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1
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Fang Y, Qin M, Zheng Q, Wang K, Han X, Yang Q, Sang X, Cao G. Role of Bile Acid Receptors in the Development and Function of Diabetic Nephropathy. Kidney Int Rep 2024; 9:3116-3133. [PMID: 39534198 PMCID: PMC11551060 DOI: 10.1016/j.ekir.2024.08.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/27/2024] [Revised: 07/25/2024] [Accepted: 08/04/2024] [Indexed: 11/16/2024] Open
Abstract
Diabetic nephropathy (DN) is a prevalent microvascular complication that occurs often in individuals with diabetes. It significantly raises the mortality rate of affected patients. Therefore, there is an urgent need to identify therapeutic targets for controlling and preventing the occurrence and development of DN. Bile acids (BAs) are now recognized as intricate metabolic integrators and signaling molecules. The activation of BAs has great promise as a therapeutic approach for preventing DN, renal damage caused by obesity, and nephrosclerosis. The nuclear receptors (NRs), farnesoid X receptor (FXR), pregnane X receptor (PXR), vitamin D receptor (VDR); and the G protein-coupled BA receptor, Takeda G-protein-coupled receptor 5 (TGR5) have important functions in controlling lipid, glucose, and energy metabolism, inflammation, as well as drug metabolism and detoxification. Over the past 10 years, there has been advancement in comprehending the biology and processes of BA receptors in the kidney, as well as in the creation of targeted BA receptor agonists. In this review, we discuss the role of BA receptors, FXR, PXR, VDR, and TGR5 in DN and their role in renal physiology, as well as the development and application of agonists that activate BA receptors for the treatment of kidney diseases.
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Affiliation(s)
- Yuanyuan Fang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Minjing Qin
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qitong Zheng
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Kuilong Wang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xin Han
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Qiao Yang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Xia'nan Sang
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Gang Cao
- School of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
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Guo Q, Hou X, Cui Q, Li S, Shen G, Luo Q, Wu H, Chen H, Liu Y, Chen A, Zhang Z. Pectin mediates the mechanism of host blood glucose regulation through intestinal flora. Crit Rev Food Sci Nutr 2023; 64:6714-6736. [PMID: 36756885 DOI: 10.1080/10408398.2023.2173719] [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] [Indexed: 02/10/2023]
Abstract
Pectin is a complex polysaccharide found in plant cell walls and interlayers. As a food component, pectin is benefit for regulating intestinal flora. Metabolites of intestinal flora, including short-chain fatty acids (SCFAs), bile acids (BAs) and lipopolysaccharides (LPS), are involved in blood glucose regulation. SCFAs promote insulin synthesis through the intestine-GPCRs-derived pathway and hepatic adenosine 5'-monophosphate (AMP)-activated protein kinase (AMPK) pathway to promote hepatic glycogen synthesis. On the one hand, BAs stimulate intestinal L cells and pancreatic α cells to secrete Glucagon-like peptide-1 (GLP-1) and peptide YY (PYY) through receptors G protein-coupled receptor (TGR5) and farnesoid X receptor (FXR). On the other hand, BAs promote hepatic glycogen synthesis through AMPK pathway. LPS inhibits the release of inflammatory cytokines through Toll-like receptors (TLRs)-myeloid differentiation factor 88 (MYD88) pathway and mitogen-activated protein kinase (MAPK) pathway, thereby alleviating insulin resistance (IR). In brief, both SCFAs and BAs promote GLP-1 secretion through different pathways, employing strategies of increasing glucose consumption and decreasing glucose production to maintain normal glucose levels. Notably, pectin can also directly inhibit the release of inflammatory cytokines through the -TLRs-MYD88 pathway. These data provide valuable information for further elucidating the relationship between pectin-intestinal flora-glucose metabolism.
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Affiliation(s)
- Qing Guo
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Xiaoyan Hou
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Qiang Cui
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Shanshan Li
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Guanghui Shen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Qingying Luo
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Hejun Wu
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Hong Chen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Yuntao Liu
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Anjun Chen
- College of Food Science, Sichuan Agricultural University, Ya'an, China
| | - Zhiqing Zhang
- College of Food Science, Sichuan Agricultural University, Ya'an, China
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Nara SJ, Jogi S, Cheruku S, Kandhasamy S, Jaipuri F, Kathi PK, Reddy S, Sarodaya S, Cook EM, Wang T, Sitkoff D, Rossi KA, Ruzanov M, Kiefer SE, Khan JA, Gao M, Reddy S, Sivaprasad Lvj S, Sane R, Mosure K, Zhuo X, Cao GG, Ziegler M, Azzara A, Krupinski J, Soars MG, Ellsworth BA, Wacker DA. Discovery of BMS-986339, a Pharmacologically Differentiated Farnesoid X Receptor Agonist for the Treatment of Nonalcoholic Steatohepatitis. J Med Chem 2022; 65:8948-8960. [PMID: 35704802 DOI: 10.1021/acs.jmedchem.2c00165] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
While several farnesoid X receptor (FXR) agonists under clinical investigation for the treatment of nonalcoholic steatohepatitis (NASH) have shown beneficial effects, adverse effects such as pruritus and elevation of plasma lipids have limited their clinical efficacy and approvability. Herein, we report the discovery and preclinical evaluation of compound 32 (BMS-986339), a nonbile acid FXR agonist with a pharmacologically distinct profile relative to our previously reported agonist BMS-986318. Compound 32 exhibited potent in vitro and in vivo activation of FXR, albeit with a context-dependent profile that resulted in tissue-selective effects in vivo. To our knowledge, this is the first report that demonstrates differential induction of Fgf15 in the liver and ileum by FXR agonists in vivo. Compound 32 demonstrated robust antifibrotic efficacy despite reduced activation of certain genes in the liver, suggesting that the additional pharmacology of BMS-986318 does not further benefit efficacy, possibly presenting an opportunity for reduced adverse effects. Further evaluation in humans is warranted to validate this hypothesis.
