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Hu Y, Sang N, Wu A, Pu J, Yan H, Luo J, Zheng P, Luo Y, Yu J, He J, Yu B, Chen D. Different types of bile acids exhibit opposite regulatory effects on lipid metabolism in finishing pigs through bile acid receptors. ANIMAL NUTRITION (ZHONGGUO XU MU SHOU YI XUE HUI) 2025; 21:25-36. [PMID: 40135169 PMCID: PMC11930731 DOI: 10.1016/j.aninu.2024.12.003] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/15/2024] [Revised: 11/20/2024] [Accepted: 12/16/2024] [Indexed: 03/27/2025]
Abstract
The purpose of this research was to investigate how different bile acids impact lipid metabolism and carcass characteristics in finishing pigs, along with the potential mechanisms involved. Twenty-one finishing pigs (Duroc×Landrace×Yorkshire [DLY]; average BW = 144.38 ± 8.92 kg) were assigned to three dietary treatments, with each treatment containing seven replicates, each consisting of one pig. The three dietary treatments included: a basic diet, a basic diet supplemented with 500 mg/kg of hyodeoxycholic acid (HDCA), and a basic diet supplemented with 500 mg/kg of lithocholic acid (LCA). The trial lasted for 28 d. Hyodeoxycholic acid was used in the in vitro experiments and added to mature 3T3-L1 adipocytes for 4 d to elucidate the mechanism by which bile acids regulate lipid metabolism. The results suggested that HDCA tended to decrease backfat thickness in finishing pigs (P = 0.094) and reduced the size of lipid droplets in 3T3-L1 adipocytes (P = 0.012), whereas LCA increased backfat thickness (P = 0.016) and induced larger lipid droplets in the abdominal adipose tissue (P = 0.003). Furthermore, HDCA enhanced the expression of Takeda G-protein-coupled receptor 5 protein and hormone-sensitive lipase (HSL) gene in backfat of pigs (P < 0.05) and increased the protein expression of phosphorylated HSL (p-HSL) in vitro (P = 0.093). Compared to HDCA, LCA addition increased the gene and protein expression of peroxisome proliferator activated receptor gamma in backfat of pigs (P < 0.05) and enhanced the expression of hepatic genes sterol regulatory element-binding protein-1c and fatty acid synthase (P < 0.05). In conclusion, HDCA enhanced lipolysis and partially decreased backfat thickness in finishing pigs, while LCA promoted lipid synthesis and increased backfat thickness of pigs. The variations in the effects of various bile acids on bile acid receptors could explain these functional differences.
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Affiliation(s)
- Yaolian Hu
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Ni Sang
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Aimin Wu
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Junning Pu
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Hui Yan
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Junqiu Luo
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Ping Zheng
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Yuheng Luo
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Jie Yu
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Jun He
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Bing Yu
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
| | - Daiwen Chen
- Key Laboratory of Animal Disease-resistant Nutrition, Ministry of Education, Animal Nutrition Institute, Sichuan Agricultural University, Ya'an 625014, China
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Zhang S, Zhang D, Xu K, Huang X, Chen Q, Chen M. The role of the farnesoid X receptor in diabetes and its complications. Mol Cell Biochem 2025; 480:2725-2736. [PMID: 39576464 DOI: 10.1007/s11010-024-05162-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2024] [Accepted: 11/10/2024] [Indexed: 01/06/2025]
Abstract
Diabetes is a metabolic disease in which tissues and organs are exposed to a hyperglycemic environment for a prolonged period. Long-term hyperglycemia can cause dysfunction of multiple organs and tissues in the body, leading to diabetic complications such as diabetic cardiomyopathy and diabetic nephropathy. Diabetes and its complications have become one of the key issues that seriously threaten the health of people worldwide. Farnesoid X receptor (FXR), as a metabolic regulator, has multiple functions in regulating insulin synthesis and secretion, insulin resistance, lipid metabolism, oxidative stress, inflammatory response, and fibrosis. It plays a key role in alleviating diabetes and its complications. In this review, we discuss the latest findings of FXR related to diabetes and its complications, focusing on its role in diabetes, diabetic nephropathy, diabetic cardiomyopathy, and diabetic liver injury. The aim is to better understand the role of FXR in diabetes and its complications and to provide new perspectives on the treatment of diabetes and its complications.
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Affiliation(s)
- Shengnan Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China
- School of Resources and Environmental Science and Engineering, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Dandan Zhang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China
| | - Kui Xu
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China
- School of Clinical Medicine, Hubei University of Science and Technology, Xianning, 437100, People's Republic of China
| | - Xingqiong Huang
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China
| | - Qingjie Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China
| | - Mi Chen
- Hubei Key Laboratory of Diabetes and Angiopathy, School of Pharmacy, Hubei University of Science and Technology, No. 88 Xianning Avenue, Xian'an District, Xianning, Hubei, People's Republic of China.
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Girisa S, Aswani BS, Manickasamy MK, Hegde M, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Restoring FXR expression as a novel treatment strategy in liver cancer and other liver disorders. Expert Opin Ther Targets 2025; 29:193-221. [PMID: 40169227 DOI: 10.1080/14728222.2025.2487465] [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: 12/08/2024] [Accepted: 03/28/2025] [Indexed: 04/03/2025]
Abstract
INTRODUCTION Liver cancer is a leading cause of cancer-associated mortality and is often linked to preexisting liver conditions. Emerging research demonstrates FXR dysregulation, particularly its reduced expression, in the pathogenesis of liver diseases, including inflammation, fibrosis, cholestatic disorders, metabolic dysregulation, and liver cancer. Therefore, this review explores the role of FXR and its agonists in mitigating these conditions. AREAS COVERED This article summarizes FXR's involvement in liver disorders, primarily emphasizing on hepatic neoplasms, and examines the potential of FXR agonists in restoring FXR activity in liver diseases, thereby preventing their progression to liver cancer. The information presented is drawn from existing preclinical and clinical studies specific to each liver disorder, sourced from PubMed. EXPERT OPINION It is well established that FXR expression is downregulated in liver disorders, contributing to disease progression. Notably, FXR agonists have demonstrated therapeutic potential in ameliorating liver diseases, including hepatocellular carcinoma. We believe that activating or restoring FXR expression with agonists offers significant promise for the treatment of liver cancer and other liver conditions. Therefore, FXR modulation by agonists, particularly in combination with other therapeutic agents, could lead to more targeted treatments, improving efficacy while reducing side effects.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Leicester, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, Saudi Arabia
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, India
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Kim SH, Park WY, Kim B, Kim JH, Song G, Park JY, Jiao W, Jung SJ, Ahn KS, Kwak HJ, Um JY. FXR-ApoC2 pathway activates UCP1-mediated thermogenesis by promoting the browning of white adipose tissues. J Biol Chem 2025; 301:108181. [PMID: 39798876 PMCID: PMC11871442 DOI: 10.1016/j.jbc.2025.108181] [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: 08/21/2024] [Revised: 12/17/2024] [Accepted: 12/27/2024] [Indexed: 01/15/2025] Open
Abstract
FXR, encoded by Nh1r4, is a nuclear receptor crucial in regulating bile acid, lipid, and glucose metabolism. Prior research has indicated that activating FXR in the liver and small intestine may offer protection against obesity and metabolic diseases. This study demonstrates the essential role of the FXR-ApoC2 pathway in promoting the browning of white adipose tissue (WAT). Increased FXR by treatment with the FXR agonist farnesol upregulated beige adipocyte markers, including UCP1, PGC1α, and PRDM16, and increased the FXR target gene, ApoC2, in beige adipocytes and cold-exposed mice. However, these effects were not observed in mature white adipocytes. Remarkably, the knockdown of FXR results in a significantly reduced expression of UCP1, PGC1α, PRDM16, and ApoC2 in beige adipocytes. While studying the interaction between the nuclear receptor RXRα and FXR in transcription regulation, it was found that the knockdown of RXRα did not control the expression of FXR under beige adipogenesis. We further investigated whether the expression of beige-related markers could be altered under ApoC2 overexpression to ascertain the mechanism of action of FXR in relation to ApoC2 regulation. The overexpression of ApoC2 in both preadipocytes and beige adipocytes led to a significant increase in the expression of UCP1 and PGC1α. These results indicate that the FXR-mediated ApoC2 pathway is essential in the browning of WAT by inducing beige adipogenesis from preadipocytes.
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Affiliation(s)
- Sang Hee Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Woo Yong Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Beomsu Kim
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Jin-Hyung Kim
- Department of Biomedical and Pharmaceutical Science, College of Pharmacy, Kyung Hee University, Seoul, Republic of Korea
| | - Gahee Song
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Ja Yeon Park
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Wenjun Jiao
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Se Jin Jung
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea
| | - Kwang Seok Ahn
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, Seoul, Republic of Korea
| | - Hyun Jeong Kwak
- Department of Bio and Fermentation Convergence Technology, Kookmin University, Seoul Republic of Korea
| | - Jae-Young Um
- Department of Science in Korean Medicine, Graduate School, Kyung Hee University, Seoul, Republic of Korea; Department of Pharmacology, College of Korean Medicine, Kyung Hee University, Seoul, Republic of Korea; Kyung Hee Institute of Convergence Korean Medicine, Kyung Hee University, Seoul, Republic of Korea.
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Havranek B, Loh R, Torre B, Redfield R, Halegoua-DeMarzio D. Glucagon-like peptide-1 receptor agonists improve metabolic dysfunction-associated steatotic liver disease outcomes. Sci Rep 2025; 15:4947. [PMID: 39930071 PMCID: PMC11811119 DOI: 10.1038/s41598-025-89408-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Accepted: 02/05/2025] [Indexed: 02/13/2025] Open
Abstract
Metabolic dysfunction-associated steatotic liver disease (MASLD) is the leading cause of chronic liver disease and is associated with significant cardiovascular morbidity and mortality. This study aims to investigate the association of glucagon-like peptide-1 (GLP-1) agonists with major cardiovascular events, clinically significant portal hypertension events, and all-cause mortality in patients with MASLD. A large, population-based retrospective cohort study was conducted using the TriNetX platform, which provided real-time access to electronic health records of 634,265 adult patients with MASLD/MASH. Propensity score matching (PSM) was employed to create two cohorts: A GLP-1 agonists group and a control group without GLP-1 agonists usage. Hazard ratios (HRs) and 95% confidence intervals (CIs) were calculated using Cox proportional hazards models along with Kaplan-Meier survival analyses to estimate outcomes at the end of 1, 3, 5, and 7 years. After PSM, 6,243 patients were included in each group. The GLP-1 agonist group had significantly lower risk of heart failure (at 7 years, HR, 0.721; 95% Cl, 0.593-0.876), composite cardiovascular events (at years 7, HR, 0.594; 95% Cl, 0.475-0.745), clinically significant portal hypertension events (at 7 years, HR, 0.463; 95% Cl, 0.348-0.611), and all-cause mortality (at 7 years, HR, 0.303; 95% Cl, 0.239-0.385). These results were consistent at 1-, 3-, 5-, and 7-years post index event. GLP-1 agonists usage in patients with MASLD is associated with reduced risk of major cardiovascular events, clinically significant portal hypertension, and all-cause mortality. These findings highlight the potential of GLP-1 agonists in MASLD/MASH management, warranting further prospective studies.
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Affiliation(s)
- Brandon Havranek
- Sidney Kimmel Medical College at Thomas Jefferson University, Philadelphia, PA, 19107, USA
| | - Rebecca Loh
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, 132 S 10th St, Suite 480, Philadelphia, PA, 19107, USA
| | - Beatriz Torre
- Department of Medicine, Thomas Jefferson University Hospital, Philadelphia, PA, 19107, USA
| | - Rachel Redfield
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, 132 S 10th St, Suite 480, Philadelphia, PA, 19107, USA
| | - Dina Halegoua-DeMarzio
- Department of Gastroenterology & Hepatology, Thomas Jefferson University Hospital, 132 S 10th St, Suite 480, Philadelphia, PA, 19107, USA.
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Kumar J, Hasan M, Mohsin S, Alzaher MH, Nagar T, Jamil A, Ahmed A, Lavu VK, Kumar S. Assessing the efficacy of farnesoid X receptor agonists in the management of metabolic dysfunction-associated steatotic liver disease: A systematic review and meta-analysis: Efficacy of Farnesoid X Receptor Agonists in Metabolic Dysfunction-associated Steatotic Liver Disease: Systematic Review and Meta-analysis. Clin Res Hepatol Gastroenterol 2025; 49:102530. [PMID: 39805519 DOI: 10.1016/j.clinre.2025.102530] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/18/2024] [Revised: 12/29/2024] [Accepted: 01/08/2025] [Indexed: 01/16/2025]
Abstract
BACKGROUND AND AIMS Several randomized clinical trials have been conducted assessing the potential efficacy of Farnesoid X receptor (FXR) agonists in patients with metabolic dysfunction-associated steatotic liver disease (MASLD). A comprehensive review and analysis were needed to evaluate the findings of these trials. Hence, this systematic review and meta-analysis aim to study the association between FXR agonists and hepatic outcomes in patients with MASLD. METHODS Systematic review and meta-analysis evaluating the efficacy of FXR agonists in 1,227 patients assigned to the FXR intervention group compared to 650 patients in the placebo group. Changes in liver enzymes and hepatic steatosis assessed by MRI-PDFF were evaluated. RESULTS FXR agonist use was associated with a significant reduction in levels of AST, (WMD= -4.51, 95% CI=[-8.39,-0.63], P=0.02); ALT (WMD= -13.02, 95% CI=[-17.85,-8.19], P<0.00001); GGT (WMD= -32.20, 95% CI=[-38.63,-25.98], P<0.00001); MRI-PDFF, (SMD= -1.14, 95% CI=[-1.92,-0.35], P=0.005). FXR agonists did not significantly affect ALP levels, (WMD= 25.04, 95% CI=[19.22,30.87], P<0.00001] CONCLUSION: Results show promising evidence supporting the efficacy of FXR agonists in reducing hepatic steatosis and biomarkers of hepatic injury such as ALT, AST, and GGT.
