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1
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Xiao M, Zhou N, Tian Z, Sun C. Endogenous Metabolites in Metabolic Diseases: Pathophysiologic Roles and Therapeutic Implications. J Nutr 2025:S0022-3166(25)00227-5. [PMID: 40250565 DOI: 10.1016/j.tjnut.2025.04.017] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2025] [Accepted: 04/14/2025] [Indexed: 04/20/2025] Open
Abstract
Breakthroughs in metabolomics technology have revealed the direct regulatory role of metabolites in physiology and disease. Recent data have highlighted the bioactive metabolites involved in the etiology and prevention and treatment of metabolic diseases such as obesity, nonalcoholic fatty liver disease, type 2 diabetes mellitus, and atherosclerosis. Numerous studies reveal that endogenous metabolites biosynthesized by host organisms or gut microflora regulate metabolic responses and disorders. Lipids, amino acids, and bile acids, as endogenous metabolic modulators, regulate energy metabolism, insulin sensitivity, and immune response through multiple pathways, such as insulin signaling cascade, chemical modifications, and metabolite-macromolecule interactions. Furthermore, the gut microbial metabolites short-chain fatty acids, as signaling regulators have a variety of beneficial impacts in regulating energy metabolic homeostasis. In this review, we will summarize information about the roles of bioactive metabolites in the pathogenesis of many metabolic diseases. Furthermore, we discuss the potential value of metabolites in the promising preventive and therapeutic perspectives of human metabolic diseases.
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Affiliation(s)
- Mengjie Xiao
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Ning Zhou
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China
| | - Zhen Tian
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
| | - Changhao Sun
- National Key Discipline, Department of Nutrition and Food Hygiene, School of Public Health, Harbin Medical University, Harbin, P. R. China; Department of Nutrition and Food Hygiene, School of Public Health, Key Laboratory of Precision Nutrition and Health, Ministry of Education, Harbin Medical University, Heilongjiang, Harbin, P. R. China.
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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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3
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Sagmeister A, Matter CM, Stähli BE, Scharl M. The Gut-Heart Axis: Effects of Intestinal Microbiome Modulation on Cardiovascular Disease-Ready for Therapeutic Interventions? Int J Mol Sci 2024; 25:13529. [PMID: 39769292 PMCID: PMC11676197 DOI: 10.3390/ijms252413529] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/28/2024] [Revised: 12/10/2024] [Accepted: 12/13/2024] [Indexed: 01/11/2025] Open
Abstract
Recent reports demonstrate an association between distinct bacteria or bacteria-derived metabolites originating from the gut microbiome and the onset or progression of cardiovascular disease (CVD). This raises the opportunity to modulate the gut microbiome to prevent or treat CVD. To investigate whether intestinal microbiome modulation can prevent or treat CVD, this systematic literature review includes all randomized clinical trials on microbiome modulation and its effects on CVD risk published between August 2018 and August 2023. Within this review, we report the modulation of the gut microbiome by a variety of interventions and their effects on CVD, focusing on cardiovascular risk factors and risk markers of CVD. Beneficial effects were observed upon lifestyle intervention and probiotics use. The most promising diets for reducing risk factors of CVD were the Mediterranean diet, high-fiber diets, polyphenol-rich diets, and diets containing polyunsaturated fatty acids. Among drug interventions, only empagliflozin showed beneficial effects on CVD risk factors. Many dietary interventions were less conclusive because of the heterogeneity of study populations, small sample sizes, and short intervention windows or follow-up. Diet, lifestyle, probiotics, or drug interventions can modulate the gut microbiome and decrease risk markers or risk factors related to CVD. Yet, their effects on clinical endpoints remain to be determined.
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Affiliation(s)
- Alexandra Sagmeister
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
| | - Christian M. Matter
- Department of Cardiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (C.M.M.); (B.E.S.)
| | - Barbara E. Stähli
- Department of Cardiology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland; (C.M.M.); (B.E.S.)
| | - Michael Scharl
- Department of Gastroenterology and Hepatology, University Hospital Zurich, University of Zurich, 8091 Zurich, Switzerland;
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4
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Lee MH, Nuccio SP, Mohanty I, Hagey LR, Dorrestein PC, Chu H, Raffatellu M. How bile acids and the microbiota interact to shape host immunity. Nat Rev Immunol 2024; 24:798-809. [PMID: 39009868 DOI: 10.1038/s41577-024-01057-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/11/2024] [Indexed: 07/17/2024]
Abstract
Bile acids are increasingly appearing in the spotlight owing to their novel impacts on various host processes. Similarly, there is growing attention on members of the microbiota that are responsible for bile acid modifications. With recent advances in technology enabling the discovery and continued identification of microbially conjugated bile acids, the chemical complexity of the bile acid landscape in the body is increasing at a rapid pace. In this Review, we summarize our current understanding of how bile acids and the gut microbiota interact to modulate immune responses during homeostasis and disease, with a particular focus on the gut.
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Affiliation(s)
- Michael H Lee
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Sean-Paul Nuccio
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA
| | - Ipsita Mohanty
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
| | - Lee R Hagey
- Department of Medicine, University of California San Diego, La Jolla, CA, USA
| | - Pieter C Dorrestein
- Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, USA
- Collaborative Mass Spectrometry Innovation Center, University of California San Diego, La Jolla, CA, USA
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
| | - Hiutung Chu
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA
- Department of Pathology, University of California San Diego, La Jolla, CA, USA
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA
| | - Manuela Raffatellu
- Division of Host-Microbe Systems and Therapeutics, Department of Paediatrics, University of California San Diego, La Jolla, CA, USA.
- Center for Microbiome Innovation, University of California San Diego, La Jolla, CA, USA.
- Chiba University-UC San Diego Center for Mucosal Immunology, Allergy and Vaccines (CU-UCSD cMAV), La Jolla, CA, USA.
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5
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Li T, Chiang JYL. Bile Acid Signaling in Metabolic and Inflammatory Diseases and Drug Development. Pharmacol Rev 2024; 76:1221-1253. [PMID: 38977324 PMCID: PMC11549937 DOI: 10.1124/pharmrev.124.000978] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2024] [Revised: 06/26/2024] [Accepted: 06/28/2024] [Indexed: 07/10/2024] Open
Abstract
Bile acids are the end products of cholesterol catabolism. Hepatic bile acid synthesis accounts for a major fraction of daily cholesterol turnover in humans. Biliary secretion of bile acids generates bile flow and facilitates biliary secretion of lipids, endogenous metabolites, and xenobiotics. In intestine, bile acids facilitate the digestion and absorption of dietary lipids and fat-soluble vitamins. Through activation of nuclear receptors and G protein-coupled receptors and interaction with gut microbiome, bile acids critically regulate host metabolism and innate and adaptive immunity and are involved in the pathogenesis of cholestasis, metabolic dysfunction-associated steatotic liver disease, alcohol-associated liver disease, type-2 diabetes, and inflammatory bowel diseases. Bile acids and their derivatives have been developed as potential therapeutic agents for treating chronic metabolic and inflammatory liver diseases and gastrointestinal disorders. SIGNIFICANCE STATEMENT: Bile acids facilitate biliary cholesterol solubilization and dietary lipid absorption, regulate host metabolism and immunity, and modulate gut microbiome. Targeting bile acid metabolism and signaling holds promise for treating metabolic and inflammatory diseases.
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Affiliation(s)
- Tiangang Li
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
| | - John Y L Chiang
- Department of Biochemistry and Physiology, Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma (T.L.); and Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio (J.Y.L.C.)
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Ronen D, Rokach Y, Abedat S, Qadan A, Daana S, Amir O, Asleh R. Human Gut Microbiota in Cardiovascular Disease. Compr Physiol 2024; 14:5449-5490. [PMID: 39109979 DOI: 10.1002/cphy.c230012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
Abstract
The gut ecosystem, termed microbiota, is composed of bacteria, archaea, viruses, protozoa, and fungi and is estimated to outnumber human cells. Microbiota can affect the host by multiple mechanisms, including the synthesis of metabolites and toxins, modulating inflammation and interaction with other organisms. Advances in understanding commensal organisms' effect on human conditions have also elucidated the importance of this community for cardiovascular disease (CVD). This effect is driven by both direct CV effects and conditions known to increase CV risk, such as obesity, diabetes mellitus (DM), hypertension, and renal and liver diseases. Cardioactive metabolites, such as trimethylamine N -oxide (TMAO), short-chain fatty acids (SCFA), lipopolysaccharides, bile acids, and uremic toxins, can affect atherosclerosis, platelet activation, and inflammation, resulting in increased CV incidence. Interestingly, this interaction is bidirectional with microbiota affected by multiple host conditions including diet, bile acid secretion, and multiple diseases affecting the gut barrier. This interdependence makes manipulating microbiota an attractive option to reduce CV risk. Indeed, evolving data suggest that the benefits observed from low red meat and Mediterranean diet consumption can be explained, at least partially, by the changes that these diets may have on the gut microbiota. In this article, we depict the current epidemiological and mechanistic understanding of the role of microbiota and CVD. Finally, we discuss the potential therapeutic approaches aimed at manipulating gut microbiota to improve CV outcomes. © 2024 American Physiological Society. Compr Physiol 14:5449-5490, 2024.
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Affiliation(s)
- Daniel Ronen
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Yair Rokach
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Suzan Abedat
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Abed Qadan
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Samar Daana
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Offer Amir
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
| | - Rabea Asleh
- Cardiovascular Research Center, Heart Institute, Hadassah Medical Center, Faculty of Medicine, Hebrew University of Jerusalem, Jerusalem, Israel
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Mourino-Alvarez L, Juarez-Alia C, Sastre-Oliva T, Perales-Sánchez I, Hernandez-Fernandez G, Chicano-Galvez E, Peralbo-Molina Á, Madruga F, Blanco-Lopez E, Tejerina T, Barderas MG. Dysregulation of Lipid Metabolism Serves as A Link Between Alzheimer's and Cardiovascular Disease, As Witnessed in A Cross-Sectional Study. Aging Dis 2024; 16:1769-1784. [PMID: 39012677 PMCID: PMC12096944 DOI: 10.14336/ad.2024.0434] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2024] [Accepted: 05/31/2024] [Indexed: 07/17/2024] Open
Abstract
Cardiovascular risk factors and established cardiovascular disease (CVD) increase the risk of suffering dementia of the Alzheimer's type (DAT). Here, we set out to define specific molecular profiles of CVD in patients with DAT to better understand its relationship, to unravel the mechanisms underlying the high risk of developing DAT in CVD patients and to define new markers of early disease. Plasma samples from patients with DAT, with and without CVD, were analyzed through a multiomics approach, with integration of metabolomics and proteomics datasets using the OmicsNet web-based tool. Metabolomics results showed an enrichment in lipids and lipid-like molecules. Similarly, the most significant cluster identified through proteomics was formed by 5 proteins related to lipoprotein and cholesterol metabolism. After integration and functional enrichment, glycerolipid metabolism, fatty acid degradation and sphingolipid metabolism were among the most significant functions. Finally, the differential expression of ABCA1 and APOH proteins was verified, in an independent cohort also including controls and patients with CVD alone. Both proteins positively correlated with phospho-Tau (181), a classical hallmark of DAT. Different molecular profiles exist in patients with DAT, with and without CVD, with exacerbated alterations in patients in which DAT and CVD co-exist. This information may help to define biomarkers like ABCA1 and APOH that identify patients with cardiovascular dysfunction that are at high risk of developing DAT. Such markers will allow more personalized interventions to be selected, a further step towards precision medicine for individuals whose molecular profiles indicate a distinct response to the same management strategies.