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Affiliation(s)
- Susheel J Nara
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Srinivas Jogi
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Srinivas Cheruku
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Sarkunam Kandhasamy
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Firoz Jaipuri
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Pavan Kalyan Kathi
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Subba Reddy
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Sanket Sarodaya
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Erica M Cook
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Tao Wang
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Doree Sitkoff
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Karen A Rossi
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Max Ruzanov
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Susan E Kiefer
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Javed A Khan
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Mian Gao
- Discovery Biotherapeutics, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Satyanarayana Reddy
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Sankara Sivaprasad Lvj
- Biocon-Bristol Myers Squibb Research and Development Center, Biocon Park, Plot No. 2 & 3, Bommasandra Phase IV, Jigani Link Road, Bangalore 560099, India
| | - Ramola Sane
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, 100 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Kathy Mosure
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, 100 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Xiaoliang Zhuo
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, 100 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Gary G Cao
- Discovery Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Milinda Ziegler
- Discovery Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Anthony Azzara
- Discovery Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - John Krupinski
- Discovery Biology, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Matthew G Soars
- Pharmaceutical Candidate Optimization, Bristol-Myers Squibb, Pharmaceutical Research Institute, 100 Binney Street, Cambridge, Massachusetts 02142, United States
| | - Bruce A Ellsworth
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
| | - Dean A Wacker
- Departments of Small Molecule Drug Discovery, Bristol-Myers Squibb, Pharmaceutical Research Institute, P.O. Box 5400, Princeton, New Jersey 08543-5400, United States
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Molecular Basis of Bile Acid-FXR-FGF15/19 Signaling Axis. Int J Mol Sci 2022; 23:ijms23116046. [PMID: 35682726 PMCID: PMC9181207 DOI: 10.3390/ijms23116046] [Citation(s) in RCA: 72] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Revised: 05/24/2022] [Accepted: 05/25/2022] [Indexed: 02/04/2023] Open
Abstract
Bile acids (BAs) are a group of amphiphilic molecules consisting of a rigid steroid core attached to a hydroxyl group with a varying number, position, and orientation, and a hydrophilic side chain. While BAs act as detergents to solubilize lipophilic nutrients in the small intestine during digestion and absorption, they also act as hormones. Farnesoid X receptor (FXR) is a nuclear receptor that forms a heterodimer with retinoid X receptor α (RXRα), is activated by BAs in the enterohepatic circulation reabsorbed via transporters in the ileum and the colon, and plays a critical role in regulating gene expression involved in cholesterol, BA, and lipid metabolism in the liver. The FXR/RXRα heterodimer also exists in the distal ileum and regulates production of fibroblast growth factor (FGF) 15/FGF19, a hormone traveling via the enterohepatic circulation that activates hepatic FGF receptor 4 (FGFR4)-β-klotho receptor complex and regulates gene expression involved in cholesterol, BA, and lipid metabolism, as well as those regulating cell proliferation. Agonists for FXR and analogs for FGF15/19 are currently recognized as a promising therapeutic target for metabolic syndrome and cholestatic diseases.
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Kim EY, Lee JM. Transcriptional Control of Trpm6 by the Nuclear Receptor FXR. Int J Mol Sci 2022; 23:ijms23041980. [PMID: 35216094 PMCID: PMC8874704 DOI: 10.3390/ijms23041980] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/17/2022] [Revised: 02/03/2022] [Accepted: 02/08/2022] [Indexed: 12/12/2022] Open
Abstract
Farnesoid x receptor (FXR) is a nuclear bile acid receptor that belongs to the nuclear receptor superfamily. It plays an essential role in bile acid biosynthesis, lipid and glucose metabolism, liver regeneration, and vertical sleeve gastrectomy. A loss of the FXR gene or dysregulations of FXR-mediated gene expression are associated with the development of progressive familial intrahepatic cholestasis, tumorigenesis, inflammation, and diabetes mellitus. Magnesium ion (Mg2+) is essential for mammalian physiology. Over 600 enzymes are dependent on Mg2+ for their activity. Here, we show that the Trpm6 gene encoding a Mg2+ channel is a direct FXR target gene in the intestinal epithelial cells of mice. FXR expressed in the intestinal epithelial cells is absolutely required for sustaining a basal expression of intestinal Trpm6 that can be robustly induced by the treatment of GW4064, a synthetic FXR agonist. Analysis of FXR ChIP-seq data revealed that intron regions of Trpm6 contain two prominent FXR binding peaks. Among them, the proximal peak from the transcription start site contains a functional inverted repeat 1 (IR1) response element that directly binds to the FXR-RXRα heterodimer. Based on these results, we proposed that an intestinal FXR-TRPM6 axis may link a bile acid signaling to Mg2+ homeostasis.
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Affiliation(s)
- Eun Young Kim
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
| | - Jae Man Lee
- Department of Biochemistry and Cell Biology, Cell and Matrix Research Institute, School of Medicine, Kyungpook National University, Daegu 41944, Korea;
- BK21 FOUR KNU Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu 41944, Korea
- Correspondence: ; Tel.: +82-53-420-4826
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Kiriyama Y, Nochi H. Physiological Role of Bile Acids Modified by the Gut Microbiome. Microorganisms 2021; 10:68. [PMID: 35056517 PMCID: PMC8777643 DOI: 10.3390/microorganisms10010068] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2021] [Revised: 12/21/2021] [Accepted: 12/29/2021] [Indexed: 12/13/2022] Open
Abstract
Bile acids (BAs) are produced from cholesterol in the liver and are termed primary BAs. Primary BAs are conjugated with glycine and taurine in the liver and then released into the intestine via the gallbladder. After the deconjugation of glycine or taurine by the gut microbiome, primary BAs are converted into secondary BAs by the gut microbiome through modifications such as dehydroxylation, oxidation, and epimerization. Most BAs in the intestine are reabsorbed and transported to the liver, where both primary and secondary BAs are conjugated with glycine or taurine and rereleased into the intestine. Thus, unconjugated primary Bas, as well as conjugated and unconjugated secondary BAs, have been modified by the gut microbiome. Some of the BAs reabsorbed from the intestine spill into the systemic circulation, where they bind to a variety of nuclear and cell-surface receptors in tissues, whereas some of the BAs are not reabsorbed and bind to receptors in the terminal ileum. BAs play crucial roles in the physiological regulation of various tissues. Furthermore, various factors, such as diet, age, and antibiotics influence BA composition. Here, we review recent findings regarding the physiological roles of BAs modified by the gut microbiome in the metabolic, immune, and nervous systems.
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Affiliation(s)
- Yoshimitsu Kiriyama
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan;
- Laboratory of Neuroendocrinology, Institute of Neuroscience, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan
| | - Hiromi Nochi
- Kagawa School of Pharmaceutical Sciences, Tokushima Bunri University, Shido 1314-1, Sanuki 769-2193, Kagawa, Japan;
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Glitscher M, Hildt E. Endosomal Cholesterol in Viral Infections - A Common Denominator? Front Physiol 2021; 12:750544. [PMID: 34858206 PMCID: PMC8632007 DOI: 10.3389/fphys.2021.750544] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Accepted: 10/22/2021] [Indexed: 12/24/2022] Open
Abstract
Cholesterol has gained tremendous attention as an essential lipid in the life cycle of virtually all viruses. These seem to have developed manifold strategies to modulate the cholesterol metabolism to the side of lipid uptake and de novo synthesis. In turn, affecting the cholesterol homeostasis has emerged as novel broad-spectrum antiviral strategy. On the other hand, the innate immune system is similarly regulated by the lipid and stimulated by its derivatives. This certainly requires attention in the design of antiviral strategies aiming to decrease cellular cholesterol, as evidence accumulates that withdrawal of cholesterol hampers innate immunity. Secondly, there are exceptions to the rule of the abovementioned virus-induced metabolic shift toward cholesterol anabolism. It therefore is of interest to dissect underlying regulatory mechanisms, which we aimed for in this minireview. We further collected evidence for intracellular cholesterol concentrations being less important in viral life cycles as compared to the spatial distribution of the lipid. Various routes of cholesterol trafficking were found to be hijacked in viral infections with respect to organelle-endosome contact sites mediating cholesterol shuttling. Thus, re-distribution of cellular cholesterol in the context of viral infections requires more attention in ongoing research. As a final aim, a pan-antiviral treatment could be found just within the transport and re-adjustment of local cholesterol concentrations. Thus, we aimed to emphasize the importance of the regulatory roles the endosomal system fulfils herein and hope to stimulate research in this field.