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Affiliation(s)
- Jai Kumar
- School of Medicine, Wayne State University, Detroit, MI, USA.
| | - Misha Hasan
- College of Medicine, Ziauddin University, Karachi, Pakistan
| | - Sana Mohsin
- College of Medicine, Ziauddin University, Karachi, Pakistan
| | | | - Tripti Nagar
- School of Medicine, Wayne State University, Detroit, MI, USA
| | - Adeena Jamil
- Department of Medicine, Dow International Medical College, Dow University of Health Sciences, Karachi, Pakistan
| | - Ali Ahmed
- School of Medicine, Wayne State University, Detroit, MI, USA
| | | | - Sarwan Kumar
- School of Medicine, Wayne State University, Detroit, MI, USA
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Luo Z, Zhou W, Xie T, Xu W, Shi C, Xiao Z, Si Y, Ma Y, Ren Q, Di L, Shan J. The role of botanical triterpenoids and steroids in bile acid metabolism, transport, and signaling: Pharmacological and toxicological implications. Acta Pharm Sin B 2024; 14:3385-3415. [PMID: 39220868 PMCID: PMC11365449 DOI: 10.1016/j.apsb.2024.04.027] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2023] [Revised: 03/28/2024] [Accepted: 04/22/2024] [Indexed: 09/04/2024] Open
Abstract
Bile acids (BAs) are synthesized by the host liver from cholesterol and are delivered to the intestine, where they undergo further metabolism by gut microbes and circulate between the liver and intestines through various transporters. They serve to emulsify dietary lipids and act as signaling molecules, regulating the host's metabolism and immune homeostasis through specific receptors. Therefore, disruptions in BA metabolism, transport, and signaling are closely associated with cholestasis, metabolic disorders, autoimmune diseases, and others. Botanical triterpenoids and steroids share structural similarities with BAs, and they have been found to modulate BA metabolism, transport, and signaling, potentially exerting pharmacological or toxicological effects. Here, we have updated the research progress on BA, with a particular emphasis on new-found microbial BAs. Additionally, the latest advancements in targeting BA metabolism and signaling for disease treatment are highlighted. Subsequently, the roles of botanical triterpenoids in BA metabolism, transport, and signaling are examined, analyzing their potential pharmacological, toxicological, or drug interaction effects through these mechanisms. Finally, a research paradigm is proposed that utilizes the gut microbiota as a link to interpret the role of these important natural products in BA signaling.
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Affiliation(s)
- Zichen Luo
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Wei Zhou
- State Key Laboratory of Natural Medicines, School of Traditional Chinese Pharmacy, China Pharmaceutical University, Nanjing 210009, China
| | - Tong Xie
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Weichen Xu
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Chen Shi
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Zihan Xiao
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Yu Si
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Yan Ma
- National Institute of Biological Sciences, Beijing 102206, China
| | - Qingling Ren
- Jiangsu CM Clinical Medicine Innovation Center for Obstetrics, Gynecology, and Reproduction, Affiliated Hospital of Nanjing University of Chinese Medicine, Nanjing 210001, China
| | - Liuqing Di
- Jiangsu Engineering Research Center for Efficient Delivery System of TCM, School of Pharmacy, Nanjing University of Chinese Medicine, Nanjing 210023, China
| | - Jinjun Shan
- Medical Metabolomics Center, Institute of Pediatrics, Jiangsu Key Laboratory of Children’s Health and Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing 210023, China
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Wang Y, Xu H, Zhou X, Chen W, Zhou H. Dysregulated bile acid homeostasis: unveiling its role in metabolic diseases. MEDICAL REVIEW (2021) 2024; 4:262-283. [PMID: 39135605 PMCID: PMC11317083 DOI: 10.1515/mr-2024-0020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Accepted: 05/13/2024] [Indexed: 08/15/2024]
Abstract
Maintaining bile acid homeostasis is essential for metabolic health. Bile acid homeostasis encompasses a complex interplay between biosynthesis, conjugation, secretion, and reabsorption. Beyond their vital role in digestion and absorption of lipid-soluble nutrients, bile acids are pivotal in systemic metabolic regulation. Recent studies have linked bile acid dysregulation to the pathogenesis of metabolic diseases, including obesity, type 2 diabetes mellitus (T2DM), and metabolic dysfunction-associated steatotic liver disease (MASLD). Bile acids are essential signaling molecules that regulate many critical biological processes, including lipid metabolism, energy expenditure, insulin sensitivity, and glucose metabolism. Disruption in bile acid homeostasis contributes to metabolic disease via altered bile acid feedback mechanisms, hormonal dysregulation, interactions with the gut microbiota, and changes in the expression and function of bile acid transporters and receptors. This review summarized the essential molecular pathways and regulatory mechanisms through which bile acid dysregulation contributes to the pathogenesis and progression of obesity, T2DM, and MASLD. We aim to underscore the significance of bile acids as potential diagnostic markers and therapeutic agents in the context of metabolic diseases, providing insights into their application in translational medicine.
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Affiliation(s)
- Yanyan Wang
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, Richmond, VA, USA
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Huangru Xu
- School of Life Science, Nanjing University, Nanjing, Jiangsu, China
| | - Xiqiao Zhou
- Department of Endocrinology, Jiangsu Province Hospital of Chinese Medicine, Nanjing University of Chinese Medicine, Nanjing, Jiangsu, China
| | - Weidong Chen
- School of Pharmaceutical Science, Anhui University of Chinese Medicine, Hefei, Anhui, China
| | - Huiping Zhou
- Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond Veterans Affairs Medical Center, Richmond, VA, USA
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Nerild HH, Brønden A, Haddouchi AE, Ellegaard AM, Hartmann B, Rehfeld JF, Holst JJ, Sonne DP, Vilsbøll T, Knop FK. Elucidating the glucose-lowering effect of the bile acid sequestrant sevelamer. Diabetes Obes Metab 2024; 26:1252-1263. [PMID: 38151760 DOI: 10.1111/dom.15421] [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] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2023] [Revised: 11/28/2023] [Accepted: 11/30/2023] [Indexed: 12/29/2023]
Abstract
AIM Bile acid sequestrants are cholesterol-lowering drugs, which also improve glycaemic control in people with type 2 diabetes. The mechanism behind the glucose-lowering effect is unknown but has been proposed to be mediated by increased glucagon-like peptide-1 (GLP-1) secretion. Here, we investigated the glucose-lowering effects of sevelamer including any contribution from GLP-1 in people with type 2 diabetes. MATERIALS AND METHODS In a randomized, double-blind, placebo-controlled, crossover study, 15 people with type 2 diabetes on metformin monotherapy underwent two 17-day treatment periods with the bile acid sequestrant sevelamer and placebo, respectively, in a randomized order and with an interposed wash-out period of minimum 6 weeks. On days 15 and 17 of each treatment period, participants underwent experimental days with 4-h liquid meal tests and application of concomitant infusion of exendin(9-39)NH2 or saline. RESULTS Compared with placebo, sevelamer improved insulin sensitivity (assessed by homeostatic model assessment of insulin resistance) and beta-cell sensitivity to glucose and lowered fasting and postprandial plasma glucose concentrations. In both treatment periods, exendin(9-39)NH2 increased postprandial glucose excursions compared with saline but without absolute or relative difference between the two treatment periods. In contrast, exendin(9-39)NH2 abolished the sevelamer-induced improvement in beta-cell glucose sensitivity. CONCLUSIONS The bile acid sequestrant sevelamer improved insulin sensitivity and beta-cell sensitivity to glucose, but using the GLP-1 receptor antagonist exendin(9-39)NH2 we were not able to detect a GLP-1-mediated glucose-lowering effect of sevelamer in individuals with type 2 diabetes. Nevertheless, the sevelamer-induced improvement of beta-cell sensitivity to glucose was shown to be GLP-1-dependent.
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Affiliation(s)
- Henriette H Nerild
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Andreas Brønden
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
| | - Abdullah E Haddouchi
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Anne-Marie Ellegaard
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
| | - Bolette Hartmann
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - Jens F Rehfeld
- Department of Clinical Biochemistry, Copenhagen University Hospital - Rigshospitalet, Copenhagen, Denmark
| | - Jens J Holst
- Department of Biomedical Sciences, Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
- the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
| | - David P Sonne
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Pharmacology, Copenhagen University Hospital - Bispebjerg and Frederiksberg, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
| | - Tina Vilsbøll
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
| | - Filip K Knop
- Center for Clinical Metabolic Research, Copenhagen University Hospital - Herlev and Gentofte, Hellerup, Denmark
- the Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Science, University of Copenhagen, Copenhagen, Denmark
- Clinical Research, Steno Diabetes Center Copenhagen, Herlev, Denmark
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10
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Sinha RA. Targeting nuclear receptors for NASH/MASH: From bench to bedside. LIVER RESEARCH (BEIJING, CHINA) 2024; 8:34-45. [PMID: 38544909 PMCID: PMC7615772 DOI: 10.1016/j.livres.2024.03.002] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 08/29/2023] [Revised: 11/27/2023] [Accepted: 03/07/2024] [Indexed: 04/17/2024]
Abstract
The onset of metabolic dysfunction-associated steatohepatitis (MASH) or non-alcoholic steatohepatitis (NASH) represents a tipping point leading to liver injury and subsequent hepatic complications in the natural progression of what is now termed metabolic dysfunction-associated steatotic liver diseases (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD). With no pharmacological treatment currently available for MASH/NASH, the race is on to develop drugs targeting multiple facets of hepatic metabolism, inflammation, and pro-fibrotic events, which are major drivers of MASH. Nuclear receptors (NRs) regulate genomic transcription upon binding to lipophilic ligands and govern multiple aspects of liver metabolism and inflammation. Ligands of NRs may include hormones, lipids, bile acids, and synthetic ligands, which upon binding to NRs regulate the transcriptional activities of target genes. NR ligands are presently the most promising drug candidates expected to receive approval from the United States Food and Drug Administration as a pharmacological treatment for MASH. This review aims to cover the current understanding of NRs, including nuclear hormone receptors, non-steroid hormone receptors, circadian NRs, and orphan NRs, which are currently undergoing clinical trials for MASH treatment, along with NRs that have shown promising results in preclinical studies.
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Affiliation(s)
- Rohit A. Sinha
- Department of Endocrinology, Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India
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11
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Tang X, Liao Q, Li Q, Jiang L, Li W, Xu J, Xiong A, Wang R, Zhao J, Wang Z, Ding L, Yang L. Lusianthridin ameliorates high fat diet-induced metabolic dysfunction-associated fatty liver disease via activation of FXR signaling pathway. Eur J Pharmacol 2024; 965:176196. [PMID: 38006926 DOI: 10.1016/j.ejphar.2023.176196] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2023] [Revised: 10/30/2023] [Accepted: 11/09/2023] [Indexed: 11/27/2023]
Abstract
Metabolic dysfunction-associated fatty liver disease (MAFLD) is a common chronic liver disease, but there are few specific medications for it. Lusianthridin, a major phenanthrene component that originates from Dendrobium Sonia, has various in vitro biological functions. In this study, we aimed to evaluate the therapeutic effects of lusianthridin on high-fat diet (HFD)-induced MAFLD as well as to examine the mechanism of its effects. We fed male mice high-fat-diet for 12 weeks to induce MAFLD and then continued to feed them, either with or without lusianthridin, for another six weeks. We found that lusianthridin decreased serum triacylglycerol, hepatic triacylglycerol, and serum low density lipoprotein cholesterol. It also reduced hepatic lipid accumulation based on the results of morphology analysis. Besides, it improved hepatic inflammation as well, including a decrease in serum alanine aminotransferase and a reduction in macrophage and neutrophil infiltration. Mechanistically, surface plasmon resonance, cell thermal shift assay and dual-luciferase report system results suggested that lusianthridin combined with farnesoid X receptor (FXR) ligand binding region and activated its transcriptional activity. Lusianthridin also decreased de no lipogenesis though inhibiting Srebp1c and downstream Scd-1, Lpin1 and Dgat2 expression in a FXR-dependent manner in oleic acid treated L02 cells. Correspondingly, lusianthridin inhibited Srebp1c and downstream lipogenesis in MAFLD liver tissues of mice at both of genetic and protein levels. Finally, the protective effects of lusianthridin on hepatic steaotosis were abolished in Fxr-/- mice. Taken together, our results suggested that lusianthridin attenuated high-fat-diet induced MAFLD via activation the FXR signaling pathway.