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Affiliation(s)
- Laura Mourino-Alvarez
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
| | - Cristina Juarez-Alia
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
| | - Tamara Sastre-Oliva
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
| | - Inés Perales-Sánchez
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
| | - German Hernandez-Fernandez
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
| | - Eduardo Chicano-Galvez
- IMIBIC Mass Spectrometry and Molecular Imaging Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba (UCO), Córdoba, Spain.
| | - Ángela Peralbo-Molina
- IMIBIC Mass Spectrometry and Molecular Imaging Unit, Maimonides Biomedical Research Institute of Cordoba (IMIBIC), Reina Sofia University Hospital, University of Cordoba (UCO), Córdoba, Spain.
| | - Felipe Madruga
- Departament of Geriatrics, Hospital Virgen del Valle, SESCAM, Toledo, Spain.
| | - Emilio Blanco-Lopez
- Department of Cardiology, Ciudad Real General University Hospital, Ciudad Real, Spain.
| | - Teresa Tejerina
- Department of Pharmacology, School of Medicine, Universidad Complutense de Madrid, Madrid, Spain.
| | - María G. Barderas
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, SESCAM, 45071 Toledo, Spain.
- Department of Vascular Physiopathology, Hospital Nacional de Paraplejicos, IDISCAM, 45071 Toledo, Spain.
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8
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Heianza Y, Xue Q, Rood J, Clish CB, Bray GA, Sacks FM, Qi L. Changes in bile acid subtypes and improvements in lipid metabolism and atherosclerotic cardiovascular disease risk: the Preventing Overweight Using Novel Dietary Strategies (POUNDS Lost) trial. Am J Clin Nutr 2024; 119:1293-1300. [PMID: 38428740 PMCID: PMC11130658 DOI: 10.1016/j.ajcnut.2024.02.019] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2023] [Revised: 01/26/2024] [Accepted: 02/26/2024] [Indexed: 03/03/2024] Open
Abstract
BACKGROUND Distinct circulating bile acid (BA) subtypes may play roles in regulating lipid homeostasis and atherosclerosis. OBJECTIVES We investigated whether changes in circulating BA subtypes induced by weight-loss dietary interventions were associated with improved lipid profiles and atherosclerotic cardiovascular disease (ASCVD) risk estimates. METHODS This study included adults with overweight or obesity (n = 536) who participated in a randomized weight-loss dietary intervention trial. Circulating primary and secondary unconjugated BAs and their taurine-/glycine-conjugates were measured at baseline and 6 mo after the weight-loss diet intervention. The ASCVD risk estimates were calculated using the validated equations. RESULTS At baseline, higher concentrations of specific BA subtypes were related to higher concentrations of atherogenic very low-density lipoprotein lipid subtypes and ASCVD risk estimates. Weight-loss diet-induced decreases in primary BAs were related to larger reductions in triglycerides and total cholesterol [every 1 standard deviation (SD) decrease of glycocholate, glycochenodeoxycholate, or taurochenodeoxycholate was related to β (standard error) -3.3 (1.3), -3.4 (1.3), or -3.8 (1.3) mg/dL, respectively; PFDR < 0.05 for all]. Greater decreases in specific secondary BA subtypes were also associated with improved lipid metabolism at 6 mo; there was β -4.0 (1.1) mg/dL per 1-SD decrease of glycoursodeoxycholate (PFDR =0.003) for changes in low-density lipoprotein cholesterol. We found significant interactions (P-interaction < 0.05) between dietary fat intake and changes in BA subtypes on changes in ASCVD risk estimates; decreases in primary and secondary BAs (such as conjugated cholate or deoxycholate) were significantly associated with improved ASCVD risk after consuming a high-fat diet, but not after consuming a low-fat diet. CONCLUSIONS Decreases in distinct BA subtypes were associated with improved lipid profiles and ASCVD risk estimates, highlighting the importance of changes in circulating BA subtypes as significant factors linked to improved lipid metabolism and ASCVD risk estimates in response to weight-loss dietary interventions. Habitual dietary fat intake may modify the associations of changes in BAs with ASCVD risk. This trial was registered at clinicaltrials.gov as NCT00072995.
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Affiliation(s)
- Yoriko Heianza
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States.
| | - Qiaochu Xue
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States
| | - Jennifer Rood
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States
| | - Clary B Clish
- Metabolomics Platform, Broad Institute of MIT and Harvard, Cambridge, MA, United States
| | - George A Bray
- Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA, United States
| | - Frank M Sacks
- Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States
| | - Lu Qi
- Department of Epidemiology, School of Public Health and Tropical Medicine, Tulane University, New Orleans, LA, United States; Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, United States.
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9
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Zhang Z, Lv T, Wang X, Wu M, Zhang R, Yang X, Fu Y, Liu Z. Role of the microbiota-gut-heart axis between bile acids and cardiovascular disease. Biomed Pharmacother 2024; 174:116567. [PMID: 38583340 DOI: 10.1016/j.biopha.2024.116567] [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: 12/13/2023] [Revised: 04/01/2024] [Accepted: 04/04/2024] [Indexed: 04/09/2024] Open
Abstract
Bile acid (BA) receptors (e.g., farnesoid X-activated receptor, muscarinic receptor) are expressed in cardiomyocytes, endothelial cells, and vascular smooth muscle cells, indicating the relevance of BAs to cardiovascular disease (CVD). Hydrophobic BAs are cardiotoxic, while hydrophilic BAs are cardioprotective. For example, fetal cardiac insufficiency in maternal intrahepatic cholestasis during pregnancy, and the degree of fetal cardiac abnormality, is closely related to the level of hydrophobic BAs in maternal blood and infant blood. However, ursodeoxycholic acid (the most hydrophilic BA) can reverse/prevent these detrimental effects of increased levels of hydrophobic BAs on the heart. The gut microbiota (GM) and GM metabolites (especially secondary BAs) have crucial roles in hypertension, atherosclerosis, unstable angina, and heart failure. Herein, we describe the relationship between CVD and the GM at the BA level. We combine the concept of the "microbiota-gut-heart axis" (MGHA) and postulate the role and mechanism of BAs in CVD development. In addition, the strategies for treating CVD with BAs under the MGHA are proposed.
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Affiliation(s)
- Ziyi Zhang
- Department of Cardiovascular Medicine, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, PR China; Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Tingting Lv
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China; Department of Cardiology, Shaoxing People's Hospital (Shaoxing Hospital, Zhejiang University School of Medicine), Shaoxing, Zhejiang, PR China
| | - Xiang Wang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Menglu Wu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Ruolin Zhang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Xiaopeng Yang
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China
| | - Yongping Fu
- Department of Cardiovascular Medicine, Affiliated Hospital of Shaoxing University, Shaoxing, Zhejiang, PR China.
| | - Zheng Liu
- Department of Pharmacology, School of Medicine, Shaoxing University, Shaoxing, Zhejiang, PR China.
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10
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Fleishman JS, Kumar S. Bile acid metabolism and signaling in health and disease: molecular mechanisms and therapeutic targets. Signal Transduct Target Ther 2024; 9:97. [PMID: 38664391 PMCID: PMC11045871 DOI: 10.1038/s41392-024-01811-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/28/2023] [Revised: 03/06/2024] [Accepted: 03/17/2024] [Indexed: 04/28/2024] Open
Abstract
Bile acids, once considered mere dietary surfactants, now emerge as critical modulators of macronutrient (lipid, carbohydrate, protein) metabolism and the systemic pro-inflammatory/anti-inflammatory balance. Bile acid metabolism and signaling pathways play a crucial role in protecting against, or if aberrant, inducing cardiometabolic, inflammatory, and neoplastic conditions, strongly influencing health and disease. No curative treatment exists for any bile acid influenced disease, while the most promising and well-developed bile acid therapeutic was recently rejected by the FDA. Here, we provide a bottom-up approach on bile acids, mechanistically explaining their biochemistry, physiology, and pharmacology at canonical and non-canonical receptors. Using this mechanistic model of bile acids, we explain how abnormal bile acid physiology drives disease pathogenesis, emphasizing how ceramide synthesis may serve as a unifying pathogenic feature for cardiometabolic diseases. We provide an in-depth summary on pre-existing bile acid receptor modulators, explain their shortcomings, and propose solutions for how they may be remedied. Lastly, we rationalize novel targets for further translational drug discovery and provide future perspectives. Rather than dismissing bile acid therapeutics due to recent setbacks, we believe that there is immense clinical potential and a high likelihood for the future success of bile acid therapeutics.
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Affiliation(s)
- Joshua S Fleishman
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA
| | - Sunil Kumar
- Department of Pharmaceutical Sciences, College of Pharmacy and Health Sciences, St. John's University, Queens, NY, USA.
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11
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Zhang L, Feng F, Wang X, Liang H, Yao X, Liu D. Dose Prediction and Pharmacokinetic Simulation of XZP-5610, a Small Molecule for NASH Therapy, Using Allometric Scaling and Physiologically Based Pharmacokinetic Models. Pharmaceuticals (Basel) 2024; 17:369. [PMID: 38543155 PMCID: PMC10975475 DOI: 10.3390/ph17030369] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/04/2024] [Revised: 02/22/2024] [Accepted: 03/03/2024] [Indexed: 04/01/2024] Open
Abstract
The objectives of this study were to support dose selection of a novel FXR agonist XZP-5610 in first-in-human (FIH) trials and to predict its liver concentrations in Chinese healthy adults. Key parameters for extrapolation were measured using in vitro and in vivo models. Allometric scaling methods were employed to predict human pharmacokinetics (PK) parameters and doses for FIH clinical trials. To simulate the PK profiles, a physiologically based pharmacokinetic (PBPK) model was developed using animal data and subsequently validated with clinical data. The PBPK model was employed to simulate XZP-5610 concentrations in the human liver across different dose groups. XZP-5610 exhibited high permeability, poor solubility, and extensive binding to plasma proteins. After a single intravenous or oral administration of XZP-5610, the PK parameters obtained from rats and beagle dogs were used to extrapolate human parameters, resulting in a clearance of 138 mL/min and an apparent volume of distribution of 41.8 L. The predicted maximum recommended starting dose (MRSD), minimal anticipated biological effect level (MABEL), and maximum tolerated dose (MTD) were 0.15, 2, and 3 mg, respectively. The PK profiles and parameters of XZP-5610, predicted using the PBPK model, demonstrated good consistency with the clinical data. By using allometric scaling and PBPK models, the doses, PK profile, and especially the liver concentrations were successfully predicted in the FIH study.
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Affiliation(s)
- Lei Zhang
- Department of Cardiology and Institute of Vascular Medicine, Peking University Third Hospital, Beijing 100191, China;
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Feifei Feng
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Xiaohan Wang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
| | - Hao Liang
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Xueting Yao
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
| | - Dongyang Liu
- Drug Clinical Trial Center, Peking University Third Hospital, Beijing 100191, China; (F.F.); (X.W.); (H.L.)