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Affiliation(s)
| | - Eberhard Hildt
- Department of Virology, Paul-Ehrlich-Institute, Langen, Germany
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Cui ZY, Han X, Jiang YC, Dou JY, Yao KC, Hu ZH, Yuan MH, Bao XX, Zhou MJ, Liu Y, Lian LH, Zhang X, Nan JX, Wu YL. Allium victorialis L. Extracts Promote Activity of FXR to Ameliorate Alcoholic Liver Disease: Targeting Liver Lipid Deposition and Inflammation. Front Pharmacol 2021; 12:738689. [PMID: 34690775 PMCID: PMC8531498 DOI: 10.3389/fphar.2021.738689] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2021] [Accepted: 08/09/2021] [Indexed: 12/20/2022] Open
Abstract
Allium victorialis L. (AVL) is a traditional medicinal plant recorded in the Compendium of Materia Medica (the Ming Dynasty). In general, it is used for hemostasis, analgesia, anti-inflammation, antioxidation, and to especially facilitate hepatoprotective effect. In recent years, it has received more and more attention due to its special nutritional and medicinal value. The present study investigates the effect and potential mechanism of AVL against alcoholic liver disease (ALD). C57BL/6 mice were fed Lieber-DeCarli liquid diet containing 5% ethanol plus a single ethanol gavage (5 g/kg), and followed up with the administration of AVL or silymarin. AML12 cells were stimulated with ethanol and incubated with AVL. AVL significantly reduced serum transaminase and triglycerides in the liver and attenuated histopathological changes caused by ethanol. AVL significantly inhibited SREBP1 and its target genes, regulated lipin 1/2, increased PPARα and its target genes, and decreased PPARγ expression caused by ethanol. In addition, AVL significantly enhanced FXR, LXRs, Sirt1, and AMPK expressions compared with the EtOH group. AVL also inhibited inflammatory factors, NLRP3, and F4/80 and MPO, macrophage and neutrophil markers. In vitro, AVL significantly reduced lipid droplets, lipid metabolism enzymes, and inflammatory factors depending on FXR activation. AVL could ameliorate alcoholic steatohepatitis, lipid deposition and inflammation in ALD by targeting FXR activation.
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Affiliation(s)
- Zhen-Yu Cui
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xin Han
- Chinese Medicine Processing Centre, College of Pharmacy, Zhejiang Chinese Medical University, Hangzhou, China
| | - Yu-Chen Jiang
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Jia-Yi Dou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Kun-Chen Yao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Zhong-He Hu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Ming-Hui Yuan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xiao-Xue Bao
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Mei-Jie Zhou
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Yue Liu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Li-Hua Lian
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
| | - Xian Zhang
- Agricultural College, Yanbian University, Yanji, China
| | - Ji-Xing Nan
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China.,Clinical Research Center, Affiliated Hospital of Yanbian University, Yanji, China
| | - Yan-Ling Wu
- Key Laboratory for Traditional Chinese Korean Medicine of Jilin Province, College of Pharmacy, Yanbian University, Yanji, China
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9
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Wang N, Wu S, Zhao J, Chen M, Zeng J, Lu G, Wang J, Zhang J, Liu J, Shi Y. Bile acids increase intestinal marker expression via the FXR/SNAI2/miR-1 axis in the stomach. Cell Oncol (Dordr) 2021; 44:1119-1131. [PMID: 34510400 PMCID: PMC8516775 DOI: 10.1007/s13402-021-00622-z] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/24/2021] [Indexed: 12/24/2022] Open
Abstract
Purpose Intestinal metaplasia (IM) is a precancerous lesion that increases the risk of subsequent gastric cancer (GC) development. Previously, miR-1 has been shown to play an essential role in the initiation of bile acid (BA)-induced IM. The objective of the present study was to investigate the mechanism underlying miR-1 inhibition by BA in gastric cells. Methods Ingenuity pathway analysis (IPA) was used to identify molecules acting upstream of miR-1. The effects of deoxycholic acid (DCA), FXR and SNAI2 on the expression of intestinal markers were assessed using quantitative real-time PCR (qRT-PCR) and Western blotting. The expression level of major molecules was detected by immunohistochemistry (IHC) in tissue microarrays. The transcriptional regulation of miR-1 was verified using luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Results We found that BA treatment caused aberrant expression of FXR and intestinal markers in gastric cells. Augmented FXR led to transcriptional activation of SNAI2, which in turn suppressed the miR-1 promoter. Moreover, we found that compared with normal tissues, the expression levels of both FXR and SNAI2 were increased and positively correlated with each other in IM tissues. Additionally, their expression showed an inverse correlation with that of miR-1 in IM tissues. Conclusions Our findings indicate that FXR may be responsible for a series of molecular changes in gastric cells after BA treatment, and that the FXR/SNAI2/miR-1 axis exhibits a crucial role in BA-induced progression of IM. Blocking the FXR-oriented axis may provide a promising approach for IM or even GC treatment. Supplementary Information The online version contains supplementary material available at 10.1007/s13402-021-00622-z.
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Affiliation(s)
- Na Wang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Siran Wu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Jing Zhao
- Xi'an Jiaotong University, Xi'an, China
| | - Min Chen
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Jiaoxia Zeng
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Guofang Lu
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Jiaojiao Wang
- Shannxi University of Chinese Medicine, Xi'an, China
| | - Jian Zhang
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China
| | - Junye Liu
- Department of Radiation Protective Medicine, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China.
| | - Yongquan Shi
- Xijing Hospital of Digestive Diseases, State Key Laboratory of Cancer Biology, Fourth Military Medical University, No. 15 West Changle Road, Xi'an, 710032, Shaanxi, China.