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Affiliation(s)
- Xiaowen Tang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qi Liao
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Qinqin Li
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Linshan Jiang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Wei Li
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jie Xu
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Aizhen Xiong
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Rufeng Wang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China
| | - Jing Zhao
- State Key Laboratory of Quality Research in Chinese Medicine, University of Macau, Macao, 999078, China
| | - Zhengtao Wang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Lili Ding
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
| | - Li Yang
- Shanghai Key Laboratory of Complex Prescription, and Ministry of Education (MOE) Key Laboratory for Standardization of Chinese Medicines and the State Administration of Traditional Chinese Medicine (SATCM) Key Laboratory for New Resources and Quality Evaluation of Chinese Medicines, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine, Shanghai, 201203, China; Shanghai R&D Center for Standardization of Traditional Chinese Medicine, Shanghai, 201203, China.
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12
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Axelrod CL, Langohr I, Dantas WS, Heintz EC, Vandanmagsar B, Yang S, Zunica ERM, Leigh Townsend R, Albaugh VL, Berthoud HR, Kirwan JP. Weight-independent effects of Roux-en-Y gastric bypass surgery on remission of nonalcoholic fatty liver disease in mice. Obesity (Silver Spring) 2023; 31:2960-2971. [PMID: 37731222 PMCID: PMC10895705 DOI: 10.1002/oby.23876] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Revised: 06/07/2023] [Accepted: 07/03/2023] [Indexed: 09/22/2023]
Abstract
OBJECTIVE Obesity is a driver of non-alcoholic fatty liver disease (NAFLD), and interventions that decrease body weight, such as bariatric surgery and/or calorie restriction (CR), may serve as effective therapies. This study compared the effects of Roux-en-Y gastric bypass surgery (RYGB) and CR on hepatic function in mice with obesity and NAFLD. METHODS C57BL/6J mice were fed a high-fat diet to promote obesity. At 16 weeks of age, mice were randomized to sham surgery (sham), RYGB, or CR weight matched to RYGB (WM). Body weight/composition, food intake, and energy expenditure (EE) were measured throughout treatment. Liver histopathology was evaluated from H&E-stained sections. Hepatic enzymes and glycogen content were determined by ELISA. Transcriptional signatures were revealed via RNA sequencing. RESULTS RYGB reduced hepatic lipid content and adiposity while increasing EE and lean body mass relative to WM. Hepatic glycogen and bile acid content were increased after RYGB relative to sham and WM. RYGB activated enterohepatic signaling and genes regulating hepatic lipid homeostasis. CONCLUSIONS RYGB improved whole-body composition and hepatic lipid homeostasis to a greater extent than CR in mice. RYGB was associated with discrete remodeling of the hepatic transcriptome, suggesting that surgery may be mechanistically additive to CR.
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Affiliation(s)
- Christopher L. Axelrod
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Ingeborg Langohr
- Department of Pathobiological Sciences, Louisiana State University, Baton Rouge, Louisiana, USA
| | - Wagner S. Dantas
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Elizabeth C. Heintz
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Bolormaa Vandanmagsar
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Shengping Yang
- Department of Biostatistics, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Elizabeth R. M. Zunica
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - R. Leigh Townsend
- Neurobiology and Nutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
- Translational and Integrative Gastrointestinal and Endocrine Research Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Vance L. Albaugh
- Translational and Integrative Gastrointestinal and Endocrine Research Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
- Metamor Institute, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - Hans-Rudolf Berthoud
- Neurobiology and Nutrition Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
| | - John P. Kirwan
- Integrative Physiology and Molecular Medicine Laboratory, Pennington Biomedical Research Center, Baton Rouge, Louisiana, USA
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13
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Gilbert MC, Setayesh T, Wan YJY. The contributions of bacteria metabolites to the development of hepatic encephalopathy. LIVER RESEARCH 2023; 7:296-303. [PMID: 38221945 PMCID: PMC10786625 DOI: 10.1016/j.livres.2022.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/17/2022]
Abstract
Over 20% of mortality during acute liver failure is associated with the development of hepatic encephalopathy (HE). Thus, HE is a complication of acute liver failure with a broad spectrum of neuropsychiatric abnormalities ranging from subclinical alterations to coma. HE is caused by the diversion of portal blood into systemic circulation through portosystemic collateral vessels. Thus, the brain is exposed to intestinal-derived toxic substances. Moreover, the strategies to prevent advancement and improve the prognosis of such a liver-brain disease rely on intestinal microbial modulation. This is supported by the findings that antibiotics such as rifaximin and laxative lactulose can alleviate hepatic cirrhosis and/or prevent HE. Together, the significance of the gut-liver-brain axis in human health warrants attention. This review paper focuses on the roles of bacteria metabolites, mainly ammonia and bile acids (BAs) as well as BA receptors in HE. The literature search conducted for this review included searches for phrases such as BA receptors, BAs, ammonia, farnesoid X receptor (FXR), G protein-coupled bile acid receptor 1 (GPBAR1 or TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and cirrhosis in conjunction with the phrase hepatic encephalopathy and portosystemic encephalopathy. PubMed, as well as Google Scholar, was the search engines used to find relevant publications.
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Affiliation(s)
- Miranda Claire Gilbert
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Tahereh Setayesh
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
| | - Yu-Jui Yvonne Wan
- Department of Pathology and Laboratory Medicine, University of California, Davis, Sacramento, CA, USA
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14
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Yang Y, Hsiao YC, Liu CW, Lu K. The Role of the Nuclear Receptor FXR in Arsenic-Induced Glucose Intolerance in Mice. TOXICS 2023; 11:833. [PMID: 37888683 PMCID: PMC10611046 DOI: 10.3390/toxics11100833] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/15/2023] [Revised: 09/26/2023] [Accepted: 09/28/2023] [Indexed: 10/28/2023]
Abstract
Inorganic arsenic in drinking water is prioritized as a top environmental contaminant by the World Health Organization, with over 230 million people potentially being exposed. Arsenic toxicity has been well documented and is associated with a plethora of human diseases, including diabetes, as established in numerous animal and epidemiological studies. Our previous study revealed that arsenic exposure leads to the inhibition of nuclear receptors, including LXR/RXR. To this end, FXR is a nuclear receptor central to glucose and lipid metabolism. However, limited studies are available for understanding arsenic exposure-FXR interactions. Herein, we report that FXR knockout mice developed more profound glucose intolerance than wild-type mice upon arsenic exposure, supporting the regulatory role of FXR in arsenic-induced glucose intolerance. We further exposed mice to arsenic and tested if GW4064, a FXR agonist, could improve glucose intolerance and dysregulation of hepatic proteins and serum metabolites. Our data showed arsenic-induced glucose intolerance was remarkably diminished by GW4064, accompanied by a significant ratio of alleviation of dysregulation in hepatic proteins (83%) and annotated serum metabolites (58%). In particular, hepatic proteins "rescued" from arsenic toxicity by GW4064 featured members of glucose and lipid utilization. For instance, the expression of PCK1, a candidate gene for diabetes and obesity that facilitates gluconeogenesis, was repressed under arsenic exposure in the liver, but revived with the GW4064 supplement. Together, our comprehensive dataset indicates FXR plays a key role and may serve as a potential therapeutic for arsenic-induced metabolic disorders.
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Affiliation(s)
| | | | | | - Kun Lu
- Department of Environmental Sciences and Engineering, University of North Carolina, Chapel Hill, NC 27599, USA
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15
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Wulfridge P, Davidovich A, Salvador AC, Manno GC, Tryggvadottir R, Idrizi A, Huda MN, Bennett BJ, Adams LG, Hansen KD, Threadgill DW, Feinberg AP. Precision pharmacological reversal of strain-specific diet-induced metabolic syndrome in mice informed by epigenetic and transcriptional regulation. PLoS Genet 2023; 19:e1010997. [PMID: 37871105 PMCID: PMC10621921 DOI: 10.1371/journal.pgen.1010997] [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: 04/18/2023] [Revised: 11/02/2023] [Accepted: 09/25/2023] [Indexed: 10/25/2023] Open
Abstract
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat, high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genome-wide DNA methylation analyses for each strain and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects revealed a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by epigenetic and transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the farnesoid X receptor pathway, and found that GW4064 exerts strain-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis. Furthermore, GW4064 treatment induced inflammatory-related gene expression changes in NOD, indicating a strain-specific effect in its associated toxicities as well as its therapeutic efficacy. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention and a mouse platform for guiding this approach.
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Affiliation(s)
- Phillip Wulfridge
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Adam Davidovich
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
| | - Anna C. Salvador
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
- Department of Nutrition, Texas A&M University, College Station, Texas, United States of America
| | - Gabrielle C. Manno
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
| | - Rakel Tryggvadottir
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - Adrian Idrizi
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - M. Nazmul Huda
- Department of Nutrition, University of California, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America
| | - Brian J. Bennett
- Department of Nutrition, University of California, Davis, California, United States of America
- Obesity and Metabolism Research Unit, USDA, ARS, Western Human Nutrition Research Center, Davis, California, United States of America
| | - L. Garry Adams
- Department of Veterinary Pathobiology, Texas A&M University, College Station, Texas, United States of America
| | - Kasper D. Hansen
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Biostatistics, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
- Department of Genetic Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
| | - David W. Threadgill
- Department of Cell Biology and Genetics, Texas A&M Health Science Center, College Station, Texas, United States of America
- Department of Nutrition, Texas A&M University, College Station, Texas, United States of America
- Department of Biochemistry & Biophysics, Texas A&M University, College Station, Texas, United States of America
| | - Andrew P. Feinberg
- Center for Epigenetics, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Biomedical Engineering, Johns Hopkins University, Baltimore, Maryland, United States of America
- Department of Medicine, Johns Hopkins School of Medicine, Baltimore, Maryland, United States of America
- Department of Mental Health, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland, United States of America
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16
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Zhang Z, Zhang B, Jiang X, Yu Y, Cui Y, Luo H, Wang B. Hyocholic acid retards renal fibrosis by regulating lipid metabolism and inflammatory response in a sheep model. Int Immunopharmacol 2023; 122:110670. [PMID: 37481851 DOI: 10.1016/j.intimp.2023.110670] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2023] [Revised: 07/15/2023] [Accepted: 07/16/2023] [Indexed: 07/25/2023]
Abstract
The kidneys are vital organs that regulate metabolic homeostasis in the body, filter waste products from the blood, and remove extrahepatic bile acids. We previously found that the dietary supplementation of hyocholic acid alleviated the sheep body lipid deposition and decreased kidney weight. This study evaluated hyocholic acid's (HCA) roles and mechanisms on lipid metabolism and anti-inflammatory function in the kidney under a high-energy diet. Histomicrograph showing the apparent improvement by HCA by attenuating structural damage. The HCA treatment reduced the renal accumulation of cholesterol. Bile acid receptors such as LXR and FXR were activated at the protein level. HCA significantly altered several genes related to immune response (NF-κB, IL-6, and MCP1) and fibrosis (TGF-β, Col1α1, and α-SMA). These significant changes correlated with renal lipid accumulation. The KEGG pathways including non-alcoholic fatty liver disease, insulin resistance, TNF signaling pathway, and Th17 cell differentiation were enriched and NF-κB, IL-6, and TGF-β were identified as the core interconnected genes. This study revealed that HCA plays an efficient role in alleviating kidney lipids accumulation and inflammatory response through crucial genes such as FXR, LXR, HMGCR, NF-κB, IL-6, MCP1, and TGF-β, and expand our understanding of HCA's role in kidney function. In conclusion, HCA mitigated kidney fibrosis, lipid metabolism disorders and immune responses induced by a high-energy diet by regulating a potential LXR/SREBP2/TGF-β-NF-κB signaling pathway.
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Affiliation(s)
- Zeping Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Boyan Zhang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Xianzhe Jiang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Yue Yu
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Yimeng Cui
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Hailing Luo
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China
| | - Bing Wang
- State Key Laboratory of Animal Nutrition, College of Animal Science and Technology, China Agricultural University, Beijing 100193, PR China.
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17
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Cheung KCP, Ma J, Loiola RA, Chen X, Jia W. Bile acid-activated receptors in innate and adaptive immunity: targeted drugs and biological agents. Eur J Immunol 2023; 53:e2250299. [PMID: 37172599 DOI: 10.1002/eji.202250299] [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: 11/29/2022] [Revised: 03/10/2023] [Accepted: 05/11/2023] [Indexed: 05/15/2023]
Abstract
Bile acid-activated receptors (BARs) such as a G-protein bile acid receptor 1 and the farnesol X receptor are activated by bile acids (BAs) and have been implicated in the regulation of microbiota-host immunity in the intestine. The mechanistic roles of these receptors in immune signaling suggest that they may also influence the development of metabolic disorders. In this perspective, we provide a summary of recent literature describing the main regulatory pathways and mechanisms of BARs and how they affect both innate and adaptive immune system, cell proliferation, and signaling in the context of inflammatory diseases. We also discuss new approaches for therapy and summarize clinical projects on BAs for the treatment of diseases. In parallel, some drugs that are classically used for other therapeutic purposes and BAR activity have recently been proposed as regulators of immune cells phenotype. Another strategy consists of using specific strains of gut bacteria to regulate BA production in the intestine.