- Center of Clinical Medical Research, Institute of Medical Innovation and Research, Peking University Third Hospital, Beijing 100191, China
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12
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Md Shahrulnizam NAN, Mohd Efendy Goon MD, Ab Rahim S, Lew SW, Sheikh Abdul Kadir SH, Ibrahim E. Palm-based tocotrienol-rich fraction (TRF) supplementation modulates cardiac sod1 expression, fxr target gene expression, and tauro-conjugated bile acid levels in aleptinemic mice fed a high-fat diet. GENES & NUTRITION 2024; 19:3. [PMID: 38413846 PMCID: PMC10898183 DOI: 10.1186/s12263-024-00742-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/15/2023] [Accepted: 02/10/2024] [Indexed: 02/29/2024]
Abstract
Tocotrienol-rich fraction (TRF) has been reported to protect the heart from oxidative stress-induced inflammation. It is, however, unclear whether the protective effects of TRF against oxidative stress involve the activation of farnesoid X receptor (fxr), a bile acid receptor, and the regulation of bile acid metabolites. In the current study, we investigated the effects of TRF supplementation on antioxidant activities, expression of fxr and its target genes in cardiac tissue, and serum untargeted metabolomics of high-fat diet-fed mice. Mice were divided into high-fat diet (HFD) with or without TRF supplementation (control) for 6 weeks. At the end of the intervention, body weight (BW), waist circumference (WC), and random blood glucose were measured. Heart tissues were collected, and the gene expression of sod1, sod2, gpx, and fxr and its target genes shp and stat3 was determined. Serum was subjected to untargeted metabolomic analysis using UHPLC-Orbitrap. In comparison to the control, the WC of the TRF-treated group was higher (p >0.05) than that of the HFD-only group, in addition there was no significant difference in weight or random blood glucose level. Downregulation of sod1, sod2, and gpx expression was observed in TRF-treated mice; however, only sod1 was significant when compared to the HFD only group. The expression of cardiac shp (fxr target gene) was significantly upregulated, but stat3 was significantly downregulated in the TRF-treated group compared to the HFD-only group. Biochemical pathways found to be influenced by TRF supplementation include bile acid secretion, primary bile acid biosynthesis, and biotin and cholesterol metabolism. In conclusion, TRF supplementation in HFD-fed mice affects antioxidant activities, and more interestingly, TRF also acts as a signaling molecule that is possibly involved in several bile acid-related biochemical pathways accompanied by an increase in cardiac fxr shp expression. This study provides new insight into TRF in deregulating bile acid receptors and metabolites in high-fat diet-fed mice.
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Affiliation(s)
- Nur Aliah Natasha Md Shahrulnizam
- Institute of Medical Molecular Biotechnology (IMMB), Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia
| | - Mohd Danial Mohd Efendy Goon
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerFoRM), Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia
| | - Sharaniza Ab Rahim
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia
| | - Sook Weih Lew
- Department of Pediatrics, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia
| | - Siti Hamimah Sheikh Abdul Kadir
- Institute of Pathology, Laboratory and Forensic Medicine (I-PPerFoRM), Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia.
- Department of Biochemistry and Molecular Medicine, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia.
| | - Effendi Ibrahim
- Department of Physiology, Faculty of Medicine, Universiti Teknologi MARA (UiTM), Cawangan Selangor, 47000 Sungai Buloh, Selangor, Malaysia.
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13
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Caparrós-Martín JA, Maher P, Ward NC, Saladié M, Agudelo-Romero P, Stick SM, Chan DC, Watts GF, O’Gara F. An Analysis of the Gut Microbiota and Related Metabolites following PCSK9 Inhibition in Statin-Treated Patients with Elevated Levels of Lipoprotein(a). Microorganisms 2024; 12:170. [PMID: 38257996 PMCID: PMC10818477 DOI: 10.3390/microorganisms12010170] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2023] [Revised: 12/26/2023] [Accepted: 01/08/2024] [Indexed: 01/24/2024] Open
Abstract
BACKGROUND Atherosclerotic cardiovascular disease (ASCVD) is a leading cause of global mortality, often associated with high blood levels of LDL cholesterol (LDL-c). Medications like statins and PCSK9 inhibitors, are used to manage LDL-c levels and reduce ASCVD risk. Recent findings connect the gut microbiota and its metabolites to ASCVD development. We showed that statins modulate the gut microbiota including the production of microbial metabolites involved in the regulation of cholesterol metabolism such as short chain fatty acids (SCFAs) and bile acids (BAs). Whether this pleiotropic effect of statins is associated with their antimicrobial properties or it is secondary to the modulation of cholesterol metabolism in the host is unknown. In this observational study, we evaluated whether alirocumab, a PCSK9 inhibitor administered subcutaneously, alters the stool-associated microbiota and the profiles of SCFAs and BAs. METHODS We used stool and plasma collected from patients enrolled in a single-sequence study using alirocumab. Microbial DNA was extracted from stool, and the bacterial component of the gut microbiota profiled following an amplicon sequencing strategy targeting the V3-V4 region of the 16S rRNA gene. Bile acids and SCFAs were profiled and quantified in stool and plasma using mass spectrometry. RESULTS Treatment with alirocumab did not alter bacterial alpha (Shannon index, p = 0.74) or beta diversity (PERMANOVA, p = 0.89) in feces. Similarly, circulating levels of SCFAs (mean difference (95% confidence interval (CI)), 8.12 [-7.15-23.36] µM, p = 0.25) and BAs (mean difference (95% CI), 0.04 [-0.11-0.19] log10(nmol mg-1 feces), p = 0.56) were equivalent regardless of PCSK9 inhibition. Alirocumab therapy was associated with increased concentration of BAs in feces (mean difference (95% CI), 0.20 [0.05-0.34] log10(nmol mg-1 feces), p = 0.01). CONCLUSION In statin-treated patients, the use of alirocumab to inhibit PCSK9 leads to elevated levels of fecal BAs without altering the bacterial population of the gut microbiota. The association of alirocumab with increased fecal BA concentration suggests an additional mechanism for the cholesterol-lowering effect of PCSK9 inhibition.
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Affiliation(s)
- Jose A. Caparrós-Martín
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia
| | - Patrice Maher
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia
| | - Natalie C. Ward
- Dobney Hypertension Centre, Medical School, The University of Western Australia, Perth, WA 6009, Australia
| | - Montserrat Saladié
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia
| | - Patricia Agudelo-Romero
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- The University of Western Australia, Perth, WA 6009, Australia
| | - Stephen M. Stick
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- The University of Western Australia, Perth, WA 6009, Australia
- Department of Respiratory Medicine, Princess Margaret Hospital for Children, Perth, WA 6008, Australia
| | - Dick C. Chan
- Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia
| | - Gerald F. Watts
- Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, WA 6009, Australia
- Cardiometabolic Service, Departments of Cardiology and Internal Medicine, Royal Perth Hospital, Perth, WA 6000, Australia
| | - Fergal O’Gara
- Wal-yan Respiratory Research Centre, Telethon Kids Institute, Perth, WA 6009, Australia
- Curtin Health Innovation Research Institute (CHIRI), Curtin University, Perth, WA 6102, Australia
- BIOMERIT Research Centre, School of Microbiology, University College Cork, T12 XF62 Cork, Ireland
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14
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Cifuentes-Silva E, Cabello-Verrugio C. Bile Acids as Signaling Molecules: Role of Ursodeoxycholic Acid in Cholestatic Liver Disease. Curr Protein Pept Sci 2024; 25:206-214. [PMID: 37594109 DOI: 10.2174/1389203724666230818092800] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2023] [Revised: 07/05/2023] [Accepted: 07/18/2023] [Indexed: 08/19/2023]
Abstract
Ursodeoxycholic acid (UDCA) is a natural substance physiologically produced in the liver. Initially used to dissolve gallstones, it is now successfully used in treating primary biliary cirrhosis and as adjuvant therapy for various hepatobiliary cholestatic diseases. However, the mechanisms underlying its beneficial effects still need to be clarified. Evidence suggests three mechanisms of action for UDCA that could benefit humans with cholestatic liver disease (CLD): protection of cholangiocytes against hydrophobic bile acid (BA) cytotoxicity, stimulation of hepatobiliary excretion, and protection of hepatocytes against BA-induced apoptosis. These mechanisms may act individually or together to potentiate them. At the molecular level, it has been observed that UDCA can generate modifications in the transcription and translation of proteins essential in the transport of BA, correcting the deficit in BA secretion in CLD, in addition to activating signaling pathways to translocate these transporters to the sites where they should fulfill their function. Inhibition of BA-induced hepatocyte apoptosis may play a role in CLD, characterized by BA retention in the hepatocyte. Thus, different mechanisms of action contribute to the improvement after UDCA administration in CLD. On the other hand, the effects of UDCA on tissues that possess receptors that may interact with BAs in pathological contexts, such as skeletal muscle, are still unclear. This work aims to describe the main molecular mechanisms by which UDCA acts in the human body, emphasizing the interaction in tissues other than the liver.
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Affiliation(s)
- Eduardo Cifuentes-Silva
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
| | - Claudio Cabello-Verrugio
- Laboratory of Muscle Pathology, Fragility, and Aging, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
- Millennium Institute on Immunology and Immunotherapy, Faculty of Life Sciences, Universidad Andres Bello, Santiago, Chile
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15
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Marchianò S, Biagioli M, Bordoni M, Morretta E, Di Giorgio C, Vellecco V, Roselli R, Bellini R, Massa C, Cari L, Urbani G, Ricci P, Monti MC, Giordano A, Brancaleone V, Bucci M, Zampella A, Distrutti E, Cieri E, Cirino G, Fiorucci S. Defective Bile Acid Signaling Promotes Vascular Dysfunction, Supporting a Role for G-Protein Bile Acid Receptor 1/Farnesoid X Receptor Agonism and Statins in the Treatment of Nonalcoholic Fatty Liver Disease. J Am Heart Assoc 2023; 12:e031241. [PMID: 37996988 PMCID: PMC10727350 DOI: 10.1161/jaha.123.031241] [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: 06/09/2023] [Accepted: 08/31/2023] [Indexed: 11/25/2023]
Abstract
BACKGROUND Patients with nonalcoholic fatty liver disease are at increased risk to develop atherosclerotic cardiovascular diseases. FXR and GPBAR1 are 2 bile acid-activated receptors exploited in the treatment of nonalcoholic fatty liver disease: whether dual GPBAR1/FXR agonists synergize with statins in the treatment of the liver and cardiovascular components of nonalcoholic fatty liver disease is unknown. METHODS AND RESULTS Investigations of human aortic samples obtained from patients who underwent surgery for aortic aneurysms and Gpbar1-/-, Fxr-/-, and dual Gpbar1-/-Fxr-/- mice demonstrated that GPBAR1 and FXR are expressed in the aortic wall and regulate endothelial cell/macrophage interactions. The expression of GPBAR1 in the human endothelium correlated with the expression of inflammatory biomarkers. Mice lacking Fxr and Gpbar1-/-/Fxr-/- display hypotension and aortic inflammation, along with altered intestinal permeability that deteriorates with age, and severe dysbiosis, along with dysregulated bile acid synthesis. Vasomotor activities of aortic rings were altered by Gpbar1 and Fxr gene ablation. In apolipoprotein E-/- and wild-type mice, BAR502, a dual GPBAR1/FXR agonist, alone or in combination with atorvastatin, reduced cholesterol and low-density lipoprotein plasma levels, mitigated the development of liver steatosis and aortic plaque formation, and shifted the polarization of circulating leukocytes toward an anti-inflammatory phenotype. BAR502/atorvastatin reversed intestinal dysbiosis and dysregulated bile acid synthesis, promoting a shift of bile acid pool composition toward FXR antagonists and GPBAR1 agonists. CONCLUSIONS FXR and GPBAR1 maintain intestinal, liver, and cardiovascular homeostasis, and their therapeutic targeting with a dual GPBAR1/FXR ligand and atorvastatin holds potential in the treatment of liver and cardiovascular components of nonalcoholic fatty liver disease.
