit A Seeland
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Hubert Hayden
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Michael Wagner
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Lukas Garnys
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bastian Strobel
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Tim-Lukas Schubert
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Florian Riedl
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Dieter Mitteregger
- Vienna Medical Innovation Center (VMIC), Group Practice LABORS.at, Vienna, Austria
| | - Michael Burnet
- Synovo GmbH, Paul-Ehrlich-Str. 15, 72076 Tübingen, Germany
| | | | - Georg Oberhuber
- Dept. of Pathology, Medical University of Vienna, Vienna, Austria
| | - Ulrich Deuschle
- Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany
| | - Nataliya Rohr-Udilova
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Bruno K Podesser
- Dept. of Biomedical Research, Medical University of Vienna, Vienna, Austria
| | - Markus Peck-Radosavljevic
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Thomas Reiberger
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria
| | - Claus Kremoser
- Phenex Pharmaceuticals, Waldhofer Strasse 104, 69123 Heidelberg, Germany
| | - Michael Trauner
- Div. of Gastroenterology and Hepatology, Dept. of Internal Medicine III, Medical University of Vienna, Vienna, Austria.
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Desai M, Mathur B, Eblimit Z, Vasquez H, Taegtmeyer H, Karpen S, Penny DJ, Moore DD, Anakk S. Bile acid excess induces cardiomyopathy and metabolic dysfunctions in the heart. Hepatology 2017; 65:189-201. [PMID: 27774647 PMCID: PMC5299964 DOI: 10.1002/hep.28890] [Citation(s) in RCA: 85] [Impact Index Per Article: 10.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/08/2016] [Revised: 09/07/2016] [Accepted: 09/30/2016] [Indexed: 12/31/2022]
Abstract
UNLABELLED Cardiac dysfunction in patients with liver cirrhosis is strongly associated with increased serum bile acid concentrations. Here we show that excess bile acids decrease fatty acid oxidation in cardiomyocytes and can cause heart dysfunction, a cardiac syndrome that we term cholecardia. Farnesoid X receptor; Small Heterodimer Partner double knockout mice, a model for bile acid overload, display cardiac hypertrophy, bradycardia, and exercise intolerance. In addition, double knockout mice exhibit an impaired cardiac response to catecholamine challenge. Consistent with this decreased cardiac function, we show that elevated serum bile acids reduce cardiac fatty acid oxidation both in vivo and ex vivo. We find that increased bile acid levels suppress expression of proliferator-activated receptor-γ coactivator 1α, a key regulator of fatty acid metabolism, and that proliferator-activated receptor-γ coactivator 1α overexpression in cardiac cells was able to rescue the bile acid-mediated reduction in fatty acid oxidation genes. Importantly, intestinal bile acid sequestration with cholestyramine was sufficient to reverse the observed heart dysfunction in the double knockout mice. CONCLUSIONS Decreased proliferator-activated receptor-γ coactivator 1α expression contributes to the metabolic dysfunction in cholecardia so that reducing serum bile acid concentrations may be beneficial against the metabolic and pathological changes in the heart. (Hepatology 2017;65:189-201).