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Affiliation(s)
- Kenneth C P Cheung
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Jiao Ma
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | | | - Xingxuan Chen
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
| | - Wei Jia
- Hong Kong Phenome Research Center, Hong Kong Baptist University, Kowloon Tong, Hong Kong, China
- Center for Translational Medicine and Shanghai Key Laboratory of Diabetes Mellitus, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China
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18
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Liu J, Sun J, Yu J, Chen H, Zhang D, Zhang T, Ma Y, Zou C, Zhang Z, Ma L, Yu X. Gut microbiome determines therapeutic effects of OCA on NAFLD by modulating bile acid metabolism. NPJ Biofilms Microbiomes 2023; 9:29. [PMID: 37258543 DOI: 10.1038/s41522-023-00399-z] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2022] [Accepted: 05/18/2023] [Indexed: 06/02/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), the most common chronic liver disease, had no approved pharmacological agents yet. Obeticholic acid (OCA), a novel bile acid derivative, was demonstrated to ameliorate NAFLD-related manifestations. Regarding the role of gut-liver axis in liver disease development, this study aimed to explore the potential role of gut microbiota in the treatment of OCA in NAFLD mice induced by the high-fat diet (HFD). Antibiotic-induced microbiome depletion (AIMD) and fecal microbiota transplantation (FMT) confirmed the critical role of gut microbiota in OCA treatment for NAFLD by effectively alleviating histopathological lesions and restoring liver function impaired by HFD. Metagenomic analysis indicated that OCA intervention in HFD mice remarkably increased the abundance of Akkermansia muciniphila, Bifidobacterium spp., Bacteroides spp., Alistipes spp., Lactobacillus spp., Streptococcus thermophilus, and Parasutterella excrementihominis. Targeted metabolomics analysis indicated that OCA could modulate host bile acids pool by reducing levels of serum hydrophobic cholic acid (CA) and chenodeoxycholic acid (CDCA), and increasing levels of serum-conjugated bile acids, such as taurodeoxycholic acid (TDCA) and tauroursodesoxycholic acid (TUDCA) in the HFD-fed mice. Strong correlations were observed between differentially abundant microbes and the shifted bile acids. Furthermore, bacteria enriched by OCA intervention exhibited much greater potential in encoding 7alpha-hydroxysteroid dehydrogenase (7α-HSDs) producing secondary bile acids rather than bile salt hydrolases (BSHs) mainly responsible for primary bile acid deconjugation. In conclusion, this study demonstrated that OCA intervention altered gut microbiota composition with specially enriched gut microbes modulating host bile acids, thus effectively alleviating NAFLD in the mice.
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Affiliation(s)
- Jianjun Liu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
- Yunnan Key Laboratory of Stem Cell and Regenerative Medicine, Institute of Biomedical Engineering, Kunming Medical University, Kunming, Yunnan, 650500, China
| | - Jiayi Sun
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China
| | - Jiangkun Yu
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China.
| | - Hang Chen
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Dan Zhang
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China
| | - Tao Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Yicheng Ma
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Chenggang Zou
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China
| | - Zhigang Zhang
- State Key Laboratory for Conservation and Utilization of Bio-Resources in Yunnan, School of Life Sciences, Yunnan University, Kunming, Yunnan, 650091, China.
| | - Lanqing Ma
- The First Affiliated Hospital, Yunnan Institute of Digestive Disease, Yunnan Clinical Research Center for Digestive Diseases, Kunming Medical University, Kunming, Yunnan, 650032, China.
| | - Xue Yu
- Department of Cardiology, Beijing Hospital, National Center of Gerontology, Institute of Geriatric Medicine, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, 100730, China.
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19
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Henry Z, Meadows V, Guo GL. FXR and NASH: an avenue for tissue-specific regulation. Hepatol Commun 2023; 7:e0127. [PMID: 37058105 PMCID: PMC10109454 DOI: 10.1097/hc9.0000000000000127] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Accepted: 02/23/2023] [Indexed: 04/15/2023] Open
Abstract
NASH is within the spectrum of NAFLD, a liver condition encompassing liver steatosis, inflammation, hepatocyte injury, and fibrosis. The prevalence of NASH-induced cirrhosis is rapidly rising and has become the leading indicator for liver transplantation in the US. There is no Food and Drug Administration (FDA)-approved pharmacological intervention for NASH. The farnesoid X receptor (FXR) is essential in regulating bile acid homeostasis, and dysregulation of bile acids has been implicated in the pathogenesis of NASH. As a result, modulators of FXR that show desirable effects in mitigating key characteristics of NASH have been developed as promising therapeutic approaches. However, global FXR activation causes adverse effects such as cholesterol homeostasis imbalance and pruritus. The development of targeted FXR modulation is necessary for ideal NASH therapeutics, but information regarding tissue-specific and cell-specific FXR functionality is limited. In this review, we highlight FXR activation in the regulation of bile acid homeostasis and NASH development, examine the current literature on tissue-specific regulation of nuclear receptors, and speculate on how FXR regulation will be beneficial in the treatment of NASH.
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Affiliation(s)
- Zakiyah Henry
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
| | - Vik Meadows
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
| | - Grace L. Guo
- Department of Pharmacology and Toxicology, Rutgers University, Piscataway, New Jersey, USA
- Environmental and Occupational Health Science Institute, Rutgers University, Piscataway, New Jersey, USA
- Department of Veterans Affairs New Jersey Health Care System, East Orange, New Jersey, USA
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20
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Wulfridge P, Davidovich A, Salvador AC, Manno GC, Tryggvadottir R, Idrizi A, Huda MN, Bennett BJ, Adams LG, Hansen KD, Threadgill DW, Feinberg AP. Precision pharmacological reversal of genotype-specific diet-induced metabolic syndrome in mice informed by transcriptional regulation. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.04.25.538156. [PMID: 37163127 PMCID: PMC10168252 DOI: 10.1101/2023.04.25.538156] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/11/2023]
Abstract
Diet-related metabolic syndrome is the largest contributor to adverse health in the United States. However, the study of gene-environment interactions and their epigenomic and transcriptomic integration is complicated by the lack of environmental and genetic control in humans that is possible in mouse models. Here we exposed three mouse strains, C57BL/6J (BL6), A/J, and NOD/ShiLtJ (NOD), to a high-fat high-carbohydrate diet, leading to varying degrees of metabolic syndrome. We then performed transcriptomic and genomic DNA methylation analyses and found overlapping but also highly divergent changes in gene expression and methylation upstream of the discordant metabolic phenotypes. Strain-specific pathway analysis of dietary effects reveals a dysregulation of cholesterol biosynthesis common to all three strains but distinct regulatory networks driving this dysregulation. This suggests a strategy for strain-specific targeted pharmacologic intervention of these upstream regulators informed by transcriptional regulation. As a pilot study, we administered the drug GW4064 to target one of these genotype-dependent networks, the Farnesoid X receptor pathway, and found that GW4064 exerts genotype-specific protection against dietary effects in BL6, as predicted by our transcriptomic analysis, as well as increased inflammatory-related gene expression changes in NOD. This pilot study demonstrates the potential efficacy of precision therapeutics for genotype-informed dietary metabolic intervention, and a mouse platform for guiding this approach.
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21
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Collins SL, Stine JG, Bisanz JE, Okafor CD, Patterson AD. Bile acids and the gut microbiota: metabolic interactions and impacts on disease. Nat Rev Microbiol 2023; 21:236-247. [PMID: 36253479 DOI: 10.1038/s41579-022-00805-x] [Citation(s) in RCA: 400] [Impact Index Per Article: 200.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/13/2022] [Indexed: 11/08/2022]
Abstract
Despite decades of bile acid research, diverse biological roles for bile acids have been discovered recently due to developments in understanding the human microbiota. As additional bacterial enzymes are characterized, and the tools used for identifying new bile acids become increasingly more sensitive, the repertoire of bile acids metabolized and/or synthesized by bacteria continues to grow. Additionally, bile acids impact microbiome community structure and function. In this Review, we highlight how the bile acid pool is manipulated by the gut microbiota, how it is dependent on the metabolic capacity of the bacterial community and how external factors, such as antibiotics and diet, shape bile acid composition. It is increasingly important to understand how bile acid signalling networks are affected in distinct organs where the bile acid composition differs, and how these networks impact infectious, metabolic and neoplastic diseases. These advances have enabled the development of therapeutics that target imbalances in microbiota-associated bile acid profiles.
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Affiliation(s)
- Stephanie L Collins
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - Jonathan G Stine
- Division of Gastroenterology and Hepatology, Department of Medicine, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Department of Public Health Sciences, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Health Liver Center, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
- Penn State Cancer Institute, Penn State Health Milton S. Hershey Medical Center, Hershey, PA, USA
| | - Jordan E Bisanz
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
| | - C Denise Okafor
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA
- Department of Chemistry, The Pennsylvania State University, University Park, PA, USA
| | - Andrew D Patterson
- Department of Biochemistry and Molecular Biology, The Pennsylvania State University, University Park, PA, USA.
- Center for Molecular Toxicology and Carcinogenesis, The Pennsylvania State University, University Park, PA, USA.
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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22
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Guo Y, Xie G, Zhang X. Role of FXR in Renal Physiology and Kidney Diseases. Int J Mol Sci 2023; 24:2408. [PMID: 36768731 PMCID: PMC9916923 DOI: 10.3390/ijms24032408] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/31/2022] [Revised: 01/18/2023] [Accepted: 01/23/2023] [Indexed: 01/27/2023] Open
Abstract
Farnesoid X receptor, also known as the bile acid receptor, belongs to the nuclear receptor (NR) superfamily of ligand-regulated transcription factors, which performs its functions by regulating the transcription of target genes. FXR is highly expressed in the liver, small intestine, kidney and adrenal gland, maintaining homeostasis of bile acid, glucose and lipids by regulating a diverse array of target genes. It also participates in several pathophysiological processes, such as inflammation, immune responses and fibrosis. The kidney is a key organ that manages water and solute homeostasis for the whole body, and kidney injury or dysfunction is associated with high morbidity and mortality. In the kidney, FXR plays an important role in renal water reabsorption and is thought to perform protective functions in acute kidney disease and chronic kidney disease, especially diabetic kidney disease. In this review, we summarize the recent advances in the understanding of the physiological and pathophysiological function of FXR in the kidney.
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Affiliation(s)
| | | | - Xiaoyan Zhang
- Health Science Center, East China Normal University, Shanghai 200241, China
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23
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GLP-1 Receptor Agonists in Non-Alcoholic Fatty Liver Disease: Current Evidence and Future Perspectives. Int J Mol Sci 2023; 24:ijms24021703. [PMID: 36675217 PMCID: PMC9865319 DOI: 10.3390/ijms24021703] [Citation(s) in RCA: 109] [Impact Index Per Article: 54.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2022] [Revised: 01/10/2023] [Accepted: 01/12/2023] [Indexed: 01/18/2023] Open
Abstract
To date, non-alcoholic fatty liver disease (NAFLD) is the most frequent liver disease, affecting up to 70% of patients with diabetes. Currently, there are no specific drugs available for its treatment. Beyond their anti-hyperglycemic effect and the surprising role of cardio- and nephroprotection, GLP-1 receptor agonists (GLP-1 RAs) have shown a significant impact on body weight and clinical, biochemical and histological markers of fatty liver and fibrosis in patients with NAFLD. Therefore, GLP-1 RAs could be a weapon for the treatment of both diabetes mellitus and NAFLD. The aim of this review is to summarize the evidence currently available on the role of GLP-1 RAs in the treatment of NAFLD and to hypothesize potential future scenarios.
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24
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Guo F, Chen K, Dong H, Hu D, Gao Y, Liu C, Laphookhieo S, Lei X. Biomimetic Total Synthesis and the Biological Evaluation of Natural Product (-)-Fargesone A as a Novel FXR Agonist. JACS AU 2022; 2:2830-2838. [PMID: 36590256 PMCID: PMC9795464 DOI: 10.1021/jacsau.2c00600] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/03/2022] [Revised: 11/24/2022] [Accepted: 11/28/2022] [Indexed: 06/17/2023]
Abstract
Farnesoid X receptor (FXR), a member of the nuclear receptor superfamily, plays an important role in maintaining or reversing metabolic homeostasis during the development of liver diseases. However, developing FXR modulators to intervene in FXR-related diseases is still an unmet clinical need. Therefore, it is significant to develop novel small-molecule agonists for drug discovery targeting FXR. Through a high-throughput chemical screen and follow-up biological validations, we first identified the natural product Fargesone A (FA) as a potent and selective FXR agonist. The limited, variable supply of FA from natural product isolation, however, has impeded its biological exploration and potential drug development. Accordingly, we have developed a biomimetic and scalable total synthesis of FA in nine steps that provides a solution to the supply of FA. Enabled by chemical synthesis, the in vivo efficacy of FA has been further investigated. The results showed that FA alleviates hepatocyte lipid accumulation and cell death in an FXR-dependent manner. Moreover, treatment of bile duct ligation (BDL)-induced liver disorder with FA ameliorates pathological features in mice. Therefore, our work lays the foundation to develop new small-molecule FXR agonists as a potential therapy for liver diseases.