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Affiliation(s)
- Silvia Marchianò
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Michele Biagioli
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Martina Bordoni
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Elva Morretta
- Department of PharmacyUniversity of SalernoSalernoItaly
| | | | | | | | - Rachele Bellini
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Carmen Massa
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Luigi Cari
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Ginevra Urbani
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Patrizia Ricci
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | | | | | | | | | - Angela Zampella
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | | | - Enrico Cieri
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
| | - Giuseppe Cirino
- Department of PharmacyUniversity of Naples Federico IINaplesItaly
| | - Stefano Fiorucci
- Department of Medicine and SurgeryUniversity of PerugiaPerugiaItaly
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16
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Biagioli M, Marchianò S, Di Giorgio C, Bordoni M, Urbani G, Bellini R, Massa C, Sami Ullah Khan R, Roselli R, Chiara Monti M, Morretta E, Giordano A, Vellecco V, Bucci M, Jilani Iqbal A, Saviano A, Ab Mansour A, Ricci P, Distrutti E, Zampella A, Cieri E, Cirino G, Fiorucci S. Activation of GPBAR1 attenuates vascular inflammation and atherosclerosis in a mouse model of NAFLD-related cardiovascular disease. Biochem Pharmacol 2023; 218:115900. [PMID: 37926268 DOI: 10.1016/j.bcp.2023.115900] [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: 08/29/2023] [Revised: 10/16/2023] [Accepted: 10/26/2023] [Indexed: 11/07/2023]
Abstract
While patients with nonalcoholic fatty liver disease (NAFLD) are at increased risk to develop clinically meaningful cardiovascular diseases (CVD), there are no approved drug designed to target the liver and CVD component of NAFLD. GPBAR1, also known as TGR5, is a G protein coupled receptor for secondary bile acids. In this study we have investigated the effect of GPBAR1 activation by BAR501, a selective GPBAR1 agonist, in Apolipoprotein E deficient (ApoE-/-) mice fed a high fat diet and fructose (Western diet), a validated model of NAFLD-associated atherosclerosis. Using aortic samples from patients who underwent surgery for abdominal aneurism, and ex vivo experiments with endothelial cells and human macrophages, we were able to co-localize the expression of GPBAR1 in CD14+ and PECAM1+ cells. Similar findings were observed in the aortic plaques from ApoE-/- mice. Treating ApoE-/- mice with BAR501, 30 mg/kg for 14 weeks, attenuated the body weight gain while ameliorated the insulin sensitivity by increasing the plasma concentrations of GLP-1 and FGF15. Activation of GPBAR1 reduced the aorta thickness and severity of atherosclerotic lesions and decreased the amount of plaques macrophages. Treating ApoE-/- mice reshaped the aortic transcriptome promoting the expression of anti-inflammatory genes, including IL-10, as also confirmed by tSNE analysis of spleen-derived macrophages. Feeding ApoE-/- mice with BAR501 redirected the bile acid synthesis and the composition of the intestinal microbiota. In conclusion, GPBAR1 agonism attenuates systemic inflammation and improve metabolic profile in a genetic/dietetic model of atherosclerosis. BAR501 might be of utility in the treatment for NAFLD-related CVD.
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Affiliation(s)
- Michele Biagioli
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Silvia Marchianò
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Martina Bordoni
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Ginevra Urbani
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Rachele Bellini
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Carmen Massa
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Rosalinda Roselli
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | | | - Elva Morretta
- Department of Pharmacy, University of Salerno, Salerno, Italy
| | - Antonino Giordano
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | | | - Asif Jilani Iqbal
- Institute of Cardiovascular Sciences (ICVS), College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Anella Saviano
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Adel Ab Mansour
- Department of Clinical Laboratory Sciences, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
| | - Patrizia Ricci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | | | - Angela Zampella
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Enrico Cieri
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy
| | - Giuseppe Cirino
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Stefano Fiorucci
- Department of Medicine and Surgery, University of Perugia, Perugia, Italy.
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17
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Lee SM, Jun DW, Yoon EL, Oh JH, Roh YJ, Lee EJ, Shin JH, Nam YD, Kim HS. Discovery biomarker to optimize obeticholic acid treatment for non-alcoholic fatty liver disease. Biol Direct 2023; 18:50. [PMID: 37626369 PMCID: PMC10463927 DOI: 10.1186/s13062-023-00407-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2023] [Accepted: 08/17/2023] [Indexed: 08/27/2023] Open
Abstract
The response rate to obeticholic acid (OCA), a potential therapeutic agent for non-alcoholic fatty liver disease, is limited. This study demonstrated that upregulation of the alternative bile acid synthesis pathway increases the OCA treatment response rate. The hepatic transcriptome and bile acid metabolite profile analyses revealed that the alternative bile acid synthesis pathway (Cyp7b1 and muricholic acid) in the OCA-responder group were upregulated compared with those in the OCA-non-responder group. Intestinal microbiome analysis also revealed that the abundances of Bacteroidaceae, Parabacteroides, and Bacteroides, which were positively correlated with the alternative bile acid synthesis pathway, were higher in the OCA-responder group than in the non-responder group. Pre-study hepatic mRNA levels of Cyp8b1 (classic pathway) were downregulated in the OCA-responder group. The OCA response rate increased up to 80% in cases with a hepatic Cyp7b1/Cyp8b1 ratio ≥ 5.0. Therefore, the OCA therapeutic response can be evaluated based on the Cyp7b1/Cyp8b1 ratio or the alternative/classic bile acid synthesis pathway activity.
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Affiliation(s)
- Seung Min Lee
- Department of Translational Medicine, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Republic of Korea
| | - Dae Won Jun
- Department of Translational Medicine, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Republic of Korea.
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-792, Republic of Korea.
| | - Eileen Laurel Yoon
- Department of Internal Medicine, Hanyang University Hospital, Hanyang University College of Medicine, 17 Haengdang-dong, Sungdong-gu, Seoul, 133-792, Republic of Korea.
| | - Ju Hee Oh
- Department of Obstetrics and Gynecology, Institute of Women's Medical Life Science, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Yoon Jin Roh
- Department of Dermatology, Chung-Ang University Hospital, Seoul, Republic of Korea
| | - Eun Jeoung Lee
- Department of Translational Medicine, Graduate School of Biomedical Science & Engineering, Hanyang University, Seoul, Republic of Korea
| | - Ji-Hee Shin
- Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, 55365, Republic of Korea
| | - Young-Do Nam
- Research Group of Personalized Diet, Korea Food Research Institute, Wanju-gun, 55365, Republic of Korea
| | - Hyun Sung Kim
- Pathology, Medical genetic, Hanyang University College of Medicine, Seoul, Republic of Korea
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18
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Abstract
PURPOSE OF REVIEW The role and underlying mechanisms mediated by dietary salt in modulating the gut microbiota and contributing to heart failure (HF) are not clear. This review summarizes the mechanisms of dietary salt and the gut-heart axis in HF. RECENT FINDINGS The gut microbiota has been implicated in several cardiovascular diseases (CVDs) including HF. Dietary factors including high consumption of salt play a role in influencing the gut microbiota, resulting in dysbiosis. An imbalance of microbial species due to a reduction in microbial diversity with accompanying immune cell activation has been implicated in the pathogenesis of HF via several mechanisms. The gut microbiota and gut-associated metabolites contribute to HF by reducing gut microbiota biodiversity and activating several signaling pathways. High dietary salt modulates the gut microbiota composition and exacerbate or induce HF by increasing the expression of the epithelial sodium/hydrogen exchanger isoform 3 in the gut, cardiac expression of beta myosin heavy chain, activation of the myocyte enhancer factor/nuclear factor of activated T cell, and salt-inducible kinase 1. These mechanisms explain the resulting structural and functional derangements in patients with HF.
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Affiliation(s)
- Sepiso K Masenga
- HAND Research Group, School of Medicine and Health Sciences, Mulungushi University, Livingstone Campus, Zambia
- Department of Medicine, Vanderbilt University Medical Center, Room 536 Robinson Research Building, Nashville, TN, 37232-6602, USA
| | - Annet Kirabo
- Department of Medicine, Vanderbilt University Medical Center, Room 536 Robinson Research Building, Nashville, TN, 37232-6602, USA.
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19
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Njeim R, Alkhansa S, Fornoni A. Unraveling the Crosstalk between Lipids and NADPH Oxidases in Diabetic Kidney Disease. Pharmaceutics 2023; 15:pharmaceutics15051360. [PMID: 37242602 DOI: 10.3390/pharmaceutics15051360] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2023] [Revised: 04/25/2023] [Accepted: 04/25/2023] [Indexed: 05/28/2023] Open
Abstract
Diabetic kidney disease (DKD) is a serious complication of diabetes mellitus and a leading cause of end-stage renal disease. Abnormal lipid metabolism and intrarenal accumulation of lipids have been shown to be strongly correlated with the development and progression of diabetic kidney disease (DKD). Cholesterol, phospholipids, triglycerides, fatty acids, and sphingolipids are among the lipids that are altered in DKD, and their renal accumulation has been linked to the pathogenesis of the disease. In addition, NADPH oxidase-induced production of reactive oxygen species (ROS) plays a critical role in the development of DKD. Several types of lipids have been found to be tightly linked to NADPH oxidase-induced ROS production. This review aims to explore the interplay between lipids and NADPH oxidases in order to provide new insights into the pathogenesis of DKD and identify more effective targeted therapies for the disease.