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10
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FXR/TGR5 mediates inflammasome activation and host resistance to bacterial infection. Biochem Biophys Rep 2021; 27:101051. [PMID: 34179517 PMCID: PMC8214033 DOI: 10.1016/j.bbrep.2021.101051] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2020] [Revised: 05/20/2021] [Accepted: 06/07/2021] [Indexed: 12/12/2022] Open
Abstract
Bacterial infections are a major cause of chronic infections and mortality. Innate immune control is crucial for protection against bacterial pathogens. Bile acids facilitate intestinal absorption of lipid-soluble nutrients and modulate various metabolic pathways through the farnesoid X receptor (FXR) and Takeda G-protein-coupled receptor 5 (TGR5). Here, we identified a new role of FXR and TGR5 in promoting inflammasome activation during bacterial infection. Caspase-1/11 activation and release of cleaved interleukin (IL)-1β in FXR- and TGR5-deficient mouse bone marrow-derived macrophages upon Listeria monocytogenes or Escherichia coli infection was significantly reduced. In contrast, FXR- or TGR5-deficiency did not affect the transcription of caspase-1/11 and IL-1β. Inflammasome activation is critical for host immune defense against bacterial infections. Consistent with this, the deletion of FXR or TGR5 impaired effective clearance of L. monocytogenes or E. coli in vitro and in vivo, which was associated with greater mortality and bacterial burden than that of wild-type mice. Pretreatment with an FXR agonist decreased bacterial burden in vitro and increased survival in vivo. Thus, FXR and TGR5 promote inflammasome-mediated antimicrobial responses and may represent novel antibacterial therapeutic targets.
FXR- or TGR5-deficiency decreases inflammasome activation upon Listeria monocytogenes or Escherichia coli infection. FXR- or TGR5-deficiency impaired effective clearance of L. monocytogenes or E. coli. FXR and TGR5 promote inflammasome-mediated antimicrobial responses.
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11
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Manipulating the Microbiome: An Alternative Treatment for Bile Acid Diarrhoea. MICROBIOLOGY RESEARCH 2021. [DOI: 10.3390/microbiolres12020023] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022] Open
Abstract
Bile acid diarrhoea (BAD) is a widespread gastrointestinal disease that is often misdiagnosed as irritable bowel syndrome and is estimated to affect 1% of the United Kingdom (UK) population alone. BAD is associated with excessive bile acid synthesis secondary to a gastrointestinal or idiopathic disorder (also known as primary BAD). Current licensed treatment in the UK has undesirable effects and has been the same since BAD was first discovered in the 1960s. Bacteria are essential in transforming primary bile acids into secondary bile acids. The profile of an individual’s bile acid pool is central in bile acid homeostasis as bile acids regulate their own synthesis. Therefore, microbiome dysbiosis incurred through changes in diet, stress levels and the introduction of antibiotics may contribute to or be the cause of primary BAD. This literature review focuses on primary BAD, providing an overview of bile acid metabolism, the role of the human gut microbiome in BAD and the potential options for therapeutic intervention in primary BAD through manipulation of the microbiome.
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12
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Jeong S, Kim IK, Kim H, Choi MJ, Lee J, Jo YS. Liver X Receptor β Related to Tumor Progression and Ribosome Gene Expression in Papillary Thyroid Cancer. Endocrinol Metab (Seoul) 2020; 35:656-668. [PMID: 32814418 PMCID: PMC7520597 DOI: 10.3803/enm.2020.667] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 06/15/2020] [Accepted: 06/26/2020] [Indexed: 01/06/2023] Open
Abstract
BACKGROUND Intracellular lipid deposition has been reported in thyroid glands in obese animal and human. To understand the regulatory mechanism of lipid metabolism in thyroid cancer, we investigated the expression status of liver X receptor (LXR) and analyzed its clinicopathological characteristics and molecular biological features. METHODS Expression status of LXR and its transcriptional targets in human cancers were analyzed using The Cancer Genome Atlas (TCGA). The gene-sets related to high LXRβ expression was investigated by gene set enrichment analysis (GSEA) using Kyoto Encyclopedia of Genes and Genomes (KEGG) signaling pathways and gene ontology biologic process. Quantitative reverse transcription polymerase chain reaction was performed in thyroid cancer samples using our validation cohort. RESULTS In contrast to low expression of LXRα, LXRβ was highly expressed in thyroid cancer compared to the other types of human cancers. High LXRβ expression was correlated with the expression of LXRβ transcriptional targets genes, such as apolipoprotein C1 (APOC1), APOC2, apolipoprotein E (APOE), ATP binding cassette subfamily G member 8 (ABCG8), sterol regulatory elementbinding protein 1c (SREBP1c), and SPOT14. Furthermore, High LXRβ expression group indicated poor clinicopathological characteristics and aggressive molecular biological features independently from the drive mutation status. Mechanistically, high LXRβ expression was coordinately related to ribosome-related gene sets. CONCLUSION The mechanistic link between LXRβ and ribosomal activity will be addressed to develop new diagnostic and therapeutic targets in thyroid cancers.
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Affiliation(s)
- Seonhyang Jeong
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
| | - In-Kyu Kim
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Hyunji Kim
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Moon Jung Choi
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Jandee Lee
- Department of Surgery, Open NBI Convergence Technology Research Laboratory, Severance Hospital, Yonsei Cancer Center, Yonsei University College of Medicine, Seoul, Korea
| | - Young Suk Jo
- Department of Internal Medicine, Yonsei University College of Medicine, Seoul, Korea
- Brain Korea 21 PLUS Project for Medical Science, Yonsei University, Seoul, Korea
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13
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Busnelli M, Manzini S, Chiesa G. The Gut Microbiota Affects Host Pathophysiology as an Endocrine Organ: A Focus on Cardiovascular Disease. Nutrients 2019; 12:E79. [PMID: 31892152 PMCID: PMC7019666 DOI: 10.3390/nu12010079] [Citation(s) in RCA: 48] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2019] [Revised: 12/18/2019] [Accepted: 12/24/2019] [Indexed: 12/12/2022] Open
Abstract
It is widely recognized that the microorganisms inhabiting our gastrointestinal tract-the gut microbiota-deeply affect the pathophysiology of the host. Gut microbiota composition is mostly modulated by diet, and gut microorganisms communicate with the different organs and tissues of the human host by synthesizing hormones and regulating their release. Herein, we will provide an updated review on the most important classes of gut microbiota-derived hormones and their sensing by host receptors, critically discussing their impact on host physiology. Additionally, the debated interplay between microbial hormones and the development of cardiovascular disease will be thoroughly analysed and discussed.
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Affiliation(s)
| | | | - Giulia Chiesa
- Department of Pharmacological and Biomolecular Sciences, Università degli Studi di Milano, 20133 Milano, Italy;
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14
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Human Postprandial Nutrient Metabolism and Low-Grade Inflammation: A Narrative Review. Nutrients 2019; 11:nu11123000. [PMID: 31817857 PMCID: PMC6950246 DOI: 10.3390/nu11123000] [Citation(s) in RCA: 30] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/07/2019] [Revised: 12/03/2019] [Accepted: 12/04/2019] [Indexed: 12/11/2022] Open
Abstract
The importance of the postprandial state has been acknowledged, since hyperglycemia and hyperlipidemia are linked with several chronic systemic low-grade inflammation conditions. Humans spend more than 16 h per day in the postprandial state and the postprandial state is acknowledged as a complex interplay between nutrients, hormones and diet-derived metabolites. The purpose of this review is to provide insight into the physiology of the postprandial inflammatory response, the role of different nutrients, the pro-inflammatory effects of metabolic endotoxemia and the anti-inflammatory effects of bile acids. Moreover, we discuss nutritional strategies that may be linked to the described pathways to modulate the inflammatory component of the postprandial response.