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Affiliation(s)
- Fusheng Guo
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
- Peking-Tsinghua
Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, People’s Republic of China
| | - Kaiqi Chen
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
| | - Haoran Dong
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
| | - Dachao Hu
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
| | - Yihui Gao
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
| | - Chendi Liu
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
| | - Surat Laphookhieo
- Center
of Chemical Innovation for Sustainability and School of Science, Mae Fah Luang University, Chiang Rai 57100, Thailand
| | - Xiaoguang Lei
- Beijing
National Laboratory for Molecular Sciences, Key Laboratory of Bioorganic
Chemistry and Molecular Engineering of Ministry of Education, Department
of Chemical Biology, College of Chemistry and Molecular Engineering, Peking University, Beijing 100871, People’s Republic of China
- Peking-Tsinghua
Center for Life Science, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, People’s Republic of China
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25
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Cai J, Rimal B, Jiang C, Chiang JYL, Patterson AD. Bile acid metabolism and signaling, the microbiota, and metabolic disease. Pharmacol Ther 2022; 237:108238. [PMID: 35792223 DOI: 10.1016/j.pharmthera.2022.108238] [Citation(s) in RCA: 169] [Impact Index Per Article: 56.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2022] [Revised: 06/13/2022] [Accepted: 06/27/2022] [Indexed: 11/24/2022]
Abstract
The diversity, composition, and function of the bacterial community inhabiting the human gastrointestinal tract contributes to host health through its role in producing energy or signaling molecules that regulate metabolic and immunologic functions. Bile acids are potent metabolic and immune signaling molecules synthesized from cholesterol in the liver and then transported to the intestine where they can undergo metabolism by gut bacteria. The combination of host- and microbiota-derived enzymatic activities contribute to the composition of the bile acid pool and thus there can be great diversity in bile acid composition that depends in part on the differences in the gut bacteria species. Bile acids can profoundly impact host metabolic and immunological functions by activating different bile acid receptors to regulate signaling pathways that control a broad range of complex symbiotic metabolic networks, including glucose, lipid, steroid and xenobiotic metabolism, and modulation of energy homeostasis. Disruption of bile acid signaling due to perturbation of the gut microbiota or dysregulation of the gut microbiota-host interaction is associated with the pathogenesis and progression of metabolic disorders. The metabolic and immunological roles of bile acids in human health have led to novel therapeutic approaches to manipulate the bile acid pool size, composition, and function by targeting one or multiple components of the microbiota-bile acid-bile acid receptor axis.
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Affiliation(s)
- Jingwei Cai
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Bipin Rimal
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA
| | - Changtao Jiang
- Department of Physiology and Pathophysiology, School of Basic Medical Sciences, Peking University, and the Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, Beijing, PR China
| | - John Y L Chiang
- Department of Integrative Medical Sciences, College of Medicine, Northeast Ohio Medical University, Rootstown, OH, USA
| | - Andrew D Patterson
- Department of Veterinary and Biomedical Sciences, The Pennsylvania State University, University Park, PA, USA.
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26
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Duan S, Li X, Fan G, Liu R. Targeting bile acid signaling for the treatment of liver diseases: From bench to bed. Biomed Pharmacother 2022; 152:113154. [PMID: 35653887 DOI: 10.1016/j.biopha.2022.113154] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/13/2022] [Accepted: 05/15/2022] [Indexed: 11/02/2022] Open
Abstract
Liver diseases and related complications have become one of the leading causes of morbidity and mortality worldwide, yet effective medicine or approved treatment approach is still limited. Thus, novel therapy is urgently required to prevent or at least slow down the growing burden of liver transplantation or even death caused by malignant liver diseases. As the irreplaceable modulator of hepatic and intestinal signaling cascades, bile acids (BAs) play complex physiological as well as pathological roles in regulating energy and immune homeostasis in various liver diseases, including but not limited to metabolic diseases and cholangiopathies, making them highly attractive therapeutic targets. In the current review, recent progress in the research of enterohepatic circulation of BAs and potential therapeutic targets of BAs signaling, especially the development of currently available treatments, including agonizts of FXR and TGR5, analogs of FGF19, inhibitors of ASBT, and the regulation of gut microbiome through fecal microbiota transplantation were extensively summarized. Their protective effects, molecular mechanisms, and outcomes of clinical trials were highlighted. The structural features of these candidates and perspectives for their future development were further discussed. In conclusion, we believe that pharmacological therapies targeting BAs signaling represent promising and efficient strategies for the treatment of complex and multifactorial liver disorders.
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Affiliation(s)
- Shuni Duan
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Xiaojiaoyang Li
- School of Life Sciences, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Guifang Fan
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China
| | - Runping Liu
- School of Materia Medica, Beijing University of Chinese Medicine, 11 Bei San Huan Dong Lu, Beijing 100029, China.
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27
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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: 15] [Impact Index Per Article: 5.0] [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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28
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Jiao TY, Ma YD, Guo XZ, Ye YF, Xie C. Bile acid and receptors: biology and drug discovery for nonalcoholic fatty liver disease. Acta Pharmacol Sin 2022; 43:1103-1119. [PMID: 35217817 PMCID: PMC9061718 DOI: 10.1038/s41401-022-00880-z] [Citation(s) in RCA: 65] [Impact Index Per Article: 21.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2021] [Accepted: 01/25/2022] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease (NAFLD), a series of liver metabolic disorders manifested by lipid accumulation within hepatocytes, has become the primary cause of chronic liver diseases worldwide. About 20%-30% of NAFLD patients advance to nonalcoholic steatohepatitis (NASH), along with cell death, inflammation response and fibrogenesis. The pathogenesis of NASH is complex and its development is strongly related to multiple metabolic disorders (e.g. obesity, type 2 diabetes and cardiovascular diseases). The clinical outcomes include liver failure and hepatocellular cancer. There is no FDA-approved NASH drug so far, and thus effective therapeutics are urgently needed. Bile acids are synthesized in hepatocytes, transported into the intestine, metabolized by gut bacteria and recirculated back to the liver by the enterohepatic system. They exert pleiotropic roles in the absorption of fats and regulation of metabolism. Studies on the relevance of bile acid disturbance with NASH render it as an etiological factor in NASH pathogenesis. Recent findings on the functional identification of bile acid receptors have led to a further understanding of the pathophysiology of NASH such as metabolic dysregulation and inflammation, and bile acid receptors are recognized as attractive targets for NASH treatment. In this review, we summarize the current knowledge on the role of bile acids and the receptors in the development of NAFLD and NASH, especially the functions of farnesoid X receptor (FXR) in different tissues including liver and intestine. The progress in the development of bile acid and its receptors-based drugs for the treatment of NASH including bile acid analogs and non-bile acid modulators on bile acid metabolism is also discussed.
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Affiliation(s)
- Ting-Ying Jiao
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yuan-di Ma
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Xiao-Zhen Guo
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
| | - Yun-Fei Ye
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China
- University of Chinese Academy of Sciences, Beijing, 100049, China
| | - Cen Xie
- State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China.
- University of Chinese Academy of Sciences, Beijing, 100049, China.
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29
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Errafii K, Khalifa O, Al-Akl NS, Arredouani A. Comparative Transcriptome Analysis Reveals That Exendin-4 Improves Steatosis in HepG2 Cells by Modulating Signaling Pathways Related to Lipid Metabolism. Biomedicines 2022; 10:1020. [PMID: 35625757 PMCID: PMC9138370 DOI: 10.3390/biomedicines10051020] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 04/09/2022] [Accepted: 04/11/2022] [Indexed: 01/27/2023] Open
Abstract
No therapy exists for non-alcoholic fatty liver disease (NAFLD). However, glucagon-like peptide receptor agonists (GLP-1RAs) showed a beneficial effect on NAFLD, although the underpinning mechanisms remain unclear due to their pleiotropic effects. We examined the implicated signaling pathways using comparative transcriptomics in a cell model of steatosis to overcome pleiotropy. We treated steatotic HepG2 cells with the GLP-1RA Exendin-4 (Ex-4). We compared the transcriptome profiles of untreated steatotic, and Ex-4-treated steatotic cells, and used Ingenuity Pathway Analysis (IPA) to identify the signaling pathways and associated genes involved in the protective effect of Ex-4. Ex-4 treatment significantly reduces steatosis. RNA-seq analysis revealed 209 differentially expressed genes (DEGs) between steatotic and untreated cells, with farnesoid X receptor/retinoid X receptor (FXR/RXR) (p = 8.9 × 10-7) activation being the top regulated canonical pathway identified by IPA. Furthermore, 1644 DEGs were identified between steatotic cells and Ex-4-treated cells, with liver X receptor/retinoid X receptor (LXR/RXR) (p = 2.02 × 10-7) and FXR/RXR (p = 3.28 × 10-7) activation being the two top canonical pathways. The top molecular and cellular functions between untreated and steatotic cells were lipid metabolism, molecular transport, and small molecular biochemistry, while organismal injury and abnormalities, endocrine system disorders, and gastrointestinal disease were the top three molecular and cellular functions between Ex-4-treated and steatotic cells. Genes overlapping steatotic cells and Ex-4-treated cells were associated with several lipid metabolism processes. Unique transcriptomic differences exist between steatotic cells and Ex-4-treated steatotic cells, providing an important resource for understanding the mechanisms that underpin the protective effect of GLP-1RAs on NAFLD and for the identification of novel therapeutic targets for NAFLD.
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Affiliation(s)
- Khaoula Errafii
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
- African Genome Center, Mohammed VI Polytechnic University (UM6P), Ben Guerir 43151, Morocco
| | - Olfa Khalifa
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Neyla S. Al-Akl
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
| | - Abdelilah Arredouani
- College of Health and Life Sciences, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar;
- Diabetes Research Center, Qatar Biomedical Research Institute, Hamad Bin Khalifa University, Qatar Foundation, Doha P.O. Box 34110, Qatar; (O.K.); (N.S.A.-A.)
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30
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Affiliation(s)
- Alessia Perino
- Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland
| | - Kristina Schoonjans
- Institute of Bioengineering, School of Life Sciences, Ecole Polytechnique Fédérale de Lausanne, Lausanne, Switzerland.
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31
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Prikhodko VA, Bezborodkina NN, Okovityi SV. Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates. Biomedicines 2022; 10:274. [PMID: 35203484 PMCID: PMC8869100 DOI: 10.3390/biomedicines10020274] [Citation(s) in RCA: 20] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/22/2022] [Accepted: 01/24/2022] [Indexed: 02/08/2023] Open
Abstract
Non-alcoholic fatty liver disease (NAFLD), or metabolic (dysfunction)-associated fatty liver disease (MAFLD), is characterized by high global incidence and prevalence, a tight association with common metabolic comorbidities, and a substantial risk of progression and associated mortality. Despite the increasingly high medical and socioeconomic burden of NAFLD, the lack of approved pharmacotherapy regimens remains an unsolved issue. In this paper, we aimed to provide an update on the rapidly changing therapeutic landscape and highlight the major novel approaches to the treatment of this disease. In addition to describing the biomolecules and pathways identified as upcoming pharmacological targets for NAFLD, we reviewed the current status of drug discovery and development pipeline with a special focus on recent evidence from clinical trials.
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Affiliation(s)
- Veronika A. Prikhodko
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
| | - Natalia N. Bezborodkina
- Zoological Institute, Russian Academy of Sciences, 1 Universitetskaya emb., 199034 St. Petersburg, Russia;
| | - Sergey V. Okovityi
- Department of Pharmacology and Clinical Pharmacology, Saint Petersburg State Chemical and Pharmaceutical University, 14A Prof. Popov Str., 197022 St. Petersburg, Russia;
- Scientific, Clinical and Educational Center of Gastroenterology and Hepatology, Saint Petersburg State University, 7/9 Universitetskaya emb., 199034 St. Petersburg, Russia
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Ma Y, Tan Z, Li Q, Fan W, Chen G, Bin Y, Zhou Y, Yi J, Luo X, Tan J, Si Z, Li J. Combined Analysis of Expression Profiles in a Mouse Model and Patients Identified BHMT2 as a New Regulator of Lipid Metabolism in Metabolic-Associated Fatty Liver Disease. Front Cell Dev Biol 2021; 9:741710. [PMID: 34869329 PMCID: PMC8636031 DOI: 10.3389/fcell.2021.741710] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2021] [Accepted: 10/19/2021] [Indexed: 01/02/2023] Open
Abstract
Metabolic associated fatty liver disease (MAFLD) is associated with obesity, type 2 diabetes mellitus, and other metabolic syndromes. Farnesoid X receptor (FXR, NR1H4) plays a prominent role in hepatic lipid metabolism. This study combined the expression of liver genes in FXR knockout (KO) mice and MAFLD patients to identify new pathogenic pathways for MAFLD based on genome-wide transcriptional profiling. In addition, the roles of new target genes in the MAFLD pathogenic pathway were also explored. Two groups of differentially expressed genes were obtained from FXR-KO mice and MAFLD patients by transcriptional analysis of liver tissue samples. The similarities and differences between the two groups of differentially expressed genes were analyzed to identify novel pathogenic pathways and target genes. After the integration analysis of differentially expressed genes, we identified 134 overlapping genes, many of which have been reported to play an important role in lipid metabolism. Our unique analysis method of comparing differential gene expression between FXR-KO mice and patients with MAFLD is useful to identify target genes and pathways that may be strongly implicated in the pathogenesis of MAFLD. The overlapping genes with high specificity were screened using the Gene Expression Omnibus (GEO) database. Through comparison and analysis with the GEO database, we determined that BHMT2 and PKLR could be highly correlated with MAFLD. Clinical data analysis and RNA interference testing in vitro confirmed that BHMT2 may a new regulator of lipid metabolism in MAFLD pathogenesis. These results may provide new ideas for understanding the pathogenesis of MAFLD and thus provide new targets for the treatment of MAFLD.