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Affiliation(s)
- Rachel Njeim
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
| | - Sahar Alkhansa
- Department of Anatomy, Cell Biology and Physiological Sciences, Faculty of Medicine, American University of Beirut, Beirut 1107-2020, Lebanon
- AUB Diabetes, American University of Beirut, Beirut 1107-2020, Lebanon
| | - Alessia Fornoni
- Katz Family Division of Nephrology and Hypertension, Department of Medicine, University of Miami Miller School of Medicine, Miami, FL 33136, USA
- Peggy and Harold Katz Family Drug Discovery Center, University of Miami Miller School of Medicine, Miami, FL 33136, USA
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20
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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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21
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Hepatic and renal improvements with FXR agonist vonafexor in individuals with suspected fibrotic NASH. J Hepatol 2023; 78:479-492. [PMID: 36334688 DOI: 10.1016/j.jhep.2022.10.023] [Citation(s) in RCA: 45] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/22/2022] [Revised: 10/04/2022] [Accepted: 10/21/2022] [Indexed: 11/11/2022]
Abstract
BACKGROUND & AIMS The LIVIFY trial investigated the safety, tolerability, and efficacy of vonafexor, a second-generation, non-bile acid farnesoid X receptor agonist in patients with suspected fibrotic non-alcoholic steatohepatitis (NASH). METHODS This double-blind phase IIa study was conducted in two parts. Patients were randomised (1:1:1:1) to receive placebo, vonafexor 100 mg twice daily (VONA-100BID), vonafexor 200 mg once daily (VONA-200QD), or 400 mg vonafexor QD (VONA-400QD) in Part A (safety run-in, pharmacokinetics/pharmacodynamics) or placebo, vonafexor 100 mg QD (VONA-100QD), or VONA-200QD (1:1:1) in Part B. The primary efficacy endpoint was a reduction in liver fat content (LFC) by MRI-proton density fat fraction, while secondary endpoints included reduced corrected T1 values and liver enzymes, from baseline to Week 12. RESULTS One hundred and twenty patients were randomised (Part A, n = 24; Part B, n = 96). In Part B, there was a significant reduction in least-square mean (SE) absolute change in LFC from baseline to Week 12 for VONA-100QD (-6.3% [0.9]) and VONA-200QD (-5.4% [0.9]), vs. placebo (-2.3% [0.9], p = 0.002 and 0.012, respectively). A >30% relative LFC reduction was achieved by 50.0% and 39.3% of patients in the VONA-100QD and VONA-200QD arms, respectively, but only in 12.5% in the placebo arm. Reductions in body weight, liver enzymes, and corrected T1 were also observed with vonafexor. Creatinine-based glomerular filtration rate improved in the active arms but not the placebo arm. Mild to moderate generalised pruritus was reported in 6.3%, 9.7%, and 18.2% of participants in the placebo, VONA-100QD, and VONA-200QD arms, respectively. CONCLUSIONS In patients with suspected fibrotic NASH, vonafexor was safe and induced potent liver fat reduction, improvement in liver enzymes, weight loss, and a possible renal benefit. CLINICAL TRIAL NUMBER (EUDRACT) 2018-003119-22. CLINICALTRIALS GOV IDENTIFIER NCT03812029. IMPACT AND IMPLICATIONS Non-alcoholic steatohepatitis (NASH) has become a leading cause of chronic liver disease worldwide. Affected patients are also at higher risk of developing chronic kidney disease. There are no approved therapies and only few options to treat this population. The phase IIa LIVIFY trial results show that single daily administration of oral vonafexor, an FXR agonist, leads in the short term to a reduction in liver fat, liver enzymes, fibrosis biomarkers, body weight and abdominal circumference, and a possible improvement in kidney function, while possible mild moderate pruritus (a peripheral FXR class effect) and an LDL-cholesterol increase are manageable with lower doses and statins. These results support exploration in longer and larger trials, with the aim of addressing the unmet medical need in NASH.
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22
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Guan X, Sun Z. The Role of Intestinal Flora and Its Metabolites in Heart Failure. Infect Drug Resist 2023; 16:51-64. [PMID: 36636378 PMCID: PMC9830706 DOI: 10.2147/idr.s390582] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Accepted: 11/25/2022] [Indexed: 01/05/2023] Open
Abstract
Intestinal flora is a complex collection of microbial communities that participate in the physiological and pathological activities of the human body through various pathways. In recent years, numerous studies have reported that intestinal flora are involved in the occurrence and development of heart failure (HF) and its metabolic products could play an important role in this progression, suggesting a great value in the clinical treatment of this condition. This study reported the interaction between intestinal flora and HF, and with intestinal flora metabolites, such as short-chain fatty acids, trimethylamine N-oxide and bile acids and urotoxins, considered as the starting point, the mechanism of the roles in HF was summarized. Additionally, the current research status and the development prospects of applying flora and metabolites to the clinical therapeutic decision of HF were discussed.
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Affiliation(s)
- Xueqing Guan
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China
| | - Zhijun Sun
- Department of Cardiology, Shengjing Hospital of China Medical University, Shenyang, People’s Republic of China,Correspondence: Zhijun Sun, Department of Cardiology, Shengjing Hospital, No. 39 of Huaxiang Road, Tiexi District, Shenyang, 110021, People’s Republic of China, Tel +86 18940251218, Fax +86 18940251218, Email
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23
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Kim JD, Zhou T, Zhang A, Li S, Gupte AA, Hamilton DJ, Fang L. AIBP Regulates Metabolism of Ketone and Lipids but Not Mitochondrial Respiration. Cells 2022; 11:cells11223643. [PMID: 36429071 PMCID: PMC9688289 DOI: 10.3390/cells11223643] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/14/2022] [Accepted: 11/15/2022] [Indexed: 11/18/2022] Open
Abstract
Accumulating evidence indicates that the APOA1 binding protein (AIBP)-a secreted protein-plays a profound role in lipid metabolism. Interestingly, AIBP also functions as an NAD(P)H-hydrate epimerase to catalyze the interconversion of NAD(P)H hydrate [NAD(P)HX] epimers and is renamed as NAXE. Thus, we call it NAXE hereafter. We investigated its role in NAD(P)H-involved metabolism in murine cardiomyocytes, focusing on the metabolism of hexose, lipids, and amino acids as well as mitochondrial redox function. Unbiased metabolite profiling of cardiac tissue shows that NAXE knockout markedly upregulates the ketone body 3-hydroxybutyric acid (3-HB) and increases or trends increasing lipid-associated metabolites cholesterol, α-linolenic acid and deoxycholic acid. Paralleling greater ketone levels, ChemRICH analysis of the NAXE-regulated metabolites shows reduced abundance of hexose despite similar glucose levels in control and NAXE-deficient blood. NAXE knockout reduces cardiac lactic acid but has no effect on the content of other NAD(P)H-regulated metabolites, including those associated with glucose metabolism, the pentose phosphate pathway, or Krebs cycle flux. Although NAXE is present in mitochondria, it has no apparent effect on mitochondrial oxidative phosphorylation. Instead, we detected more metabolites that can potentially improve cardiac function (3-HB, adenosine, and α-linolenic acid) in the Naxe-/- heart; these mice also perform better in aerobic exercise. Our data reveal a new role of NAXE in cardiac ketone and lipid metabolism.
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Affiliation(s)
- Jun-dae Kim
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
| | - Teng Zhou
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
| | - Aijun Zhang
- Center for Bioenergetics, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, 6550 Fannin St., Houston, TX 77030, USA
| | - Shumin Li
- Center for Bioenergetics, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
| | - Anisha A. Gupte
- Center for Bioenergetics, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, 6550 Fannin St., Houston, TX 77030, USA
| | - Dale J. Hamilton
- Center for Bioenergetics, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, 6550 Fannin St., Houston, TX 77030, USA
- Weill Cornell Medical College, Cornell University, 407 E 61st St., New York, NY 10065, USA
| | - Longhou Fang
- Center for Cardiovascular Regeneration, Department of Cardiovascular Sciences, Houston Methodist Research Institute, 6550 Fannin St., Houston, TX 77030, USA
- Department of Medicine, Houston Methodist, Weill Cornell Medicine Affiliate, 6550 Fannin St., Houston, TX 77030, USA
- Weill Cornell Medical College, Cornell University, 407 E 61st St., New York, NY 10065, USA
- Correspondence: ; Tel.: +713-363-9012; Fax: +713-363-9782
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24
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Min YW, Rezaie A, Pimentel M. Bile Acid and Gut Microbiota in Irritable Bowel Syndrome. J Neurogastroenterol Motil 2022; 28:549-561. [PMID: 36250362 PMCID: PMC9577585 DOI: 10.5056/jnm22129] [Citation(s) in RCA: 28] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 08/31/2022] [Indexed: 01/18/2023] Open
Abstract
Gut microbiota and their metabolites like bile acid (BA) have been investigated as causes of irritable bowel syndrome (IBS) symptoms. Primary BAs are synthesized and conjugated in the liver and released into the duodenum. BA biotransformation by gut microbiota begins in the intestine and results in production of a broad range of secondary BAs. Deconjugation is considered the gateway reaction for further modification and is mediated by bile salt hydrolase, which is widely expressed by the gut microbiota. However, gut bacteria that convert primary BAs to secondary BAs belong to a limited number of species, mainly Clostridiales. Like gut microbiota modify BA profile, BAs can shape gut microbiota via direct and indirect actions. BAs have prosecretory effects and regulates gut motility. BAs can also affect gut sensitivity. Because of the vital role of the gut microbiota and BAs in gut function, their bidirectional relationship may contribute to the pathophysiology of IBS. Individuals with IBS have been reported to have altered microbial profiles and modified BA profiles. A significant increase in fecal primary BA and a corresponding decrease in secondary BA have been observed in IBS with predominant diarrhea. In addition, primary BA was positively correlated with IBS symptoms. In IBS with predominant diarrhea, bacteria with reduced abundance mainly belonged to the genera in Ruminococcaceae and exhibited a negative correlation with primary BAs. Integrating the analysis of the gut microbiota and BAs could better understanding of IBS pathophysiology. The gap in this field needs to be further filled in the future.
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Affiliation(s)
- Yang Won Min
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Department of Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
| | - Ali Rezaie
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
| | - Mark Pimentel
- Medically Associated Science and Technology (MAST) Program, Cedars-Sinai, Los Angeles, CA, USA.,Karsh Division of Gastroenterology and Hepatology, Department of Medicine, Cedars-Sinai, Los Angeles, CA, USA
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25
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Zhao J, Wang Y, Wang Y, Gao J, Yang H, Wu X, Li H. Transcription Factor FXR Activates DHRS9 to Inhibit the Cell Oxidative Phosphorylation and Suppress Colon Cancer Progression. Anal Cell Pathol (Amst) 2022; 2022:8275574. [PMID: 36340269 PMCID: PMC9629925 DOI: 10.1155/2022/8275574] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 05/23/2022] [Accepted: 07/20/2022] [Indexed: 01/23/2025] Open
Abstract
BACKGROUND Colon cancer is a common gastrointestinal malignancy. It has been discovered that Farnesoid X receptor (FXR) plays an imperative regulatory role in multitype cancers in recent years. However, its regulatory mechanism in colon cancer has not been clearly explored. This study intended to explore the molecular regulatory mechanism of FXR and its downstream genes on the malignant progression of colon cancer. METHODS The mRNA and protein expression of FXR in colon cancer cells were measured by quantitative real-time polymerase chain reaction and Western blot. The effects of FXR on the biological function of colon cancer cells were measured by Cell Counting Kit-8, colony formation, and transwell assays. The downstream target gene of FXR was predicted by bioinformatics analysis and found to be associated with cellular oxidative phosphorylation. The binding relationship between FXR and its downstream gene dehydrogenase/reductase member 9 (DHRS9) was verified through luciferase reporter assay and chromatin immunoprecipitation assay. The changes of oxidative phosphorylation were detected by Western blot and oxygen consumption rate determination. The effect of FXR/DHRS9 axis on the malignant progression of colon cancer cells was further confirmed by rescue experiments. RESULTS FXR was underexpressed in colon cancer tissues and cells, and overexpressing FXR could repress the malignant behaviors of colon cancer cells. Besides, DHRS9 was a downstream gene of FXR, and FXR/DHRS9 inhibited the deterioration of colon cancer through inhibiting oxidative phosphorylation. Moreover, promoting FXR expression in colon cancer cells could partially reverse the biological function changes caused by silencing DHRS9 expression. CONCLUSION FXR inhibited the oxidative phosphorylation and inhibited the malignant progression of colon cancer cells via targeting DHRS9.