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15
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Wouters E, de Wit NM, Vanmol J, van der Pol SMA, van het Hof B, Sommer D, Loix M, Geerts D, Gustafsson JA, Steffensen KR, Vanmierlo T, Bogie JFJ, Hendriks JJA, de Vries HE. Liver X Receptor Alpha Is Important in Maintaining Blood-Brain Barrier Function. Front Immunol 2019; 10:1811. [PMID: 31417573 PMCID: PMC6685401 DOI: 10.3389/fimmu.2019.01811] [Citation(s) in RCA: 33] [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: 02/06/2019] [Accepted: 07/17/2019] [Indexed: 12/17/2022] Open
Abstract
Dysfunction of the blood-brain barrier (BBB) contributes significantly to the pathogenesis of several neuroinflammatory diseases, including multiple sclerosis (MS). Potential players that regulate BBB function are the liver X receptors (LXRs), which are ligand activated transcription factors comprising two isoforms, LXRα, and LXRβ. However, the role of LXRα and LXRβ in regulating BBB (dys)function during neuroinflammation remains unclear, as well as their individual involvement. Therefore, the goal of the present study is to unravel whether LXR isoforms have different roles in regulating BBB function under neuroinflammatory conditions. We demonstrate that LXRα, and not LXRβ, is essential to maintain barrier integrity in vitro. Specific knockout of LXRα in brain endothelial cells resulted in a more permeable barrier with reduced expression of tight junctions. Additionally, the observed dysfunction was accompanied by increased endothelial inflammation, as detected by enhanced expression of vascular cell adhesion molecule (VCAM-1) and increased transendothelial migration of monocytes toward inflammatory stimuli. To unravel the importance of LXRα in BBB function in vivo, we made use of the experimental autoimmune encephalomyelitis (EAE) MS mouse model. Induction of EAE in a constitutive LXRα knockout mouse and in an endothelial specific LXRα knockout mouse resulted in a more severe disease score in these animals. This was accompanied by higher numbers of infiltrating leukocytes, increased endothelial VCAM-1 expression, and decreased expression of the tight junction molecule claudin-5. Together, this study reveals that LXRα is indispensable for maintaining BBB integrity and its immune quiescence. Targeting the LXRα isoform may help in the development of novel therapeutic strategies to prevent BBB dysfunction, and thereby neuroinflammatory disorders.
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Affiliation(s)
- Elien Wouters
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Nienke M. de Wit
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Jasmine Vanmol
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Susanne M. A. van der Pol
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Bert van het Hof
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
| | - Daniela Sommer
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Melanie Loix
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Dirk Geerts
- Department of Medical Biology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Jan Ake Gustafsson
- Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, United States
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Knut R. Steffensen
- Division of Clinical Chemistry, Department of Laboratory Medicine, Karolinska Institute, Stockholm, Sweden
| | - Tim Vanmierlo
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
- Division Translational Neuroscience, School for Mental Health and Neuroscience, Maastricht University, Maastricht, Netherlands
| | - Jeroen F. J. Bogie
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Jerome J. A. Hendriks
- School of Life Sciences, Biomedical Research Institute, Hasselt University, Diepenbeek, Belgium
| | - Helga E. de Vries
- Department of Molecular Cell Biology and Immunology, Amsterdam Neuroscience, MS Center Amsterdam, Amsterdam UMC, Vrije Universiteit Amsterdam, Amsterdam, Netherlands
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16
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Samant H, Manatsathit W, Dies D, Shokouh-Amiri H, Zibari G, Boktor M, Alexander JS. Cholestatic liver diseases: An era of emerging therapies. World J Clin Cases 2019; 7:1571-1581. [PMID: 31367616 PMCID: PMC6658370 DOI: 10.12998/wjcc.v7.i13.1571] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2019] [Revised: 06/05/2019] [Accepted: 06/10/2019] [Indexed: 02/05/2023] Open
Abstract
Recently the field of cholestasis has expanded enormously reflecting an improved understanding of the molecular mechanisms underlying bile secretion and its perturbation in chronic cholestatic disease. Novel anti-cholestatic therapeutic options have been developed for patients not favorably responding to ursodeoxycholic acid (UDCA), the current standard treatment for cholestatic liver disease. Important novel treatment targets now also include nuclear receptors involved in bile acid (BA) homoeostasis like farnesoid X receptor and G protein-coupled receptors e.g., the G-protein-coupled BA receptor "transmembrane G coupled receptor 5". Fibroblast growth factor-19 and enterohepatic BA transporters also deserve attention as additional drug targets as does the potential treatment agent norUDCA. In this review, we discuss recent and future promising therapeutic agents and their potential molecular mechanisms in cholestatic liver disorders.
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Affiliation(s)
- Hrishikesh Samant
- Division of Gastroenterology and Hepatology, Department of medicine, LSU health, Shreveport, LA 71103, United States
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Wuttiporn Manatsathit
- Division of Gastroenterology and Hepatology, University of Nebraska, Omaha, NE 68194, United States
| | - David Dies
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Hosein Shokouh-Amiri
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Gazi Zibari
- John C McDonald Transplant Center, Willis Knighton Medical Center, Shreveport, LA 71103, United States
| | - Moheb Boktor
- Division of Gastroenterology and Hepatology, Department of medicine, LSU health, Shreveport, LA 71103, United States
| | - Jonathan Steve Alexander
- Department of Molecular and Cellular Physiology, Louisiana State University, School of Medicine, Shreveport, LA 71103, United States
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17
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Wu W, Wu Q, Liu X. Chronic activation of FXR-induced liver growth with tissue-specific targeting Cyclin D1. Cell Cycle 2019; 18:1784-1797. [PMID: 31223053 DOI: 10.1080/15384101.2019.1634955] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
The nuclear receptor (FXR) plays essential roles in maintaining bile acid and lipid homeostasis by regulating diverse target genes. And its agonists were promising agents for treating various liver diseases. Nevertheless, the potential side effect of chronic FXR activation by specific agonists is not fully understood. In this study, we investigated the mechanism of FXR agonist WAY-362450 induced liver enlargement during treating liver diseases. We demonstrated that chronic ingestion of WAY-362450 induced liver hypertrophy instead of hyperplasia in mouse. Global transcriptional pattern was also examined in mouse livers after treatment with WAY-362450 by RNA-seq assay. Through GO and KEGG enrichment analyses, we demonstrated that the expression of Cyclin D1 (Ccnd1) among the cell cycle-regulating genes was notably increased in WAY-362450-treated mouse liver. Activation of FXR-induced Ccnd1 expression in hepatocyte in a time-dependent manner in vivo and in vitro. Through bioinformatics analysis and ChIP assay, we identified FXR as a direct transcriptional activator of Ccnd1 through binding to a potential enhancer, which was specifically active in livers. We also found active histone acetylation was essential for Ccnd1 induction by FXR. Thus, our study indicated that activation of FXR-induced harmless liver hypertrophy with spatiotemporal modulation of Ccnd1. With a better understanding of the mechanism of tissue-specific gene regulation by FXR, it is beneficial for development and appropriate application of its specific agonist in preventing hepatic diseases.