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Affiliation(s)
- Yongqiang Ma
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China.,Transplant Medical Research Center, Second Xiangya Hospital, Central South University, Changsha, China
| | - Zhi Tan
- Department of Gastroenterology, The First Hospital of Changsha, Changsha, China
| | - Qiang Li
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China.,Transplant Medical Research Center, Second Xiangya Hospital, Central South University, Changsha, China
| | - Wenling Fan
- Department of Gastroenterology, The First Hospital of Changsha, Changsha, China
| | - Guangshun Chen
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China.,Transplant Medical Research Center, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yangyang Bin
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China
| | - Yi Zhou
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China
| | - Junfang Yi
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiaohua Luo
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jieqiong Tan
- Center for Medical Genetics, School of Life Science, Central South University, Changsha, China
| | - Zhongzhou Si
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China.,Transplant Medical Research Center, Second Xiangya Hospital, Central South University, Changsha, China
| | - Jiequn Li
- Department of Liver Transplant, Second Xiangya Hospital, Central South University, Changsha, China.,Transplant Medical Research Center, Second Xiangya Hospital, Central South University, Changsha, China
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FXR, a Key Regulator of Lipid Metabolism, Is Inhibited by ER Stress-Mediated Activation of JNK and p38 MAPK in Large Yellow Croakers ( Larimichthys crocea) Fed High Fat Diets. Nutrients 2021; 13:nu13124343. [PMID: 34959897 PMCID: PMC8706856 DOI: 10.3390/nu13124343] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2021] [Revised: 11/26/2021] [Accepted: 11/26/2021] [Indexed: 12/13/2022] Open
Abstract
High-fat diets induced abnormal lipid accumulation in the liver of cultured fish that caused body damage and diseases. The purpose of this research was to investigate the role and mechanism of farnesoid X receptor (FXR) in regulating lipid metabolism and to determine how high-fat diets affect FXR expression in large yellow croakers. The results showed that ligand-meditated FXR-activation could prevent abnormal lipid accumulation in the liver and hepatocytes of large yellow croakers. FXR activation increased the expression of lipid catabolism-related genes while decreasing the expression of lipogenesis-related genes. Further investigation found that the promoter activity of proliferator-activated receptor α (PPARα) could be increased by croaker FXR. Through the influence of SHP on LXR, FXR indirectly decreased the promoter activity of sterol regulatory element binding protein 1 (SREBP1) in large yellow croakers. Furthermore, the findings revealed that endoplasmic reticulum (ER)-stress-induced-activation of JNK and P38 MAPK participated in the reduction of FXR induced by high-fat diets. Then, hepatocyte nuclear factor 1α (HNF1α) was confirmed to be an FXR regulator in large yellow croaker, and it was reduced by high-fat diets and ER stress. In addition, co-expression of c-Jun with HNF1α inhibited the effect of HNF1α on FXR promoter, and suppression of P38 MAPK could relieve the HNF1α expression reduction caused by ER stress activation. In summary, the present study showed that FXR mediated lipid metabolism can prevent abnormal lipid accumulation through regulating PPARα and SREBP1 in large yellow croakers, while high-fat diets can suppress FXR expression by ER stress mediated-activation of JNK and P38 MAPK pathways. This research could benefit the study of FXR functions in vertebrate evolution and the development of therapy or preventative methods for nutrition-related disorders.
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Yu JS, Youn GS, Choi J, Kim C, Kim BY, Yang S, Lee JH, Park T, Kim BK, Kim YB, Roh SW, Min BH, Park HJ, Yoon SJ, Lee NY, Choi YR, Kim HS, Gupta H, Sung H, Han SH, Suk KT, Lee DY. Lactobacillus lactis and Pediococcus pentosaceus-driven reprogramming of gut microbiome and metabolome ameliorates the progression of non-alcoholic fatty liver disease. Clin Transl Med 2021; 11:e634. [PMID: 34965016 PMCID: PMC8715831 DOI: 10.1002/ctm2.634] [Citation(s) in RCA: 85] [Impact Index Per Article: 21.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/03/2021] [Revised: 10/11/2021] [Accepted: 10/17/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Although microbioa-based therapies have shown putative effects on the treatment of non-alcoholic fatty liver disease (NAFLD), it is not clear how microbiota-derived metabolites contribute to the prevention of NAFLD. We explored the metabolomic signature of Lactobacillus lactis and Pediococcus pentosaceus in NAFLD mice and its association in NAFLD patients. METHODS We used Western diet-induced NAFLD mice, and L. lactis and P. pentosaceus were administered to animals in the drinking water at a concentration of 109 CFU/g for 8 weeks. NAFLD severity was determined based on liver/body weight, pathology and biochemistry markers. Caecal samples were collected for the metagenomics by 16S rRNA sequencing. Metabolite profiles were obtained from caecum, liver and serum. Human stool samples (healthy control [n = 22] and NAFLD patients [n = 23]) were collected to investigate clinical reproducibility for microbiota-derived metabolites signature and metabolomics biomarker. RESULTS L. lactis and P. pentosaceus supplementation effectively normalized weight ratio, NAFLD activity score, biochemical markers, cytokines and gut-tight junction. While faecal microbiota varied according to the different treatments, key metabolic features including short chain fatty acids (SCFAs), bile acids (BAs) and tryptophan metabolites were analogously restored by both probiotic supplementations. The protective effects of indole compounds were validated with in vitro and in vivo models, including anti-inflammatory effects. The metabolomic signatures were replicated in NAFLD patients, accompanied by the comparable levels of Firmicutes/Bacteroidetes ratio, which was significantly higher (4.3) compared with control (0.6). Besides, the consequent biomarker panel with six stool metabolites (indole, BAs, and SCFAs) showed 0.922 (area under the curve) in the diagnosis of NAFLD. CONCLUSIONS NAFLD progression was robustly associated with metabolic dys-regulations in the SCFAs, bile acid and indole compounds, and NAFLD can be accurately diagnosed using the metabolites. L. lactis and P. pentosaceus ameliorate NAFLD progression by modulating gut metagenomic and metabolic environment, particularly tryptophan pathway, of the gut-liver axis.
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Affiliation(s)
- Jeong Seok Yu
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | - Gi Soo Youn
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Jieun Choi
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | - Chang‐Ho Kim
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
| | | | | | | | - Tae‐Sik Park
- Department of Life ScienceGachon UniversitySungnamRepublic of Korea
| | - Byoung Kook Kim
- Chong Kun Dang Bio Research InstituteGyeonggi‐doRepublic of Korea
| | - Yeon Bee Kim
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
- Microbiology and Functionality Research GroupWorld Institute of KimchiGwangjuRepublic of Korea
| | - Seong Woon Roh
- Microbiology and Functionality Research GroupWorld Institute of KimchiGwangjuRepublic of Korea
| | - Byeong Hyun Min
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hee Jin Park
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Sang Jun Yoon
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Na Young Lee
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Ye Rin Choi
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hyeong Seob Kim
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Haripriya Gupta
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Hotaik Sung
- School of MedicineKyungpook National UniversityDaeguRepublic of Korea
| | - Sang Hak Han
- Department of PathologyHallym University College of MedicineChuncheonRepublic of Korea
| | - Ki Tae Suk
- Institute for Liver and Digestive DiseasesHallym UniversityChuncheonRepublic of Korea
| | - Do Yup Lee
- Department of Agricultural BiotechnologyCenter for Food and BioconvergenceResearch Institute for Agricultural and Life SciencesSeoul National UniversitySeoulRepublic of Korea
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Ferrell JM, Chiang JY. Bile acid receptors and signaling crosstalk in the liver, gut and brain. LIVER RESEARCH 2021; 5:105-118. [PMID: 39957847 PMCID: PMC11791822 DOI: 10.1016/j.livres.2021.07.002] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/18/2021] [Accepted: 07/14/2021] [Indexed: 02/06/2023]
Abstract
Bile acids are physiological detergents derived from cholesterol that aid in digestion and nutrient absorption, and they play roles in glucose, lipid, and energy metabolism and in gut microbiome and metabolic homeostasis. Bile acids mediate crosstalk between the liver and gut through bactericidal modulation of the gut microbiome, while gut microbes influence the composition of the circulating bile acid pool. Recent research indicates bile acids may also be important mediators of neurological disease by acting as peripheral signaling molecules that activate bile acid receptors in the blood-brain barrier and in the brain itself. This review highlights the role of bile acids in maintaining liver and gut microbe homeostasis, as well as their function as mediators of cellular signaling in the liver-gut-brain axis.
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Affiliation(s)
- Jessica M. Ferrell
- Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
| | - John Y.L. Chiang
- Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, OH, USA
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36
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Yagai T, Yan T, Luo Y, Takahashi S, Aibara D, Kim D, Brocker CN, Levi M, Motohashi H, Gonzalez FJ. Feedback repression of PPARα signaling by Let-7 microRNA. Cell Rep 2021; 36:109506. [PMID: 34380035 PMCID: PMC8424520 DOI: 10.1016/j.celrep.2021.109506] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2019] [Revised: 03/12/2021] [Accepted: 07/20/2021] [Indexed: 11/08/2022] Open
Abstract
Peroxisome proliferator-activated receptor α (PPARα) controls hepatic lipid homeostasis and is the target of lipid-lowering fibrate drugs. PPARα activation represses expression of let-7 microRNA (miRNA), but the function of let-7 in PPARα signaling and lipid metabolism is unknown. In the current study, a hepatocyte-specific let-7b/c2 knockout (let7b/c2ΔHep) mouse line is generated, and these mice are found to exhibit pronounced resistance to diet-induced obesity and fatty liver. Let-7 inhibition by hepatocyte-specific let-7 sponge expression shows similar phenotypes as let7b/c2ΔHep mice. RNA sequencing (RNA-seq) analysis reveals that hepatic PPARα signaling is repressed in let7b/c2ΔHep mice. Protein expression of the obligate PPARα heterodimer partner retinoid X receptor α (RXRα) is reduced in the livers of let7b/c2ΔHep mice. Ring finger protein 8 (Rnf8), which is a direct target of let-7, is elevated in let7b/c2ΔHep mouse liver and identified as a E3 ubiquitin ligase for RXRα. This study highlights a let-7-RNF8-RXRα regulatory axis that modulates hepatic lipid catabolism.
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Affiliation(s)
- Tomoki Yagai
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Tingting Yan
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Yuhong Luo
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shogo Takahashi
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington DC, USA
| | - Daisuke Aibara
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Donghwan Kim
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Chad N Brocker
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Moshe Levi
- Department of Biochemistry and Molecular and Cellular Biology, Georgetown University, Washington DC, USA
| | - Hozumi Motohashi
- Department of Gene Expression Regulation, Institute of Development, Aging and Cancer, Tohoku University, Sendai 980-8575, Japan
| | - Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA.
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Petrescu AD, DeMorrow S. Farnesoid X Receptor as Target for Therapies to Treat Cholestasis-Induced Liver Injury. Cells 2021; 10:cells10081846. [PMID: 34440614 PMCID: PMC8392259 DOI: 10.3390/cells10081846] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2021] [Revised: 07/16/2021] [Accepted: 07/17/2021] [Indexed: 02/06/2023] Open
Abstract
Recent studies on liver disease burden worldwide estimated that cirrhosis is the 11th most common cause of death globally, and there is a great need for new therapies to limit the progression of liver injuries in the early stages. Cholestasis is caused by accumulation of hydrophobic bile acids (BA) in the liver due to dysfunctional BA efflux or bile flow into the gall bladder. Therefore, strategies to increase detoxification of hydrophobic BA and downregulate genes involved in BA production are largely investigated. Farnesoid X receptor (FXR) has a central role in BA homeostasis and recent publications revealed that changes in autophagy due to BA-induced reactive oxygen species and increased anti-oxidant response via nuclear factor E2-related factor 2 (NRF2), result in dysregulation of FXR signaling. Several mechanistic studies have identified new dysfunctions of the cholestatic liver at cellular and molecular level, opening new venues for developing more performant therapies.