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Affiliation(s)
- Moreshwar Desai
- Section of Pediatric Critical Care, Baylor College of Medicine, Houston, TX
| | - Bhoomika Mathur
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL
| | - Zeena Eblimit
- Section of Pediatric Critical Care, Baylor College of Medicine, Houston, TX
| | - Hernan Vasquez
- Dept. of Cardiology University of Texas Health Sciences Center, Houston, TX
| | | | - Saul Karpen
- Pediatric Gastroenterology, Emory School of Medicine, Atlanta, GA
| | - Daniel J. Penny
- Department of Pediatric Cardiology, Baylor College of Medicine, Houston, TX
| | - David D. Moore
- Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL
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Zhang R, Ran H, Peng L, Zhang Y, Shen W, Sun T, Cao F, Chen Y. Farnesoid X receptor regulates vasoreactivity via Angiotensin II type 2 receptor and the kallikrein-kinin system in vascular endothelial cells. Clin Exp Pharmacol Physiol 2016; 43:327-34. [PMID: 26710942 DOI: 10.1111/1440-1681.12535] [Citation(s) in RCA: 7] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2014] [Revised: 12/21/2015] [Accepted: 12/23/2015] [Indexed: 01/02/2023]
Abstract
Vascular farnesoid X receptor (FXR) ligands have been shown previously to regulate vascular tension. This study investigated whether FXR activation regulates vasoreactivity via the angiotensin II (Ang II) type 2 receptor (AT2 R) and the kallikrein-kinin system in rat aortic vascular endothelial cells (RAECs). Protein abundances of Ang II type 1 receptor (AT1 R), AT2 R, bradykinin type 1/2 receptor (B1 R, B2 R), small heterodimer partner-1 (SHP-1) and the endothelial and inducible NO synthases (eNOS/iNOS) were analysed by Western blotting. Real-time quantitative polymerase chain reaction was performed to analyse expression of eNOS and iNOS mRNA. Kallikrein activity and bradykinin content were assayed using spectrophotometry and a bradykinin assay kit, respectively. Aortic vasoconstriction and vasodilation were also investigated following FXR activation in the presence or absence of AT2 R and B2 R blockade. It was found that the FXR agonists GW4064 and INT-747, in a dose-dependent manner, increased the protein abundance of AT2 R, B2 R and SHP-1 and decreased that of AT1 R. AT2 R blockade with PD123319 reversed effects of FXR agonists on kallikrein activity and levels of SHP-1, B2 R and bradykinin. Moreover, it was found that GW4064 and INT-747 upregulated expression of eNOS and enhanced NOS activity, which attenuated vasoconstriction and induced vasodilation, respectively. These effects were partially reversed by PD123319 and by B2 R blockade with HOE140. The current work suggests that FXR regulates vascular tension by controlling the eNOS-NO system via activation of a pathway mediated by AT2 R-B2 R pathway in RAECs.
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Affiliation(s)
- Ran Zhang
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Haihong Ran
- Department of Geriatric Haematology, Chinese PLA General Hospital, Beijing, China
| | - Liang Peng
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Ying Zhang
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Wenbin Shen
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Ting Sun
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Feng Cao
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
| | - Yundai Chen
- Department of Cardiology, Chinese PLA General Hospital, Beijing, China
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Fiorucci S, Zampella A, Cirino G, Bucci M, Distrutti E. Decoding the vasoregulatory activities of bile acid-activated receptors in systemic and portal circulation: role of gaseous mediators. Am J Physiol Heart Circ Physiol 2016; 312:H21-H32. [PMID: 27765751 DOI: 10.1152/ajpheart.00577.2016] [Citation(s) in RCA: 39] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/29/2016] [Revised: 10/04/2016] [Accepted: 10/04/2016] [Indexed: 01/06/2023]
Abstract
Bile acids are end products of cholesterol metabolism generated in the liver and released in the intestine. Primary and secondary bile acids are the result of the symbiotic relation between the host and intestinal microbiota. In addition to their role in nutrient absorption, bile acids are increasingly recognized as regulatory signals that exert their function beyond the intestine by activating a network of membrane and nuclear receptors. The best characterized of these bile acid-activated receptors, GPBAR1 (also known as TGR5) and the farnesosid-X-receptor (FXR), have also been detected in the vascular system and their activation mediates the vasodilatory effects of bile acids in the systemic and splanchnic circulation. GPBAR1, is a G protein-coupled receptor, that is preferentially activated by lithocholic acid (LCA) a secondary bile acid. GPBAR1 is expressed in endothelial cells and liver sinusoidal cells (LSECs) and responds to LCA by regulating the expression of both endothelial nitric oxide synthase (eNOS) and cystathionine-γ-lyase (CSE), an enzyme involved in generation of hydrogen sulfide (H2S). Activation of CSE by GPBAR1 ligands in LSECs is due to genomic and nongenomic effects, involves protein phosphorylation, and leads to release of H2S. Despite that species-specific effects have been described, vasodilation caused by GPBAR1 ligands in the liver microcirculation and aortic rings is abrogated by inhibition of CSE but not by eNOS inhibitor. Vasodilation caused by GPBAR1 (and FXR) ligands also involves large conductance calcium-activated potassium channels likely acting downstream to H2S. The identification of GPBAR1 as a vasodilatory receptor is of relevance in the treatment of complex disorders including metabolic syndrome-associated diseases, liver steatohepatitis, and portal hypertension.