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Affiliation(s)
- Weibin Wu
- a The International Peace Maternity and Child Health Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai , China.,b Shanghai Key Laboratory of Embryo Original Diseases , Shanghai , China.,c Shanghai Municipal Key Clinical Specialty , Shanghai , China
| | - Qing Wu
- d Department of Gynecology and Obstetrics , Central Hospital of Minhang District , Shanghai , China
| | - Xinmei Liu
- a The International Peace Maternity and Child Health Hospital, School of Medicine , Shanghai Jiao Tong University , Shanghai , China.,b Shanghai Key Laboratory of Embryo Original Diseases , Shanghai , China.,c Shanghai Municipal Key Clinical Specialty , Shanghai , China
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18
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The Biosynthesis, Signaling, and Neurological Functions of Bile Acids. Biomolecules 2019; 9:biom9060232. [PMID: 31208099 PMCID: PMC6628048 DOI: 10.3390/biom9060232] [Citation(s) in RCA: 120] [Impact Index Per Article: 20.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/13/2019] [Accepted: 06/14/2019] [Indexed: 12/13/2022] Open
Abstract
Bile acids (BA) are amphipathic steroid acids synthesized from cholesterol in the liver. They act as detergents to expedite the digestion and absorption of dietary lipids and lipophilic vitamins. BA are also considered to be signaling molecules, being ligands of nuclear and cell-surface receptors, including farnesoid X receptor and Takeda G-protein receptor 5. Moreover, BA also activate ion channels, including the bile acid-sensitive ion channel and epithelial Na+ channel. BA regulate glucose and lipid metabolism by activating these receptors in peripheral tissues, such as the liver and brown and white adipose tissue. Recently, 20 different BA have been identified in the central nervous system. Furthermore, BA affect the function of neurotransmitter receptors, such as the muscarinic acetylcholine receptor and γ-aminobutyric acid receptor. BA are also known to be protective against neurodegeneration. Here, we review recent findings regarding the biosynthesis, signaling, and neurological functions of BA.
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19
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Ticho AL, Malhotra P, Dudeja PK, Gill RK, Alrefai WA. Bile Acid Receptors and Gastrointestinal Functions. LIVER RESEARCH 2019; 3:31-39. [PMID: 32368358 PMCID: PMC7197881 DOI: 10.1016/j.livres.2019.01.001] [Citation(s) in RCA: 84] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Bile acids modulate several gastrointestinal functions including electrolyte secretion and absorption, gastric emptying, and small intestinal and colonic motility. High concentrations of bile acids lead to diarrhea and are implicated in the development of esophageal, gastric and colonic cancer. Alterations in bile acid homeostasis are also implicated in the pathophysiology of irritable bowel syndrome (IBS) and inflammatory bowel disease (IBD). Our understanding of the mechanisms underlying these effects of bile acids on gut functions has been greatly enhanced by the discovery of bile acid receptors, including the nuclear receptors: farnesoid X receptor (FXR), vitamin D receptor (VDR), pregnane X receptor (PXR), and constitutive androstane receptor (CAR); and the G protein-coupled receptors: Takeda G protein-coupled receptor (TGR5), sphingosine-1-phosphate receptor 2 (S1PR2), and muscarinic acetylcholine receptor M3 (M3R).. For example, various studies provided evidence demonstrating the anti-inflammatory effects FXR and TGR5 activation in models of intestinal inflammation. In addition, TGR5 activation in enteric neurons was recently shown to increase colonic motility, which may lead to bile acid-induced diarrhea. Interestingly, TGR5 induces the secretion of glucagon-like peptide-1 (GLP-1) from L-cells to enhance insulin secretion and modulate glucose metabolism. Because of the importance of these receptors, agonists of TGR5 and intestine-specific FXR agonists are currently being tested as an option for the treatment of diabetes mellitus and primary bile acid diarrhea, respectively. This review summarizes current knowledge of the functional roles of bile acid receptors in the gastrointestinal tract.
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Affiliation(s)
- Alexander L. Ticho
- Department of Physiology and Biophysics, College of Medicine, University of Illinois at Chicago
| | - Pooja Malhotra
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago
| | - Pradeep K. Dudeja
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago,Jesse Brown VA Medical Center, Chicago, IL
| | - Ravinder K. Gill
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago
| | - Waddah A. Alrefai
- Division of Gastroenterology & Hepatology, Department of Medicine, College of Medicine, University of Illinois at Chicago,Jesse Brown VA Medical Center, Chicago, IL,To whom correspondence should be addressed: Waddah A. Alrefai, MD: Research Career Scientist, Jesse Brown VA Medical Center, Professor of Medicine, Department of Medicine, University of Illinois at Chicago, Chicago, IL 60612; ; Tel. (312) 569-7429; Fax. (312) 569-8114
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20
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Aibara D, Matsusue K, Takiguchi S, Gonzalez FJ, Yamano S. Fat-specific protein 27 is a novel target gene of liver X receptor α. Mol Cell Endocrinol 2018; 474:48-56. [PMID: 29454584 PMCID: PMC6594021 DOI: 10.1016/j.mce.2018.02.006] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/17/2017] [Revised: 01/16/2018] [Accepted: 02/12/2018] [Indexed: 12/12/2022]
Abstract
Fat-specific protein 27 (FSP27) is highly expressed in the fatty liver of genetically obese ob/ob mice and promotes hepatic triglyceride (TG) accumulation. The nuclear hormone receptor liver X receptor α (LXRα) also plays a critical role in the control of TG levels in the liver. The present study demonstrated transcriptional regulation of Fsp27a and Fsp27b genes by LXRα. Treatment with the LXR ligand T0901317 markedly increased Fsp27a and Fsp27b mRNAs in wild-type C57BL/6J and ob/ob mouse livers. A reporter assay indicated that two LXR-responsive elements (LXREs) are necessary for LXRα-dependent induction of Fsp27a and Fsp27b promoter activities. Furthermore, the LXRα/retinoid X receptor α complex is capable of directly binding to the two LXREs both in vitro and in vivo. These results suggest that LXRα positively regulates Fsp27a and Fsp27b expression through two functional LXREs. Fsp27a/b are novel LXR target genes in the ob/ob fatty liver.