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Affiliation(s)
- Jinlai Zhao
- Gastrointestinal surgery, Tangshan Central Hospital, Tangshan, Hebei 063000, China
| | - Yigang Wang
- Anus and intestine surgery, Tangshan Central Hospital, Tangshan, 063000 Hebei, China
| | - Yang Wang
- Gastrointestinal surgery, Tangshan Central Hospital, Tangshan, Hebei 063000, China
| | - Jianchao Gao
- Gastrointestinal surgery, Tangshan Central Hospital, Tangshan, Hebei 063000, China
| | - Haichao Yang
- Gastrointestinal surgery, Tangshan Central Hospital, Tangshan, Hebei 063000, China
| | - Xiaotang Wu
- Hebei University of Economics and Business, Shijiazhuang, Hebei 050062, China
| | - Hua Li
- Gastrointestinal surgery, Tangshan Central Hospital, Tangshan, Hebei 063000, China
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26
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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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27
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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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28
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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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Zhou W, Anakk S. Enterohepatic and non-canonical roles of farnesoid X receptor in controlling lipid and glucose metabolism. Mol Cell Endocrinol 2022; 549:111616. [PMID: 35304191 PMCID: PMC9245558 DOI: 10.1016/j.mce.2022.111616] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/13/2022] [Accepted: 01/24/2022] [Indexed: 12/11/2022]
Abstract
Farnesoid X receptor (FXR) is a nuclear receptor that transcriptionally regulates bile acid homeostasis along with nutrient metabolism. In addition to the gastrointestinal (GI) tract, FXR expression has been widely noted in kidney, adrenal gland, pancreas, adipose, skeletal muscle, heart, and brain. Except for the liver and gut, the relevance of FXR signaling in metabolism in other tissues remains poorly understood. This review examines the classical and non-canonical tissue-specific roles of FXR in regulating, lipids, and glucose homeostasis under normal and diseased states. FXR activation has been reported to be protective against cholestasis, nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), type 2 diabetes, cardiovascular and kidney diseases. Several ongoing clinical trials are investigating FXR ligands as a therapeutic target for primary biliary cholangitis (PBC) and NASH, which substantiate the significance of FXR signaling in modulating metabolic processes. This review highlights that FXR ligands, albeit an attractive therapeutic target for treating metabolic diseases, tissue-specific modulation of FXR may be the key to overcoming some of the adverse clinical effects.
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Affiliation(s)
- Weinan Zhou
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA
| | - Sayeepriyadarshini Anakk
- Department of Molecular and Integrative Physiology, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Cancer Center at Illinois, University of Illinois at Urbana-Champaign, Urbana, IL, USA; Division of Nutritional Sciences, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
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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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Cao S, Yang X, Zhang Z, Wu J, Chi B, Chen H, Yu J, Feng S, Xu Y, Li J, Zhang Y, Wang X, Wang Y. Discovery of a tricyclic farnesoid X receptor agonist HEC96719, a clinical candidate for treatment of non-alcoholic steatohepatitis. Eur J Med Chem 2021; 230:114089. [PMID: 34998040 DOI: 10.1016/j.ejmech.2021.114089] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2021] [Revised: 12/24/2021] [Accepted: 12/26/2021] [Indexed: 11/04/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is becoming the most predominant burden of chronic liver disease worldwide. Non-alcoholic steatohepatitis (NASH), the progressive form of NAFLD, can develop into cirrhosis and hepatocellular cancer. Unfortunately, current options for therapeutic treatment of NASH are very limited. Among multiple pathways in NASH, farnesoid X receptor (FXR), a nuclear bile acid receptor, is well-recognized as an important effective target. Here we report the synthesis and characterization of compound HEC96719 a novel tricyclic FXR agonist based on a prior high-affinity nonsteroidal molecule GW4064. HEC96719 exhibits excellent potency superior to GW4064 and obeticholic acid in in vitro and in vivo assays of FXR activation. It also shows higher FXR selectivity and more favorable tissue distribution dominantly in liver and intestine. Preclinical data on pharmacokinetic properties, efficacy, and safety profiles overall indicate that HEC96719 is a promising drug candidate for NASH treatment.
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Affiliation(s)
- Shengtian Cao
- Southern Medical University Biomedical Research Center, Guangdong Provincial Research Center for Liver Fibrosis, Southern Medical University, Guangzhou, Guangdong, China; Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Xinye Yang
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Zheng Zhang
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Junwen Wu
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Bo Chi
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Hong Chen
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Jianghong Yu
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Shanshan Feng
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Yulin Xu
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Jing Li
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Yingjun Zhang
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China
| | - Xiaojun Wang
- Sunshine Lake Pharma Co Ltd, HEC Pharm Group, HEC Research and Development Center, Dongguan, Guangdong, China.
| | - Yan Wang
- Southern Medical University Biomedical Research Center, Guangdong Provincial Research Center for Liver Fibrosis, Southern Medical University, Guangzhou, Guangdong, China.
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Fiorucci S, Distrutti E. Linking liver metabolic and vascular disease via bile acid signaling. Trends Mol Med 2021; 28:51-66. [PMID: 34815180 DOI: 10.1016/j.molmed.2021.10.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2021] [Revised: 10/22/2021] [Accepted: 10/22/2021] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is a metabolic disorder affecting over one quarter of the global population. Liver fat accumulation in NAFLD is promoted by increased de novo lipogenesis leading to the development of a proatherosclerotic lipid profile and atherosclerotic cardiovascular disease (CVD). The CVD component of NAFLD is the main determinant of patient outcome. The farnesoid X receptor (FXR) and the G protein bile acid-activated receptor 1 (GPBAR1) are bile acid-activated receptors that modulate inflammation and lipid and glucose metabolism in the liver and CV system, and are thus potential therapeutic targets. We review bile acid signaling in liver, metabolic tissues, and the CV system, and we propose the development of dual FXR/GPBAR1 ligands, intestine-restricted FXR ligands, or statin combinations to limit side effects and effectively manage the liver and CV components of NAFLD.
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Affiliation(s)
- Stefano Fiorucci
- Dipartimento di Medicina e Chirurgia, Università di Perugia, Perugia, Italy.
| | - Eleonora Distrutti
- Struttura Complessa di Gastroenterologia ed Epatologia, Azienda Ospedaliera di Perugia, Perugia, Italy
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Arjama M, Mehnath S, Rajan M, Jeyaraj M. Engineered Hyaluronic Acid-Based Smart Nanoconjugates for Enhanced Intracellular Drug Delivery. J Pharm Sci 2021; 112:1603-1614. [PMID: 34678274 DOI: 10.1016/j.xphs.2021.10.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 10/12/2021] [Accepted: 10/12/2021] [Indexed: 12/20/2022]
Abstract
Bacterial polysaccharides can be easily modified to offer dual stimuli-responsive drug delivery systems with double targeting potential. In this research work, bacterial polysaccharides hyaluronic acid (HA) were functionalized with α-tocopherol polyethylene glycol succinate (TPGS) and cholic acid (CA) to form multifunctional polysaccharides nanoconjugates (TPGS-HA-CA). Smart nanoconjugates were synthesized by forming a redox-responsive disulfide bond, and it is composed of double targeting ligands. Doxorubicin (DOX) encapsulated smart nanoconjugates were exhibited an average size of 200 nm with a uniform core-shell structure. It serves the pH-responsive side chain modulation of TPGS-HA-CA, which affords a high degree of swelling at acidic pH. Under the pH 5.0 it shows 57% of release due to the side chain modulation of C-H/N-H. Polysaccharides nanoconjugates exhibited the double stimuli-responsive drug delivery by rapid disassembly of disulfide linkage, which exhibited 72% drug release (pH 5.0+GSH 10 mM). In cytotoxic studies, DOX@TPGS-HA-CA exhibited a higher cytotoxic effect compared to DOX. Hyaluronic acid functionalization with CA, TPGS increases cell internalization, and dual stimuli activity promotes more cell death. Overall, multifunctional polysaccharides hydrogel nanoconjugates is a prospective material that has great potential for targeting breast cancer therapy.
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Affiliation(s)
- Mukherjee Arjama
- National Centre for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 25, Tamil Nadu, India
| | - Sivaraj Mehnath
- National Centre for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 25, Tamil Nadu, India
| | - Mariappan Rajan
- Department of Natural Products Chemistry, School of Chemistry, Madurai Kamaraj University, Madurai 21, Tamil Nadu, India
| | - Murugaraj Jeyaraj
- National Centre for Nanoscience and Nanotechnology, University of Madras, Guindy Campus, Chennai 25, Tamil Nadu, India.
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34
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Fang X, Zhang S, Wang Z, Zhou J, Qi C, Song J. Cigarette smoke extract combined with LPS down-regulates the expression of MRP2 in chronic pulmonary inflammation may be related to FXR. Mol Immunol 2021; 137:174-186. [PMID: 34273652 DOI: 10.1016/j.molimm.2021.06.019] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 06/13/2021] [Accepted: 06/25/2021] [Indexed: 01/19/2023]
Abstract
The transporter multidrug resistance protein 2 (MRP2) plays an important role in chronic pulmonary inflammation by transporting cigarette smoke and other related inflammatory mediators. However, it is not completely clear whether pulmonary inflammation caused by cigarette smoke extract (CSE) and lipopolysaccharide (LPS) is related to MRP2 and its signal factors. In this study, CSE combined with LPS was used to establish an inflammation model in vivo and in vitro. We found that compared with the control group, after CSE combined with LPS treatment, the expression of MRP2 in rat lung tissue in vivo and human alveolar cell line in vitro was down-regulated, while the expression of inflammatory factors was up-regulated. Through silencing and overexpression of FXR, it was found that silent FXR could down-regulate MRP2 and up-regulate the expression of inflammatory factors. On the contrary, overexpression of FXR could up-regulate MRP2 and down-regulate the expression of inflammatory factors. Our results show that CSE combined with LPS can down-regulate the expression of MRP2 under inflammatory conditions, and the down-regulation of MRP2 expression may be achieved partly through the FXR signal pathway.
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Affiliation(s)
- Xin Fang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Shuyi Zhang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Zihao Wang
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jian Zhou
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Chuanzong Qi
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China
| | - Jue Song
- Institute for Anhui Province Key Laboratory of Major Autoimmune Diseases, Anhui Institute of Innovative Drugs, School of Pharmacy, Anhui Medical University, Hefei, China; Institute for the Key Laboratory of Anti-inflammatory and Immune Medicines, Ministry of Education, Hefei, China.