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Affiliation(s)
- Stefano Fiorucci
- Department of Surgical and Biomedical Sciences, University of Perugia, Perugia, Italy;
| | - Angela Zampella
- Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and
| | - Mariarosaria Bucci
- Department of Pharmacy, University of Naples "Federico II," Naples, Italy; and
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Moraes LA, Unsworth AJ, Vaiyapuri S, Ali MS, Sasikumar P, Sage T, Flora GD, Bye AP, Kriek N, Dorchies E, Molendi-Coste O, Dombrowicz D, Staels B, Bishop-Bailey D, Gibbins JM. Farnesoid X Receptor and Its Ligands Inhibit the Function of Platelets. Arterioscler Thromb Vasc Biol 2016; 36:2324-2333. [PMID: 27758768 DOI: 10.1161/atvbaha.116.308093] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2015] [Accepted: 09/20/2016] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Although initially seemingly paradoxical because of the lack of nucleus, platelets possess many transcription factors that regulate their function through DNA-independent mechanisms. These include the farnesoid X receptor (FXR), a member of the superfamily of ligand-activated transcription factors, that has been identified as a bile acid receptor. In this study, we show that FXR is present in human platelets and FXR ligands, GW4064 and 6α-ethyl-chenodeoxycholic acid, modulate platelet activation nongenomically. APPROACH AND RESULTS FXR ligands inhibited the activation of platelets in response to stimulation of collagen or thrombin receptors, resulting in diminished intracellular calcium mobilization, secretion, fibrinogen binding, and aggregation. Exposure to FXR ligands also reduced integrin αIIbβ3 outside-in signaling and thereby reduced the ability of platelets to spread and to stimulate clot retraction. FXR function in platelets was found to be associated with the modulation of cyclic guanosine monophosphate levels in platelets and associated downstream inhibitory signaling. Platelets from FXR-deficient mice were refractory to the actions of FXR agonists on platelet function and cyclic nucleotide signaling, firmly linking the nongenomic actions of these ligands to the FXR. CONCLUSIONS This study provides support for the ability of FXR ligands to modulate platelet activation. The atheroprotective effects of GW4064, with its novel antiplatelet effects, indicate FXR as a potential target for the prevention of atherothrombotic disease.