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Affiliation(s)
- Anca D. Petrescu
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
| | - Sharon DeMorrow
- Division of Pharmacology and Toxicology, College of Pharmacy, The University of Texas at Austin, Austin, TX 78712, USA;
- Department of Internal Medicine, Dell Medical School, The University of Texas at Austin, Austin, TX 78712, USA
- Central Texas Veterans Health Care System, Temple, TX 78712, USA
- Correspondence: ; Tel.: +1-512-495-5779
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Shi Z, Chen G, Cao Z, Wu F, Lei H, Chen C, Song Y, Liu C, Li J, Zhou J, Lu Y, Zhang L. Gut Microbiota and Its Metabolite Deoxycholic Acid Contribute to Sucralose Consumption-Induced Nonalcoholic Fatty Liver Disease. JOURNAL OF AGRICULTURAL AND FOOD CHEMISTRY 2021; 69:3982-3991. [PMID: 33755449 DOI: 10.1021/acs.jafc.0c07467] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
Abstract
As important signal metabolites within enterohepatic circulation, bile acids (BAs) play a pivotal role during the occurrence and development of diet-induced nonalcoholic fatty liver disease (NAFLD). Here, we evaluated the functional effects of BAs and gut microbiota contributing to sucralose consumption-induced NAFLD of mice. The results showed that sucralose consumption significantly upregulated the abundance of intestinal genera Bacteroides and Clostridium, which produced deoxycholic acid (DCA) accumulating in multiple biological matrixes including feces, serum, and liver of mice. Subsequently, elevated hepatic DCA, one of the endogenous antagonists of the farnesol X receptor (Fxr), inhibited hepatic gene expression including a small heterodimer partner (Shp) and Fxr leading to sucralose-induced NAFLD in mice. Dietary supplements with fructo-oligosaccharide or metformin markedly restored genera Bacteroides and Clostridium abundance and the DCA level of sucralose-consuming mice, which eventually ameliorated NAFLD. These findings highlighted the effects of gut microbiota and its metabolite DCA on sucralose-induced NAFLD of mice.
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Affiliation(s)
- Zunji Shi
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
| | - Gui Chen
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Zheng Cao
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Fang Wu
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Hehua Lei
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
| | - Chuan Chen
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Yuchen Song
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- University of Chinese Academy of Sciences, Beijing 100049, China
| | - Caixiang Liu
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
| | - Jinquan Li
- Key Laboratory of Environment Correlative Dietology, College of Food Science and Technology, Huazhong Agricultural University, Wuhan 430070, China
| | - Jinlin Zhou
- Engineering Research Academy of High Value Utilization of Green Plants, Meizhou 514021, China
| | - Yujing Lu
- School of Biomedical and Pharmaceutical Sciences, Guangdong University of Technology, Guangzhou 510006, China
- Engineering Research Academy of High Value Utilization of Green Plants, Meizhou 514021, China
| | - Limin Zhang
- Chinese Academy of Sciences (CAS) Key Laboratory of Magnetic Resonance in Biological Systems, State Key Laboratory of Magnetic Resonance and Atomic and Molecular Physics, National Centre for Magnetic Resonance in Wuhan, Innovation Academy for Precision Measurement Science and Technology, CAS, Wuhan 430071, China
- Engineering Research Academy of High Value Utilization of Green Plants, Meizhou 514021, China
- Wuhan National Laboratory for Optoelectronics, Huazhong University of Science and Technology, Wuhan 430074, China
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Girisa S, Rana V, Parama D, Dutta U, Kunnumakkara AB. Differential roles of farnesoid X receptor (FXR) in modulating apoptosis in cancer cells. ADVANCES IN PROTEIN CHEMISTRY AND STRUCTURAL BIOLOGY 2021; 126:63-90. [PMID: 34090620 DOI: 10.1016/bs.apcsb.2021.02.006] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Cancer is one of the leading causes of mortality in the world. The conventional treatment strategies of cancer are surgery, radiation, and chemotherapy. However, in the advanced stage of the disease chemotherapy is the prime treatment and it is effective in only less than 10% of the patients. Therefore, there is an urgent need to find out novel therapeutic targets and delineate the mechanism of action of these targets for better management of this disease. Recent studies have shown that some of the proteins have differential role in different cancers. Therefore, it is pertinent that the targeting of these proteins should be based on the type of cancer. The nuclear receptor, FXR, is one of the vital proteins that regulate cell apoptosis. Besides, it also regulates other processes such as cell proliferation, angiogenesis, invasion, and migration. Studies suggest that the low or high expression of FXR is associated with the progression of carcinogenesis depending on the cancer types. Due to the diverse expression, it functions as both tumor suppressor and promoter. Previous studies suggest the overexpression of FXR in breast, lung, esophageal, and prostate cancer, which is related to poor survival and poor prognosis in patients. Therefore, targeting FXR with agonists and antagonists play different outcome in different cancers. Hence, this review describes the role of FXR in different cancers and the role of its inhibitors and activators for the prevention and treatment of various cancers.
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Affiliation(s)
- Sosmitha Girisa
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Varsha Rana
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Dey Parama
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India
| | - Uma Dutta
- Cell and Molecular Biology Laboratory, Department of Zoology, Cotton University, Guwahati, Assam, India
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory and DBT-AIST International Center for Translational and Environmental Research (DAICENTER), Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, Assam, India.
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Cariello M, Piccinin E, Moschetta A. Transcriptional Regulation of Metabolic Pathways via Lipid-Sensing Nuclear Receptors PPARs, FXR, and LXR in NASH. Cell Mol Gastroenterol Hepatol 2021; 11:1519-1539. [PMID: 33545430 PMCID: PMC8042405 DOI: 10.1016/j.jcmgh.2021.01.012] [Citation(s) in RCA: 71] [Impact Index Per Article: 17.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2020] [Revised: 01/19/2021] [Accepted: 01/19/2021] [Indexed: 02/07/2023]
Abstract
Nonalcoholic fatty liver disease comprises a wide spectrum of liver injuries from simple steatosis to steatohepatitis and cirrhosis. Nonalcoholic steatohepatitis (NASH) is defined when liver steatosis is associated with inflammation, hepatocyte damage, and fibrosis. A genetic predisposition and environmental insults (ie, dietary habits, obesity) are putatively responsible for NASH progression. Here, we present the impact of the lipid-sensing nuclear receptors in the pathogenesis and treatment of NASH. In detail, we discuss the pros and cons of the putative transcriptional action of the fatty acid sensors (peroxisome proliferator-activated receptors), the bile acid sensor (farnesoid X receptor), and the oxysterol sensor (liver X receptors) in the pathogenesis and bona fide treatment of NASH.
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Affiliation(s)
- Marica Cariello
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy
| | - Elena Piccinin
- Department of Basic Medical Sciences, Neurosciences and Sense Organs, University of Bari "Aldo Moro," Bari, Italy
| | - Antonio Moschetta
- Department of Interdisciplinary Medicine, University of Bari "Aldo Moro," Bari, Italy; National Institute for Biostructures and Biosystems (INBB), Rome, Italy; Scientific Institute for Research, Hospitalization and Healthcare (IRCCS) Istituto Tumori Giovanni Paolo II, Bari, Italy.
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Zhao S, Peng W, Li X, Wang L, Yin W, Wang YD, Hou R, Chen WD. Pharmacophore modeling and virtual screening studies for discovery of novel farnesoid X receptor (FXR) agonists. RSC Adv 2021; 11:2158-2166. [PMID: 35424145 PMCID: PMC8693749 DOI: 10.1039/d0ra09320c] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2020] [Accepted: 12/27/2020] [Indexed: 01/07/2023] Open
Abstract
Farnesoid X receptor (FXR) agonists would be considered as an important therapeutic strategy for several chronic liver and metabolic diseases. Here we have employed an integrated virtual screening by combining ligand-based pharmacophore mapping and molecular docking to identify novel nonsteroidal FXR agonists. Eighteen compounds were selected for in vitro FXR agonistic activity assay, and results showed five compounds exhibiting promising FXR agonistic activity. Among these compounds, compounds F4 and F17 were the most remarkable in vitro activity by using homogeneous time resolved fluorescence (HTRF) assay and the full-length FXR reporter gene assay in HepG2 cells. Real-time PCR assay was performed to measure the expression of FXR target genes. Compounds F4 and F17 increased small heterodimer partner (SHP), in turn, suppress mRNA levels of cholesterol 7-alpha-hydroxylase (CYP7A1). The obtained compounds F4 and F17 from this study may be potential leads for developing novel FXR agonists in the treatment of metabolic diseases.
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Affiliation(s)
- Shizhen Zhao
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wenjing Peng
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Xinping Li
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Le Wang
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wenbo Yin
- Key Laboratory of Structure-Based Drug Design and Discovery, Ministry of Education, School of Pharmaceutical Engineering, Shenyang Pharmaceutical University 103 Wenhua Road, Shenhe District Shenyang 110016 PR China
| | - Yan-Dong Wang
- State Key Laboratory of Chemical Resource Engineering, College of Life Science and Technology, Beijing University of Chemical Technology Beijing China
| | - Ruifang Hou
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
| | - Wei-Dong Chen
- Key Laboratory of Receptors-Mediated Gene Regulation and Drug Discovery, People's Hospital of Hebi, School of Medicine, Henan University Henan China
- Key Laboratory of Molecular Pathology, School of Basic Medical Science, Inner Mongolia Medical University Hohhot China
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Xie Y, Chen L, Xu Z, Li C, Ni Y, Hou M, Chen L, Chang H, Yang Y, Wang H, He R, Chen R, Qian L, Luo Y, Zhang Y, Li N, Zhu Y, Ji M, Liu Y. Predictive Modeling of MAFLD Based on Hsp90α and the Therapeutic Application of Teprenone in a Diet-Induced Mouse Model. Front Endocrinol (Lausanne) 2021; 12:743202. [PMID: 34659125 PMCID: PMC8515197 DOI: 10.3389/fendo.2021.743202] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/17/2021] [Accepted: 09/03/2021] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND AND AIMS The heat shock protein (Hsp) 90α is induced by stress and regulates inflammation through multiple pathways. Elevated serum Hsp90α had been found in nonalcoholic steatohepatitis (NASH). Geranylgeranylacetone (GGA, also called teprenone) is a terpenoid derivative. It was reported to induce Hsp and alleviate insulin resistance. We aimed to evaluate the Hsp90α as a biomarker in predicting metabolic-associated fatty liver disease (MAFLD) and define the therapeutic effects of geranylgeranylacetone for the disease. METHODS A clinical study was conducted to analyze the elements associated with Hsp90α, and a predictive model of MAFLD was developed based on Hsp90α. The histopathological correlation between Hsp90α and MAFLD was investigated through a diet-induced mouse model. Furthermore, GGA was applied to the mouse model. RESULTS Serum Hsp90α was increased in patients with MAFLD. A positive linear relationship was found between age, glycosylated hemoglobin (HbA1c), MAFLD, and serum Hsp90α. Meanwhile, a negative linear relationship with body mass index (BMI) was found. A model using Hsp90α, BMI, HbA1c, and ALT was established for predicting MAFLD. The area under the receiver operating characteristic (ROC) curves was 0.94 (95% CI 0.909-0.971, p = 0.000). The sensitivity was 84.1%, and the specificity was 93.1%. In vitro experiments, GGA induced Hsp90α in steatosis cells. In the mice model, Hsp90α decreased in the GGA treatment group. Hepatic steatosis, inflammation, insulin resistance, and glucose intolerance were improved in the GGA-treated group. Serum Hsp90α was positively correlated with steatohepatitis activity according to hepatic histopathology. CONCLUSIONS Serum Hsp90α was elevated in MAFLD, and a positive correlation between serum Hsp90α and the grade of activity of steatohepatitis was observed. The model using BMI, HbA1c, and alanine aminotransferase (ALT) had a good value to predict MAFLD. The findings also revealed the effectiveness of GGA in the treatment of MAFLD.
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Affiliation(s)
- Yuan Xie
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Lu Chen
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Zhipeng Xu
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Chen Li
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Yangyue Ni
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Min Hou
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Lin Chen
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Hao Chang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Yuxuan Yang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Huiquan Wang
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
| | - Rongbo He
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Rourou Chen
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Li Qian
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yan Luo
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Ying Zhang
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Na Li
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Yuxiao Zhu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
| | - Minjun Ji
- Department of Pathogen Biology, Jiangsu Province Key Laboratory of Modern Pathogen Biology, Center for Global Health, Nanjing Medical University, Nanjing, China
- *Correspondence: Minjun Ji, ; Yu Liu,
| | - Yu Liu
- Department of Endocrinology, Sir Run Run Hospital, Nanjing Medical University, Nanjing, China
- *Correspondence: Minjun Ji, ; Yu Liu,
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Maroni L, Fianchi F, Miele L, Svegliati Baroni G. The pathophysiology of gut–liver connection. THE COMPLEX INTERPLAY BETWEEN GUT-BRAIN, GUT-LIVER, AND LIVER-BRAIN AXES 2021:97-122. [DOI: 10.1016/b978-0-12-821927-0.00002-4] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
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Chen MJ, Liu C, Wan Y, Yang L, Jiang S, Qian DW, Duan JA. Enterohepatic circulation of bile acids and their emerging roles on glucolipid metabolism. Steroids 2021; 165:108757. [PMID: 33161055 DOI: 10.1016/j.steroids.2020.108757] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/24/2020] [Revised: 09/28/2020] [Accepted: 10/29/2020] [Indexed: 12/12/2022]
Abstract
Bile acids (BAs) are amphiphilic molecules with a nonpolar steroid carbon skeleton and a polar carboxylate side chain. Recently, BAs have aroused the attention of scholars due to their potential roles on metabolic diseases. As important endogenous ligands, BAs are wildly active in the enterohepatic circulation, during which microbiota play a significant role in promoting the hydrolysis and dehydroxylation of BAs. Besides, many pathways initiated by BAs including glucolipid metabolism and inflammation signaling pathways have been reported to regulate the host metabolism and maintain immune homeostasis. Herein, the characteristics on the enterohepatic circulation and metabolism of BAs are systematically summarized. Moreover, the regulation mechanism of the glucolipid metabolism by BAs is intensively discussed. Worthily, FXR and TGR5, which are involved in glucolipid metabolism, are the prime candidates for targeted therapies of chronic metabolic diseases such as diabetes and hypercholesterolemia.