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Affiliation(s)
- Daisuke Aibara
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
| | - Kimihiko Matsusue
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Soichi Takiguchi
- Institute for Clinical Research, National Kyushu Cancer Center, 3-1-1 Notame, Minami-ku, Fukuoka 811-1395, Japan
| | - Frank J Gonzalez
- Laboratory of Metabolism, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA
| | - Shigeru Yamano
- Faculty of Pharmaceutical Science, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan
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21
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Beyond the Foam Cell: The Role of LXRs in Preventing Atherogenesis. Int J Mol Sci 2018; 19:ijms19082307. [PMID: 30087224 PMCID: PMC6121590 DOI: 10.3390/ijms19082307] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Revised: 08/01/2018] [Accepted: 08/02/2018] [Indexed: 12/24/2022] Open
Abstract
Atherosclerosis is a chronic condition associated with cardiovascular disease. While largely identified by the accumulation of lipid-laden foam cells within the aorta later on in life, atherosclerosis develops over several stages and decades. During atherogenesis, various cell types of the aorta acquire a pro-inflammatory phenotype that initiates the cascade of signaling events facilitating the formation of these foam cells. The liver X receptors (LXRs) are nuclear receptors that upon activation induce the expression of transporters responsible for promoting cholesterol efflux. In addition to promoting cholesterol removal from the arterial wall, LXRs have potent anti-inflammatory actions via the transcriptional repression of key pro-inflammatory cytokines. These beneficial functions sparked an interest in the potential to target LXRs and the development of agonists as anti-atherogenic agents. These early studies focused on mediating the contributions of macrophages to the underlying pathogenesis. However, further evidence has since demonstrated that LXRs reduce atherosclerosis through their actions in multiple cell types apart from those monocytes/macrophages that infiltrate the lesion. LXRs and their target genes have profound effects on multiple other cells types of the hematopoietic system. Furthermore, LXRs can also mediate dysfunction within vascular cell types of the aorta including endothelial and smooth muscle cells. Taken together, these studies demonstrate the whole-body benefits of LXR activation with respect to anti-atherogenesis, and that LXRs remain a viable target for the treatment of atherosclerosis, with a reach which extends beyond plaque macrophages.
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22
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Abstract
Liver X receptors α and β (LXRα and LXRβ) are nuclear receptors with pivotal roles in the transcriptional control of lipid metabolism. Transcriptional activity of LXRs is induced in response to elevated cellular levels of cholesterol. LXRs bind to and regulate the expression of genes that encode proteins involved in cholesterol absorption, transport, efflux, excretion and conversion to bile acids. The coordinated, tissue-specific actions of the LXR pathway maintain systemic cholesterol homeostasis and regulate immune and inflammatory responses. LXRs also regulate fatty acid metabolism by controlling the lipogenic transcription factor sterol regulatory element-binding protein 1c and regulate genes that encode proteins involved in fatty acid elongation and desaturation. LXRs exert important effects on the metabolism of phospholipids, which, along with cholesterol, are major constituents of cellular membranes. LXR activation preferentially drives the incorporation of polyunsaturated fatty acids into phospholipids by inducing transcription of the remodelling enzyme lysophosphatidylcholine acyltransferase 3. The ability of the LXR pathway to couple cellular sterol levels with the saturation of fatty acids in membrane phospholipids has implications for several physiological processes, including lipoprotein production, dietary lipid absorption and intestinal stem cell proliferation. Understanding how LXRs regulate membrane composition and function might provide new therapeutic insight into diseases associated with dysregulated lipid metabolism, including atherosclerosis, diabetes mellitus and cancer.
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Affiliation(s)
- Bo Wang
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
| | - Peter Tontonoz
- Department of Pathology and Laboratory Medicine, Molecular Biology Institute, David Geffen School of Medicine, University of California, Los Angeles, CA, USA.
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23
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Shapiro H, Kolodziejczyk AA, Halstuch D, Elinav E. Bile acids in glucose metabolism in health and disease. J Exp Med 2018; 215:383-396. [PMID: 29339445 PMCID: PMC5789421 DOI: 10.1084/jem.20171965] [Citation(s) in RCA: 308] [Impact Index Per Article: 44.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 12/11/2017] [Accepted: 12/19/2017] [Indexed: 12/11/2022] Open
Abstract
Bile acids (BAs) are cholesterol-derived metabolites that facilitate the intestinal absorption and transport of dietary lipids. Recently, BAs also emerged as pivotal signaling molecules controlling glucose, lipid, and energy metabolism by binding to the nuclear hormone farnesoid X receptor (FXR) and Takeda G protein receptor 5 (TGR5) in multiple organs, leading to regulation of intestinal incretin secretion, hepatic gluconeogenesis, glycogen synthesis, energy expenditure, inflammation, and gut microbiome configuration. Alterations in BA metabolism and signaling are associated with obesity and type 2 diabetes mellitus (T2DM), whereas treatment of T2DM patients with BA sequestrants, or bariatric surgery in morbidly obese patients, results in a significant improvement in glycemic response that is associated with changes in the BA profile and signaling. Herein, we review the roles of BAs in glucose metabolism in health and disease; highlight the limitations, unknowns, and challenges in understanding the impact of BAs on the glycemic response; and discuss how this knowledge may be harnessed to develop innovative therapeutic approaches for the treatment of hyperglycemia and diabetes.
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Affiliation(s)
- Hagit Shapiro
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | | | - Daniel Halstuch
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
| | - Eran Elinav
- Department of Immunology, Weizmann Institute of Science, Rehovot, Israel
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24
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Shi JF, Li YK, Ren K, Xie YJ, Yin WD, Mo ZC. Characterization of cholesterol metabolism in Sertoli cells and spermatogenesis (Review). Mol Med Rep 2018; 17:705-713. [PMID: 29115523 PMCID: PMC5780145 DOI: 10.3892/mmr.2017.8000] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2017] [Accepted: 08/31/2017] [Indexed: 01/21/2023] Open
Abstract
The Sertoli cell, which is the supporting cell of spermatogenesis, has an important role in the endocrine and paracrine control of spermatogenesis. Functionally, it provides the cells of the seminiferous epithelium with nutrition, conveys mature spermatids to the lumen of seminiferous tubules, secretes androgen‑binding protein and interacts with endocrine Leydig cells. In addition, the levels of cholesterol, as well as its intermediates, vary greatly between nongonadal tissues and the male reproductive system. Throughout spermatogenesis, a dynamic and constant alteration in the membrane lipid composition of Sertoli cells occurs. In several mammalian species, testis meiosis‑activating sterol and desmosterol, as well as other cholesterol precursors, accumulate in the testes and spermatozoa. In addition, certain cholesterogenic genes exhibit stage‑specific expression patterns during spermatogenesis, including the cytochrome P450 enzyme lanosterol 14α‑demethylase. Inconsistency in the patterns of gene expression during spermatogenesis indicates a cell‑type specific and complex temporary modulation of lipids and cholesterol, which also implicates the dynamic interactions between Sertoli cells and germ cells. Furthermore, in the female reproductive tract and during epididymal transit, which is a prerequisite for valid fertilization, the modulation of cholesterol occurring in spermatozoal membranes further indicates the functional importance of sterol compounds in spermatogenesis. However, the exact role of cholesterol metabolism in Sertoli cells in sperm production is unknown. The present review article describes the progress made in the research regarding the characteristics of the Sertoli cell, particularly the regulation of its cholesterol metabolism during spermatogenesis.