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Affiliation(s)
- Leonardo A Moraes
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK.,Department of Physiology & NUS Immunology Program, Centre for Life Sciences, Yong Loo Lin School of Medicine, National University of Singapore, 117456, Singapore
| | - Amanda J Unsworth
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | | | - Marfoua S Ali
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Parvathy Sasikumar
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Tanya Sage
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Gagan D Flora
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Alex P Bye
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Neline Kriek
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
| | - Emilie Dorchies
- European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France
| | - Olivier Molendi-Coste
- European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France
| | - David Dombrowicz
- European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), F-59000, Lille, France; INSERM UMR1011, F-59000 Lille, France, University of Lille, F-59000 Lille, France; Institut Pasteur de Lille, F-59019 Lille, France
| | - David Bishop-Bailey
- Comparative Biomedical Sciences, Royal Veterinary College, University of London, London, NW1 OTU, UK
| | - Jonathan M Gibbins
- Institute for Cardiovascular and Metabolic Research, School of Biological Sciences, Harborne Building, University of Reading, Reading, Berkshire, RG6 6AS, UK
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Fiorucci S, Distrutti E. Targeting the transsulfuration-H2S pathway by FXR and GPBAR1 ligands in the treatment of portal hypertension. Pharmacol Res 2016; 111:749-756. [PMID: 27475883 DOI: 10.1016/j.phrs.2016.07.040] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/30/2016] [Revised: 07/25/2016] [Accepted: 07/26/2016] [Indexed: 12/12/2022]
Abstract
Cirrhosis is a end-stage disease of the liver in which fibrogenesis, angiogenesis and distortion of intrahepatic microcirculation lead to increased intrahepatic resistance to portal blood flow, a condition known as portal hypertension. Portal hypertension is maintained by a variety of molecular mechanisms including sinusoidal endothelial cells (LSECs) hyporeactivity, activation of hepatic stellate cells (HSCs), reduction in hepatic endothelial nitric oxide synthase (eNOS) activity along with increased eNOS-derived NO generation in the splanchnic and systemic circulations. A reduction of the expression/function of the two major hydrogen sulfide (H2S)-producing enzymes, cystathionine γ-lyase (CSE) and cystathionine β-synthase (CBS), has also been demonstrated. A deficit in the transsulfuration pathway leading to the accumulation of homocysteine might contribute to defective generation of H2S and endothelial hyporeactivity. Bile acids are ligands for nuclear receptors, such as farnesoid X receptor (FXR), and G-protein-coupled receptors (GPCRs), such as the G-protein bile acid receptor 1 (GPBAR1). FXR and GPBAR1 ligands regulate the expression/activity of CSE by both genomic and non-genomic effects and have been proved effective in protecting against endothelial dysfunction observed in rodent models of cirrhosis. GPBAR1, a receptor for secondary bile acids, is selectively expressed by LSECs and its activation increases the expression of CSE and attenuates the production of endotelin-1, a potent vasoconstrictor agent. In vivo GPBAR1 ligand attenuates the imbalance between vasodilatory and vaso-constricting agents, making GPBAR1 a promising target in the treatment of portal hypertension.
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MESH Headings
- Animals
- Antihypertensive Agents/therapeutic use
- Cystathionine gamma-Lyase/metabolism
- Endothelium, Vascular/drug effects
- Endothelium, Vascular/metabolism
- Endothelium, Vascular/physiopathology
- Humans
- Hydrogen Sulfide/metabolism
- Hypertension, Portal/drug therapy
- Hypertension, Portal/metabolism
- Hypertension, Portal/physiopathology
- Ligands
- Liver/drug effects
- Liver/metabolism
- Nitric Oxide/metabolism
- Portal Pressure/drug effects
- Receptors, Cytoplasmic and Nuclear/agonists
- Receptors, Cytoplasmic and Nuclear/metabolism
- Receptors, G-Protein-Coupled/agonists
- Receptors, G-Protein-Coupled/metabolism
- Signal Transduction/drug effects
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Affiliation(s)
- Stefano Fiorucci
- Department of Surgical and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi 1, 06132, Perugia, Italy.
| | - Eleonora Distrutti
- S.C. di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, 06132, Perugia, Italy.