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The pathophysiological function of non-gastrointestinal farnesoid X receptor. Pharmacol Ther 2021; 226:107867. [PMID: 33895191 DOI: 10.1016/j.pharmthera.2021.107867] [Citation(s) in RCA: 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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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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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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Obeticholic acid ameliorates hepatorenal syndrome in ascitic cirrhotic rats by down-regulating the renal 8-iso-PGF2α-activated COX-TXA2 pathway. Clin Sci (Lond) 2020; 134:2055-2073. [PMID: 32725149 DOI: 10.1042/cs20200452] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2020] [Revised: 07/28/2020] [Accepted: 07/28/2020] [Indexed: 12/16/2022]
Abstract
BACKGROUNDS/AIMS The present study explores the potential of chronic treatment with the Foresaid X receptor (FXR) agonist obeticholic acid (OCA), which inhibits oxidative stress-related pathogenesis, in ascitic cirrhotic rats with hepatorenal syndrome (HRS) developed 6 weeks after bile duct ligation (BDL). METHODS Systemic, splanchnic, and renal hemodynamics and pathogenic cascades were measured in ascitic BDL and sham rats receiving 2-weeks of either vehicle or OCA treatments (sham-OCA and BDL-OCA groups), and NRK-52E cells, rat kidney tubular epithelial cells. RESULTS Chronic OCA treatment significantly normalized portal hypertension, glomerular filtration rate, urine output, renal blood flow; decreased ascites, renal vascular resistance, serum creatinine, and the release of renal tubular damage markers, including urinary neutrophil gelatinase-associated lipocalin (uNGAL) and kidney injury moleculae-1 (uKim-1) in BDL-OCA rats. In the BDL group, inhibition of the renal oxidative stress (8-iso-PGF2α)-activated cyclooxygenase-thromboxane A2 [COX-TXA2] pathway, apoptosis, and tubular injury accompanied by a decrease in hyper-responsiveness to the vasoconstrictor 8-iso-PGF2α in perfused kidneys. In vitro experiments revealed that 8-iso-PGF2α induced oxidative stress, release of reactive oxygen species, and cell apoptosis, which were reversed by concomitant incubation with the FXR agonist. CONCLUSIONS Through the inhibition of renal 8-iso-PGF2α production and the down-regulation of the COX-TXA2 pathway, our study suggests that chronic OCA treatment can ameliorate the HRS in ascitic cirrhotic rats. Thus, OCA is an agent with antioxidative stress, antivasoconstrictive, antiapoptotic properties which benefit ascitic, cirrhotic rats with systemic, hepatic, and renal abnormalities.
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Role of Farnesoid X Receptor in the Pathogenesis of Respiratory Diseases. Can Respir J 2020; 2020:9137251. [PMID: 33294085 PMCID: PMC7714608 DOI: 10.1155/2020/9137251] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2020] [Revised: 11/02/2020] [Accepted: 11/13/2020] [Indexed: 12/14/2022] Open
Abstract
Farnesoid X receptor (FXR) is a bile acid receptor encoded by the Nr1h4 gene. FXR plays an important role in maintaining the stability of the internal environment and the integrity of many organs, including the liver and intestines. The expression of FXR in nondigestible tissues other than in the liver and small intestine is known as the expression of “nonclassical” bile acid target organs, such as blood vessels and lungs. In recent years, several studies have shown that FXR is widely involved in the pathogenesis of various respiratory diseases, such as chronic obstructive pulmonary disease, bronchial asthma, and idiopathic pulmonary fibrosis. Moreover, a number of works have confirmed that FXR can regulate the bile acid metabolism in the body and exert its anti-inflammatory and antifibrotic effects in the airways and lungs. In addition, FXR may be used as a potential therapeutic target for some respiratory diseases. For example, FXR can regulate the tumor microenvironment by regulating the balance of inflammatory and immune responses in the body to promote the occurrence and development of non-small-cell lung cancer (NSCLC), thereby being considered a potential target for immunotherapy of NSCLC. In this article, we provide an overview of the internal relationship between FXR and respiratory diseases to track the progress that has been achieved thus far in this direction and suggest potential therapeutic prospects of FXR in respiratory diseases.
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40
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Borg MJ, Rayner CK, Jones KL, Horowitz M, Xie C, Wu T. Gastrointestinal Mechanisms Underlying the Cardiovascular Effect of Metformin. Pharmaceuticals (Basel) 2020; 13:410. [PMID: 33266396 PMCID: PMC7700183 DOI: 10.3390/ph13110410] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2020] [Revised: 11/20/2020] [Accepted: 11/20/2020] [Indexed: 02/07/2023] Open
Abstract
Metformin, the most widely prescribed drug therapy for type 2 diabetes, has pleiotropic benefits, in addition to its capacity to lower elevated blood glucose levels, including mitigation of cardiovascular risk. The mechanisms underlying the latter remain unclear. Mechanistic studies have, hitherto, focused on the direct effects of metformin on the heart and vasculature. It is now appreciated that effects in the gastrointestinal tract are important to glucose-lowering by metformin. Gastrointestinal actions of metformin also have major implications for cardiovascular function. This review summarizes the gastrointestinal mechanisms underlying the action of metformin and their potential relevance to cardiovascular benefits.
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Affiliation(s)
- Malcolm J. Borg
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Christopher K. Rayner
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
| | - Karen L. Jones
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Michael Horowitz
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
| | - Cong Xie
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
| | - Tongzhi Wu
- Adelaide Medical School and Centre of Research Excellence in Translating Nutritional Science to Good Health, The University of Adelaide, Adelaide 5000, Australia; (M.J.B.); (C.K.R.); (K.L.J.); (M.H.); (C.X.)
- Endocrine and Metabolic Unit, Royal Adelaide Hospital, Adelaide 5000, Australia
- Institute of Diabetes, School of Medicine, Southeast University, Nanjing 210096, China
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Perino A, Demagny H, Velazquez-Villegas L, Schoonjans K. Molecular Physiology of Bile Acid Signaling in Health, Disease, and Aging. Physiol Rev 2020; 101:683-731. [PMID: 32790577 DOI: 10.1152/physrev.00049.2019] [Citation(s) in RCA: 237] [Impact Index Per Article: 47.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Over the past two decades, bile acids (BAs) have become established as important signaling molecules that enable fine-tuned inter-tissue communication from the liver, their site of production, over the intestine, where they are modified by the gut microbiota, to virtually any organ, where they exert their pleiotropic physiological effects. The chemical variety of BAs, to a large extent determined by the gut microbiome, also allows for a complex fine-tuning of adaptive responses in our body. This review provides an overview of the mechanisms by which BA receptors coordinate several aspects of physiology and highlights new therapeutic strategies for diseases underlying pathological BA signaling.
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Hadrien Demagny
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Laura Velazquez-Villegas
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, Ecole Polytechnique Fédérale de Lausanne, Lausanne (EPFL), Switzerland
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42
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Yan Y, Wang S, Wang R, Jiang P, Chen Y, Zhang L, Hou C, Zhang L. Transcriptional regulation of microRNA-126a by farnesoid X receptor in vitro and in vivo. Biotechnol Lett 2020; 42:1327-1336. [PMID: 32221722 DOI: 10.1007/s10529-020-02864-7] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2019] [Accepted: 03/12/2020] [Indexed: 12/15/2022]
Abstract
OBJECTIVES Recent research has indicated the microRNA-126a (miR-126a) is an endothelial cell-specific and highly conserved endogenous small non-coding RNA molecule. It contributes to the vascular integrity and angiogenesis, but the molecular regulation mechanism of miR-126a remains unknown. RESULTS Herein, quantitative real-time polymerase chain reaction (qRT-PCR) results showed that Farnesoid X Receptor (FXR) activation promoted miR-126a expression in HepG2, LO2, and Hep1-6 cells. Furthermore, FXR was found to transcriptionally regulate the miR-126a by binding to its DR8 site. The binding site of FXR was confirmed on intron 6 or 7 of miR-126a host gene epidermal growth factor-like domain 7 (EGFL7) by luciferase reporter assays, electrophoretic mobility shift assays (EMSAs) and chromatin immunoprecipitation (ChIP) assays. CONCLUSIONS All these data collectively suggest that FXR regulates transcripts of miR-126a by binding to DR8 in miR-126a gene promoter. This study may provide a molecular therapeutic target for angiogenic disorders, aging, and liver failure.
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Affiliation(s)
- Yi Yan
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Shichao Wang
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Rui Wang
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Puxuan Jiang
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Yaqing Chen
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Liang Zhang
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Chenjiao Hou
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China
| | - Lisheng Zhang
- College of Veterinary Medicine, Bio-medical Center, Huazhong Agricultural University, Wuhan, Hubei, 430070, China.
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Abstract
PURPOSE OF REVIEW Studies have identified several effects of bile acids (BAs) in glucose homeostasis, energy expenditure, and body weight control, through receptor-dependent and independent mechanisms. BAs are produced from cholesterol and characterized by their structures, which result from enzymes in the liver and the gut microbiota. The aim of this review is to characterize the effects of BA structure and composition on diabetes. RECENT FINDINGS The hydroxyl groups of BAs interact with binding pockets of receptors and enzymes that affect glucose homeostasis. Human and animal studies show that BA composition is associated with insulin resistance and food intake regulation. The hydroxylation of BAs and BA composition contributes to glucose regulation. Modulation of BA composition has the potential to improve glucose metabolism.
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Affiliation(s)
- Sei Higuchi
- Naomi Berrie Diabetes Center and Department of Pathology and Cell Biology, Columbia University, New York, NY, USA.
- Russ Berrie Pavilion, Room 315, 1150 St. Nicholas Ave., New York, NY, 10032, USA.
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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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Hepatic Bile Acid Reuptake in the Rat Depends on Bile Acid Conjugation but Not on Agonistic Properties towards FXR and TGR5. Molecules 2020; 25:molecules25102371. [PMID: 32443832 PMCID: PMC7288213 DOI: 10.3390/molecules25102371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2020] [Revised: 04/25/2020] [Accepted: 05/13/2020] [Indexed: 11/24/2022] Open
Abstract
Farnesoid X receptor (FXR) and Takeda G-protein coupled receptor 5 (TGR5) are the two known bile acid (BA) sensitive receptors and are expressed in the intestine and liver as well as in extra-enterohepatic tissues. The physiological effects of extra-enterohepatic FXR/TRG5 remain unclear. Further, the extent BAs escape liver reabsorption and how they interact with extra-enterohepatic FXR/TGR5 is understudied. We investigated if hepatic BA reuptake differed between BAs agonistic for FXR and TGR5 compared to non-agonists in the rat. Blood was collected from the portal vein and inferior caval vein from anesthetized rats before and 5, 20, 30, and 40 min post stimulation with sulfated cholecystokinin-8. Plasma concentrations of 20 different BAs were assessed by liquid chromatography coupled to mass spectrometry. Total portal vein BA AUC was 3–4 times greater than in the vena cava inferior (2.7 ± 0.6 vs. 0.7 ± 0.2 mM x min, p < 0.01, n = 8) with total unconjugated BAs being 2–3-fold higher than total conjugated BAs (AUC 8–10 higher p < 0.05 for both). However, in both cases, absolute ratios varied greatly among different BAs. The average hepatic reuptake of BAs agonistic for FXR/TGR5 was similar to non-agonists. However, as the sum of non-agonist BAs in vena portae was 2–3-fold higher than the sum agonist (p < 0.05), the peripheral BA pool was composed mostly of non-agonist BAs. We conclude that hepatic BA reuptake varies substantially by type and does not favor FXR/TGR5 BAs agonists.