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Affiliation(s)
- Meng-Jun Chen
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Chen Liu
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Yue Wan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Lei Yang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Shu Jiang
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
| | - Da-Wei Qian
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China
| | - Jin-Ao Duan
- Jiangsu Collaborative Innovation Center of Chinese Medicinal Resources Industrialization, Nanjing University of Chinese Medicine, Nanjing 210023, PR China.
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Li C, Yang J, Wang Y, Qi Y, Yang W, Li Y. Farnesoid X Receptor Agonists as Therapeutic Target for Cardiometabolic Diseases. Front Pharmacol 2020; 11:1247. [PMID: 32982723 PMCID: PMC7479173 DOI: 10.3389/fphar.2020.01247] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2020] [Accepted: 07/29/2020] [Indexed: 12/12/2022] Open
Abstract
Cardiometabolic diseases are characterized as a combination of multiple risk factors for cardiovascular disease (CVD) and metabolic diseases including diabetes mellitus and dyslipidemia. Cardiometabolic diseases are closely associated with cell glucose and lipid metabolism, inflammatory response and mitochondrial function. Farnesoid X Receptor (FXR), a metabolic nuclear receptor, are found to be activated by primary BAs such as chenodeoxycholic acid (CDCA), cholic acid (CA) and synthetic agonists such as obeticholic acid (OCA). FXR plays crucial roles in regulating cholesterol homeostasis, lipid metabolism, glucose metabolism, and intestinal microorganism. Recently, emerging evidence suggests that FXR agonists are functional for metabolic syndrome and cardiovascular diseases and are considered as a potential therapeutic agent. This review will discuss the pathological mechanism of cardiometabolic disease and reviews the potential mechanisms of FXR agonists in the treatment of cardiometabolic disease.
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Affiliation(s)
- Chao Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Jie Yang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yu Wang
- Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yingzi Qi
- School of Health, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Wenqing Yang
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China
| | - Yunlun Li
- Experimental Center, Shandong University of Traditional Chinese Medicine, Jinan, China.,Cardiovascular Department, Affiliated Hospital of Shandong University of Traditional Chinese Medicine, Jinan, China
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Li T, Tuo B. Pathophysiology of hepatic Na +/H + exchange (Review). Exp Ther Med 2020; 20:1220-1229. [PMID: 32742358 PMCID: PMC7388279 DOI: 10.3892/etm.2020.8888] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2019] [Accepted: 05/15/2020] [Indexed: 02/06/2023] Open
Abstract
Na+/H+ exchangers (NHEs) are a family of membrane proteins that contribute to exchanging one intracellular proton for one extracellular sodium. The family of NHEs consists of nine known members, NHE1-9. Each isoform represents a different gene product that has unique tissue expression, membrane localization, physiological effects, pathological regulation and sensitivity to drug inhibitors. NHE1 was the first to be discovered and is often referred to as the 'housekeeping' isoform of the NHE family. NHEs are not only involved in a variety of physiological processes, including the control of transepithelial Na+ absorption, intracellular pH, cell volume, cell proliferation, migration and apoptosis, but also modulate complex pathological events. Currently, the vast majority of review articles have focused on the role of members of the NHE family in inflammatory bowel disease, intestinal infectious diarrhea and digestive system tumorigenesis, but only a few reviews have discussed the role of NHEs in liver disease. Therefore, the present review described the basic biology of NHEs and highlighted their physiological and pathological effects in the liver.
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Affiliation(s)
- Tingting Li
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
| | - Biguang Tuo
- Department of Gastroenterology, Affiliated Hospital, Zunyi Medical University, Zunyi, Guizhou 563000, P.R. China
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Jia ET, Liu ZY, Pan M, Lu JF, Ge QY. Regulation of bile acid metabolism-related signaling pathways by gut microbiota in diseases. J Zhejiang Univ Sci B 2020; 20:781-792. [PMID: 31489798 DOI: 10.1631/jzus.b1900073] [Citation(s) in RCA: 32] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Over the past decade, there has been increasing attention on the interaction between microbiota and bile acid metabolism. Bile acids are not only involved in the metabolism of nutrients, but are also important in signal transduction for the regulation of host physiological activities. Microbial-regulated bile acid metabolism has been proven to affect many diseases, but there have not been many studies of disease regulation by microbial receptor signaling pathways. This review considers findings of recent research on the core roles of farnesoid X receptor (FXR), G protein-coupled bile acid receptor (TGR5), and vitamin D receptor (VDR) signaling pathways in microbial-host interactions in health and disease. Studying the relationship between these pathways can help us understand the pathogenesis of human diseases, and lead to new solutions for their treatments.
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Affiliation(s)
- Er-Teng Jia
- State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
| | - Zhi-Yu Liu
- State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
| | - Min Pan
- School of Medicine, Southeast University, Nanjing 210097, China
| | - Jia-Feng Lu
- Center of Reproduction and Genetics, Affiliated Suzhou Hospital of Nanjing Medical University, Suzhou Municipal Hospital, Suzhou 215002, China
| | - Qin-Yu Ge
- State Key Laboratory of Bioelectronics, School of Biological Science & Medical Engineering, Southeast University, Nanjing 210096, China
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Alsaggar M, Bdour S, Ababneh Q, El-Elimat T, Qinna N, Alzoubi KH. Silibinin attenuates adipose tissue inflammation and reverses obesity and its complications in diet-induced obesity model in mice. BMC Pharmacol Toxicol 2020; 21:8. [PMID: 31973745 PMCID: PMC6979281 DOI: 10.1186/s40360-020-0385-8] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2019] [Accepted: 01/17/2020] [Indexed: 01/21/2023] Open
Abstract
Background Obesity is a multifactorial chronic disease that comprises several pathological events, such as adipose hypertrophy, fatty liver and insulin resistance. Inflammation is a key contributer to development of these events, and therefore, targeting inflammation is increasingly considered for management of obesity and its complications. The aim of the current study was to investigate therapeutic outcomes of anti-inflammatory activities of the natural compound Silibinin in reversing obesity and its complication in mice. Methods C57BL/6 male mice were fed high-fat diet for 8 weeks until development of obesity, and then injected with 50 mg/kg silibinin intraperitoneally twice per week, or vehicle for 8 weeks. Throughout the experiment, mice were continuously checked for body weight and food intake, and glucose tolerance test was performed toward the end of the experiment. Animals were sacrificed and serum and tissues were collected for biochemical, histological, and gene expression analysis to assess silibinin effects on adipose inflammation, fat accumulation, liver adipogenesis and glucose homeostasis. Results Silibinin treatment reversed adipose tissue inflammation and adipocyte hypertrophy, and blocked progression in weight gain and obesity development with no significant effects on rates of food intake. Silibinin also reversed fatty liver disease and restored glucose homeostasis in treated animals, and reversed hyperglycemia, hyperinsulinemia and hypertriglyceridemia. Conclusion In this study, we demonstrated that silibinin as an anti-inflammatory therapy is a potential alternative to manage obesity, as well as its related complications. Moreover, silibinin-based therapies could further evolve as a novel treatment to manage various inflammation-driven disorders.
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Affiliation(s)
- Mohammad Alsaggar
- Department of Pharmaceutical Technology, School of Pharmacy, Jordan University of Science and Technology, P.O. Box 3030, Irbid, 22110, Jordan.
| | - Shifa Bdour
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan
| | - Qutaibah Ababneh
- Department of Biotechnology and Genetic Engineering, Jordan University of Science and Technology, Irbid, Jordan
| | - Tamam El-Elimat
- Department of Medicinal Chemistry and Pharmacognosy, Jordan University of Science and Technology, Irbid, Jordan
| | - Nidal Qinna
- Department of Pharmacology and Biomedical Sciences, University of Petra, Amman, Jordan
| | - Karem H Alzoubi
- Department of Clinical Pharmacy, Jordan University of Science and Technology, Irbid, Jordan
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Brønden A, Knop FK. Gluco-Metabolic Effects of Pharmacotherapy-Induced Modulation of Bile Acid Physiology. J Clin Endocrinol Metab 2020; 105:5601203. [PMID: 31630179 DOI: 10.1210/clinem/dgz025] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/17/2019] [Revised: 08/04/2019] [Accepted: 10/04/2019] [Indexed: 02/08/2023]
Abstract
CONTEXT The discovery and characterization of the bile acid specific receptors farnesoid X receptor (FXR) and Takeda G protein-coupled receptor 5 (TGR5) have facilitated a wealth of research focusing on the link between bile acid physiology and glucose metabolism. Modulation of FXR and TGR5 activation have been demonstrated to affect the secretion of glucagon-like peptide 1, insulin, and glucagon as well as energy expenditure and gut microbiota composition, with potential beneficial effects on glucose metabolism. EVIDENCE ACQUISITION A search strategy based on literature searches in on PubMed with various combinations of the key words FXR, TGR5, agonist, apical sodium-dependent bile acid transporter (ASBT), bile acid sequestrant, metformin, and glucose metabolism has been applied to obtain material for the present review. Furthermore, manual searches including scanning of reference lists in relevant papers and conference proceedings have been performed. EVIDENCE SYNTHESIS This review provides an outline of the link between bile acid and glucose metabolism, with a special focus on the gluco-metabolic impact of treatment modalities with modulating effects on bile acid physiology; including FXR agonists, TGR5 agonists, ASBT inhibitors, bile acid sequestrants, and metformin. CONCLUSIONS Any potential beneficial gluco-metabolic effects of FXR agonists remain to be established, whereas the clinical relevance of TGR5-based treatment modalities seems limited because of substantial safety concerns of TGR5 agonists observed in animal models. The glucose-lowering effects of ASBT inhibitors, bile acid sequestrants, and metformin are at least partly mediated by modulation of bile acid circulation, which might allow an optimization of these bile acid-modulating treatment modalities. (J Clin Endocrinol Metab XX: 00-00, 2019).
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Affiliation(s)
- Andreas Brønden
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
| | - Filip K Knop
- Center for Clinical M etabolic Research, Gentofte Hospital, University of Copenhagen, DK-2900 Hellerup, Denmark
- Department of Clinical Medicine, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Novo Nordisk Center for Basic Metabolic Research, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen N, Denmark
- Steno Diabetes Copenhagen, DK-2820 Gentofte, Denmark
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Hu H, Lin A, Kong M, Yao X, Yin M, Xia H, Ma J, Liu H. Intestinal microbiome and NAFLD: molecular insights and therapeutic perspectives. J Gastroenterol 2020; 55:142-158. [PMID: 31845054 PMCID: PMC6981320 DOI: 10.1007/s00535-019-01649-8] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2019] [Accepted: 11/19/2019] [Indexed: 02/07/2023]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is the hepatic manifestation of dysregulated lipid and glucose metabolism, which is often associated with obesity, dyslipidemia and insulin resistance. In view of the high morbidity and health risks of NAFLD, the lack of effective cure has drawn great attention. In recent years, a line of evidence has suggested a close linkage between the intestine and liver diseases such as NAFLD. We summarized the composition and characteristics of intestinal microbes and reviewed molecular insights into the intestinal microbiome in development and progression of NAFLD. Intestinal microbes mainly include bacteria, archaea, viruses and fungi, and the crosstalk between non-bacterial intestinal microbes and human liver diseases should be paid more attention. Intestinal microbiota imbalance may not only increase the intestinal permeability to gut microbes but also lead to liver exposure to harmful substances that promote hepatic lipogenesis and fibrosis. Furthermore, we focused on reviewing the latest "gut-liver axis"-targeting treatment, including the application of antibiotics, probiotics, prebiotics, synbiotics, farnesoid X receptor agonists, bile acid sequestrants, gut-derived hormones, adsorbents and fecal microbiota transplantation for NAFLD. In this review, we also discussed the potential mechanisms of "gut-liver axis" manipulation and efficacy of these therapeutic strategies for NAFLD treatment.
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Affiliation(s)
- Haiming Hu
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Aizhen Lin
- grid.477392.cHubei Provincial Hospital of Traditional Chinese Medicine, Wuhan, Hubei China
| | - Mingwang Kong
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Xiaowei Yao
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Mingzhu Yin
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Hui Xia
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Jun Ma
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
| | - Hongtao Liu
- grid.257143.60000 0004 1772 1285Hubei University of Chinese Medicine, Wuhan, Hubei China
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