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Li L, Zhang Q, Peng J, Jiang C, Zhang Y, Shen L, Dong J, Wang Y, Jiang Y. Activation of farnesoid X receptor downregulates monocyte chemoattractant protein-1 in murine macrophage. Biochem Biophys Res Commun 2015; 467:841-6. [DOI: 10.1016/j.bbrc.2015.10.056] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2015] [Accepted: 10/10/2015] [Indexed: 02/07/2023]
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Tam JCW, Ko CH, Koon CM, Cheng Z, Lok WH, Lau CP, Leung PC, Fung KP, Chan WY, Lau CBS. Identification of Target Genes Involved in Wound Healing Angiogenesis of Endothelial Cells with the Treatment of a Chinese 2-Herb Formula. PLoS One 2015; 10:e0139342. [PMID: 26430762 PMCID: PMC4591983 DOI: 10.1371/journal.pone.0139342] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2014] [Accepted: 09/11/2015] [Indexed: 01/10/2023] Open
Abstract
Angiogenesis is vitally important in diabetic wound healing. We had previously demonstrated that a Chinese 2-herb formula (NF3) significantly stimulated angiogenesis of HUVEC in wound healing. However, the molecular mechanism has not yet been elucidated. In line with this, global expression profiling of NF3-treated HUVEC was performed so as to assess the regulatory role of NF3 involved in the underlying signaling pathways in wound healing angiogenesis. The microarray results illustrated that different panels of differentially expressed genes were strictly governed in NF3-treated HUVEC in a time-regulated manner. The microarray analysis followed by qRT-PCR and western blotting verification of NF3-treated HUVEC at 6 h revealed the involvement of various genes in diverse biological process, e.g., MAP3K14 in anti-inflammation; SLC5A8 in anti-tumorogenesis; DNAJB7 in protein translation; BIRC5, EPCAM, INSL4, MMP8 and NPR3 in cell proliferation; CXCR7, EPCAM, HAND1 and MMP8 in migration; CXCR7, EPCAM and MMP8 in tubular formation; and BIRC5, CXCR7, EPCAM, HAND1, MMP8 and UBD in angiogenesis. After 16 h incubation of NF3, other sets of genes were shown with differential expression in HUVEC, e.g., IL1RAPL2 and NR1H4 in anti-inflammation; miR28 in anti-tumorogenesis; GRIN1 and LCN1 in anti-oxidation; EPB41 in intracellular signal transduction; PRL and TFAP2A in cell proliferation; miR28, PRL and SCG2 in cell migration; PRL in tubular formation; and miR28, NR1H4 and PRL in angiogenesis. This study provided concrete scientific evidence in support of the regulatory role of NF3 on endothelial cells involved in wound healing angiogenesis.
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Affiliation(s)
- Jacqueline Chor Wing Tam
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chun Hay Ko
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Chi Man Koon
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Zhang Cheng
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Wong Hing Lok
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ching Po Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Ping Chung Leung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Kwok Pui Fung
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Wai Yee Chan
- School of Biomedical Sciences, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
| | - Clara Bik San Lau
- Institute of Chinese Medicine, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- State Key Laboratory of Phytochemistry and Plant Resources in West China, The Chinese University of Hong Kong, Shatin, New Territories, Hong Kong
- * E-mail:
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Ye L, Jiang Y, Zuo X. Farnesoid-X-receptor expression in monocrotaline-induced pulmonary arterial hypertension and right heart failure. Biochem Biophys Res Commun 2015; 467:164-70. [PMID: 26392308 DOI: 10.1016/j.bbrc.2015.09.067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/06/2015] [Accepted: 09/11/2015] [Indexed: 12/19/2022]
Abstract
OBJECTIVE The farnesoid-X-receptor (FXR) is a metabolic nuclear receptor superfamily member that is highly expressed in enterohepatic tissue and is also expressed in the cardiovascular system. Multiple nuclear receptors, including FXR, play a pivotal role in cardiovascular disease (CVD). Pulmonary arterial hypertension (PAH) is an untreatable cardiovascular system disease that leads to right heart failure (RHF). However, the potential physiological/pathological roles of FXR in PAH and RHF are unknown. We therefore compared FXR expression in the cardiovascular system in PAH, RHF and a control. METHODS AND RESULTS Hemodynamic parameters and morphology were assessed in blank solution-exposed control, monocrotaline (MCT)-exposed PAH (4 weeks) and RHF (7 weeks) Sprague-Dawley rats. Real-time reverse transcription polymerase chain reaction (real-time RT-PCR), Western blot (WB), immunohistochemistry (IHC) analysis and immunofluorescence (IF) analysis were performed to assess FXR levels in the lung and heart tissues of MCT-induced PAH and RHF rats. In normal rats, low FXR levels were detected in the heart, and nearly no FXR was expressed in rat lungs. However, FXR expression was significantly elevated in PAH and RHF rat lungs but reduced in PAH and RHF rat right ventricular (RV) tissues. FXR expression was reduced only in RHF rat left ventricular (LV) tissues. CONCLUSIONS The differential expression of FXR in MCT-induced PAH lungs and heart tissues in parallel with PAH pathophysiological processes suggests that FXR contributes to PAH.