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46
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Novakovic M, Rout A, Kingsley T, Kirchoff R, Singh A, Verma V, Kant R, Chaudhary R. Role of gut microbiota in cardiovascular diseases. World J Cardiol 2020; 12:110-122. [PMID: 32431782 PMCID: PMC7215967 DOI: 10.4330/wjc.v12.i4.110] [Citation(s) in RCA: 110] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/08/2019] [Revised: 03/03/2020] [Accepted: 03/12/2020] [Indexed: 02/06/2023] Open
Abstract
The human gut is colonized by a community of microbiota, primarily bacteria, that exist in a symbiotic relationship with the host. Intestinal microbiota-host interactions play a critical role in the regulation of human physiology. Deleterious changes to the composition of gut microbiota, referred to as gut dysbiosis, has been linked to the development and progression of numerous diseases, including cardiovascular disease (CVD). Imbalances in host-microbial interaction impair homeostatic mechanisms that regulate health and can activate multiple pathways leading to CVD risk factor progression. Most CVD risk factors, including aging, obesity, dietary patterns, and a sedentary lifestyle, have been shown to induce gut dysbiosis. Dysbiosis is associated with intestinal inflammation and reduced integrity of the gut barrier, which in turn increases circulating levels of bacterial structural components and microbial metabolites, including trimethylamine-N-oxide and short-chain fatty acids, that may facilitate the development of CVD. This article reviews the normal function and composition of the gut microbiome, mechanisms leading to the leaky gut syndrome, its mechanistic link to CVD and potential novel therapeutic approaches aimed towards restoring gut microbiome and CVD prevention. As CVD is the leading cause of deaths globally, investigating the gut microbiota as a locus of intervention presents a novel and clinically relevant avenue for future research.
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Affiliation(s)
- Marko Novakovic
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD 21215, United States
| | - Amit Rout
- Department of Internal Medicine, Sinai Hospital of Baltimore, Baltimore, MD 21215, United States
| | - Thomas Kingsley
- Department of Internal Medicine, Division of Hospital Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Robert Kirchoff
- Department of Internal Medicine, Division of Hospital Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States
| | - Amteshwar Singh
- Department of Internal Medicine, Division of Hospital Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, United States
| | - Vipin Verma
- Department of Internal Medicine, Medical University of South Carolina/AnMed Campus, Charleston, SC 29425, United States
| | - Ravi Kant
- Division of Endocrinology, Diabetes and Nutrition, Medical University of South Carolina/Anmed Campus, Anderson, SC 29621, United States
| | - Rahul Chaudhary
- Department of Internal Medicine, Division of Hospital Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States.
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Chiang JYL, Ferrell JM, Wu Y, Boehme S. Bile Acid and Cholesterol Metabolism in Atherosclerotic Cardiovascular Disease and Therapy. CARDIOLOGY PLUS 2020; 5:159-170. [PMID: 34350368 PMCID: PMC8330388] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/03/2022] Open
Abstract
Dysregulation of lipid metabolism is a major factor contributing to atherosclerotic cardiovascular disease (ACVD), which is the number one cause of death in western countries. The liver plays a central role in maintaining whole body cholesterol homeostasis via catabolism of cholesterol to bile acids, as well as biliary cholesterol excretion. The liver synthesizes lipoproteins that transport dietary cholesterol and fats to muscle and adipose tissue, directs reverse cholesterol transport of excess cholesterol from extrahepatic tissues and macrophages to the liver to convert to bile acids, and thus, protects against metabolism-related nonalcoholic fatty liver disease (NAFLD) and ACVD. Liver fibrosis/nonalcoholic steatohepatitis increases the risk and prevalence of cardiovascular disease morbidity and mortality. Bile acids are signaling molecules and metabolic regulators that activate farnesoid X receptor and G protein-coupled bile acid receptor-1 to regulate lipid, glucose, and energy metabolism. The bidirectional regulation of bile acids and the gut microbiota determine the rate of bile acid synthesis, the bile acid pool size, and the composition of the circulating bile acid pool. The liver-intestine-heart axis regulates lipid metabolism, inflammation, and the pathogenesis of metabolic diseases such as ACVD, NAFLD, diabetes, and obesity. This review focuses on the roles of liver-to-intestine, liver-to-heart and intestine-to-heart axes in cholesterol, lipoprotein, and bile acid metabolism; signaling in heart health and ACVD; and drug therapies for atherosclerosis.
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Affiliation(s)
- John Y. L. Chiang
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Jessica M. Ferrell
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Yue Wu
- Department of Cardiology, First Affiliated Hospital of Xi’an Jiaotong University, Xi’an, China
| | - Shannon Boehme
- Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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48
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Mouries J, Brescia P, Silvestri A, Spadoni I, Sorribas M, Wiest R, Mileti E, Galbiati M, Invernizzi P, Adorini L, Penna G, Rescigno M. Microbiota-driven gut vascular barrier disruption is a prerequisite for non-alcoholic steatohepatitis development. J Hepatol 2019; 71:1216-1228. [PMID: 31419514 PMCID: PMC6880766 DOI: 10.1016/j.jhep.2019.08.005] [Citation(s) in RCA: 436] [Impact Index Per Article: 72.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/21/2018] [Revised: 07/29/2019] [Accepted: 08/02/2019] [Indexed: 02/06/2023]
Abstract
BACKGROUND & AIMS Fatty liver disease, including non-alcoholic fatty liver (NAFLD) and steatohepatitis (NASH), has been associated with increased intestinal barrier permeability and translocation of bacteria or bacterial products into the blood circulation. In this study, we aimed to unravel the role of both intestinal barrier integrity and microbiota in NAFLD/NASH development. METHODS C57BL/6J mice were fed with high-fat diet (HFD) or methionine-choline-deficient diet for 1 week or longer to recapitulate aspects of NASH (steatosis, inflammation, insulin resistance). Genetic and pharmacological strategies were then used to modulate intestinal barrier integrity. RESULTS We show that disruption of the intestinal epithelial barrier and gut vascular barrier (GVB) are early events in NASH pathogenesis. Mice fed HFD for only 1 week undergo a diet-induced dysbiosis that drives GVB damage and bacterial translocation into the liver. Fecal microbiota transplantation from HFD-fed mice into specific pathogen-free recipients induces GVB damage and epididymal adipose tissue enlargement. GVB disruption depends on interference with the WNT/β-catenin signaling pathway, as shown by genetic intervention driving β-catenin activation only in endothelial cells, preventing GVB disruption and NASH development. The bile acid analogue and farnesoid X receptor agonist obeticholic acid (OCA) drives β-catenin activation in endothelial cells. Accordingly, pharmacologic intervention with OCA protects against GVB disruption, both as a preventive and therapeutic agent. Importantly, we found upregulation of the GVB leakage marker in the colon of patients with NASH. CONCLUSIONS We have identified a new player in NASH development, the GVB, whose damage leads to bacteria or bacterial product translocation into the blood circulation. Treatment aimed at restoring β-catenin activation in endothelial cells, such as administration of OCA, protects against GVB damage and NASH development. LAY SUMMARY The incidence of fatty liver disease is reaching epidemic levels in the USA, with more than 30% of adults having NAFLD (non-alcoholic fatty liver disease), which can progress to more severe non-alcoholic steatohepatitis (NASH). Herein, we show that disruption of the intestinal epithelial barrier and gut vascular barrier are early events in the development of NASH. We show that the drug obeticholic acid protects against barrier disruption and thereby prevents the development of NASH, providing further evidence for its use in the prevention or treatment of NASH.
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Affiliation(s)
- Juliette Mouries
- Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy
| | - Paola Brescia
- Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy
| | - Alessandra Silvestri
- Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy
| | - Ilaria Spadoni
- Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy
| | - Marcel Sorribas
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland
| | - Reiner Wiest
- Maurice Müller Laboratories, Department for Biomedical Research, University of Bern, Bern, Switzerland,Department of Visceral Surgery and Medicine, Bern University Hospital, University of Bern, Bern, Switzerland
| | - Erika Mileti
- European Institute of Oncology, Department of Experimental Oncology, 20139 Milan, MI, Italy
| | - Marianna Galbiati
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, MI, Italy
| | - Pietro Invernizzi
- Division of Gastroenterology and Center for Autoimmune Liver Diseases, Department of Medicine and Surgery, University of Milan-Bicocca, Milan, MI, Italy
| | | | - Giuseppe Penna
- Humanitas Clinical and Research Center – IRCCS –, via Manzoni 56, 20089 Rozzano, MI, Italy,Postbiotica srl, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy
| | - Maria Rescigno
- Humanitas Clinical and Research Center - IRCCS -, via Manzoni 56, 20089 Rozzano, MI, Italy; Humanitas University, Department of Biomedical Sciences, Via Rita Levi Montalcini, 20090 Pieve Emanuele, MI, Italy.
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49
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T MM, T A, P BK, Fathima A, Khanum F. In-silico therapeutic investigations of arjunic acid and arjungenin as an FXR agonist and validation in 3T3-L1 adipocytes. Comput Biol Chem 2019; 84:107163. [PMID: 31767507 DOI: 10.1016/j.compbiolchem.2019.107163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2019] [Revised: 11/06/2019] [Accepted: 11/08/2019] [Indexed: 12/31/2022]
Abstract
The present study was to illustrate the agonistic property of arjungenin and arjunic acid towards farnesoid X receptor protein (FXR).The pharmacokinetic properties like molecular interactions, absorption, distribution, metabolism, elimination and toxicity (ADMET) of the ligands were checked through in-silico studies. Protein-ligand docking was carried out using autodock software. Molecular docking analysis confirmed strong binding energy and interaction of arjungenin and arjunic acid with the target protein and the ADMET profiles identified for both compounds were promising.Further in vitro studies were performed in 3T3-L1 adipocyte to verify the agonistic property of arjungenin and arjunic acid. Oil red O staining was done to check differentiation induction. Adiponectin, leptin, triglycerides and total cholesterol levels were quantified. The mRNA expression of FXR, Cyp7a1, PPAR-γ and SREBP-1c were quantified using fluorescent real-time PCR. Cytotoxicity assay was confirmed that up to 150 μM concentration there is no significant cell death on treatment with arjunic acid and arjungenin. Treatment with arjungenin and arjunic acid confirms increased differentiation of the cells with significant (P < 0.05) increase in adiponectin (118.07% and 132.92%) and leptin (133.52% and 149.74%) protein levels compared to the negative control group. After treatment with arjungenin and arjunic acid in 3T3-L1 preadipocytes the mRNA expression of FXR, PPAR-γ and SREBP-1c were significantly (P < 0.01) increased and cyp7a1 was significantly (P < 0.01) decreased when compared with the negative control group. Overall, our results suggest that arjungenin and arjunic acid acts as an FXR agonist and may be useful for rational therapeutic strategies as a novel drug to treat cholesterol mediated metabolic syndrome and insulin resistance.
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Affiliation(s)
- Mohan Manu T
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Anand T
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India.
| | - Bhuvanesh Kumar P
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Asra Fathima
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
| | - Farhath Khanum
- Nutrition, Biochemistry and Toxicology Division, Defence Food Research Laboratory, Mysuru, 570011, India
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50
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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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