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Affiliation(s)
- Lusi Ye
- Department of Rheumatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China; Department of Rheumatology, The First Affiliated Hospital, Wenzhou Medical University, Wenzhou, Zhejiang 325015, China
| | - Ying Jiang
- Department of Rheumatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China
| | - Xiaoxia Zuo
- Department of Rheumatology, Xiangya Hospital, Central South University, 87 Xiangya Road, Changsha, Hunan 410008, China.
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Li C, Li J, Weng X, Lan X, Chi X. Farnesoid X receptor agonist CDCA reduces blood pressure and regulates vascular tone in spontaneously hypertensive rats. ACTA ACUST UNITED AC 2015; 9:507-516.e7. [DOI: 10.1016/j.jash.2015.04.006] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2014] [Revised: 04/24/2015] [Accepted: 04/28/2015] [Indexed: 12/20/2022]
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50
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Ellulu MS, Khaza'ai H, Abed Y, Rahmat A, Ismail P, Ranneh Y. Role of fish oil in human health and possible mechanism to reduce the inflammation. Inflammopharmacology 2015; 23:79-89. [PMID: 25676565 DOI: 10.1007/s10787-015-0228-1] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/29/2014] [Accepted: 01/20/2015] [Indexed: 12/31/2022]
Abstract
The roles of Omega-3 FAs are inflammation antagonists, while Omega-6 FAs are precursors for inflammation. The plant form of Omega-3 FAs is the short-chain α-linolenic acid, and the marine forms are the long-chain fatty acids: docosahexaenoic acid and eicosapentaenoic acid. Omega-3 FAs have unlimited usages, and they are considered as omnipotent since they may benefit heart health, improve brain function, reduce cancer risks and improve people's moods. Omega-3 FAs also have several important biological effects on a range of cellular functions that may decrease the onset of heart diseases and reduce mortality among patients with coronary heart disease, possibly by stabilizing the heart's rhythm and by reducing blood clotting. Some review studies have described the beneficial roles of Omega-3 FAs in cardiovascular diseases (CVDs), cancer, diabetes, and other conditions, including inflammation. Studies of the effect of Omega-3 FAs gathered from studies in diseased and healthy population. CVDs including atherosclerosis, coronary heart diseases, hypertension, and metabolic syndrome were the major fields of investigation. In studies of obesity, as the central obesity increased, the level of adipocyte synthesis of pro-inflammatory cytokines like tumor necrosis factor alpha (TNF-α) and interleukin 6 (IL-6) were increased and the level of anti-inflammatory adiponectin was decreased indicating a state of inflammation. The level of C reactive protein (CRP) synthesized from hepatocyte is increased by the influence of IL-6. CRP can be considered as a marker of systemic inflammation associated with increased risks of CVDs. In molecular studies, Omega-3 FAs have direct effects on reducing the inflammatory state by reducing IL-6, TNF-α, CRP and many other factors. While the appropriate dosage along with the administrative duration is not known, the scientific evidence-based recommendations for daily intake are not modified.
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Affiliation(s)
- Mohammed S Ellulu
- Department of Nutrition and Dietetics, Faculty of Medicine and Health Sciences, Universiti Putra Malaysia, 43400, Serdang, Selangor, Malaysia,
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