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Affiliation(s)
- Jin-Feng Shi
- Institute of Cardiovascular Disease, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
- Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, Hunan 421001, P.R. China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan 421001, P.R. China
| | - Yu-Kun Li
- Department of Histology and Embryology, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Kun Ren
- Institute of Cardiovascular Disease, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
- Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, Hunan 421001, P.R. China
| | - Yuan-Jie Xie
- Department of Histology and Embryology, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
| | - Wei-Dong Yin
- Institute of Cardiovascular Disease, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
- Key Laboratory for Arteriosclerology of Hunan Province, Hengyang, Hunan 421001, P.R. China
- Hunan Province Cooperative Innovation Center for Molecular Target New Drug Study, Hengyang, Hunan 421001, P.R. China
| | - Zhong-Cheng Mo
- Department of Histology and Embryology, Medical School, University of South China, Hengyang, Hunan 421001, P.R. China
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25
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Xiao H, Li P, Li X, He H, Wang J, Guo F, Zhang J, Wei L, Zhang H, Shi Y, Hou L, Shen L, Chen Z, Du C, Fu S, Zhang P, Hao F, Wang P, Xu D, Liang W, Tian X, Zhang A, Cheng X, Yang L, Wang X, Zhang X, Li J, Chen S. Synthesis and Biological Evaluation of a Series of Bile Acid Derivatives as FXR Agonists for Treatment of NASH. ACS Med Chem Lett 2017; 8:1246-1251. [PMID: 29259742 DOI: 10.1021/acsmedchemlett.7b00318] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2017] [Accepted: 10/31/2017] [Indexed: 11/30/2022] Open
Abstract
Farnesoid X receptor (FXR) has become a particularly attractive target for the discovery of drugs for the treatment of liver and metabolic diseases. Obeticholic acid (INT-747), a FXR agonist, has advanced into clinical phase III trials in patients with nonalcoholic steatohepatitis (NASH), but adverse effects (e.g., pruritus, LDL increase) were observed. Pruritus might be induced by Takeda G-protein-coupled receptor 5 (TGR5, GPBAR1), and there are chances to develop FXR agonists with higher selectivity over TGR5. In this letter, novel bile acids bearing different modifications on ring A and side chain of INT-747 are reported and discussed. Our results indicated that the side chain of INT-747 is amenable to a variety of chemical modifications with good FXR potency in vitro. Especially, compound 18 not only showed promising FXR potency and excellent pharmacokinetic properties, but also proved superior pharmacological efficacy in the HFD + CCl4 model.
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Affiliation(s)
- Hualing Xiao
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Peng Li
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Xiaolin Li
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Haiying He
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Jianhua Wang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Fengxun Guo
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Jiliang Zhang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Luxia Wei
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Hongmei Zhang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Yueyuan Shi
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Lijuan Hou
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Liang Shen
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Zhengxia Chen
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Chunyan Du
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Shouliang Fu
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Pengtao Zhang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Fei Hao
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Ping Wang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Deming Xu
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Wei Liang
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Xin Tian
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Aiming Zhang
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Xingdong Cheng
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Ling Yang
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Xiangjian Wang
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Xiquan Zhang
- Chia Tai Tianqing Pharmaceutical Group Co. Ltd., Building 9,
No. 699-8, Xuanwu Road, Nanjing, Jiangsu 210023, P. R. China
| | - Jian Li
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
| | - Shuhui Chen
- WuXi AppTec (Shanghai) Co., Ltd., 288 FuTe Zhong
Road, Shanghai 200131, P. R. China
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26
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Yang M, Li J, Wu J, Wang H, Guo B, Wu C, Shou X, Yang N, Zhang Z, McManus DP, Zhang F, Zhang W. Cloning and characterization of an Echinococcus granulosus ecdysteroid hormone nuclear receptor HR3-like gene. ACTA ACUST UNITED AC 2017; 24:36. [PMID: 28971798 PMCID: PMC5625357 DOI: 10.1051/parasite/2017037] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2017] [Accepted: 09/04/2017] [Indexed: 12/13/2022]
Abstract
Cystic echinococcosis is an important parasitic zoonosis caused by the dog tapeworm Echinococcus granulosus. Little is known about adult worm development at the molecular level. Transcription analysis showed that the E. granulosus hormone receptor 3-like (EgHR3) gene was expressed in protoscoleces and adult worms, indicating its role in early adult development. In this study, we cloned and characterized EgHR3 showing that its cDNA contains an open reading frame (ORF) of 1890 bp encoding a 629 amino acid protein, which has a DNA-binding domain (DBD) and a ligand-binding domain (LBD). Immunolocalization revealed the protein was localized in the parenchyma of protoscoleces and adult worms. Real-time PCR analysis showed that EgHR3 was expressed significantly more in adults than in other stages of development (p<0.01) and that its expression was especially high in the early stage of adult worm development induced by bile acids. EgHR3 siRNA silenced 69–78% of the level of transcription in protoscoleces, which resulted in killing 43.6–60.9% of protoscoleces after 10 days of cultivation in vitro. EgHR3 may play an essential role in early adult worm development and in maintaining adult biological processes and may represent a novel drug or vaccine target against echinococcosis.
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Affiliation(s)
- Mei Yang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, 14 Shengli Road, Urumqi 830046, PR China - Basic Medical College of Xinjiang Medical University, Urumqi 830011, PR China
| | - Jun Li
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Jun Wu
- Public Health College of Xinjiang Medical University, Urumqi 830011, PR China
| | - Hui Wang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Baoping Guo
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Chuanchuan Wu
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Xi Shou
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Ning Yang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
| | - Zhuangzhi Zhang
- Molecular Parasitology Laboratory, QIMR Berghofer, Herston, QLD, 4006, Australia
| | - Donald P McManus
- Veterinary Research Institute, Xinjiang Academy of Animal Sciences, Urumqi 830000, PR China
| | - Fuchun Zhang
- Xinjiang Key Laboratory of Biological Resources and Genetic Engineering, College of Life Science and Technology, Xinjiang University, 14 Shengli Road, Urumqi 830046, PR China
| | - Wenbao Zhang
- State Key Laboratory of Pathogenesis, Prevention and Treatment of Central Asian High Incidence Diseases, The First Affiliated Hospital of Xinjiang Medical University, Urumqi 830011, PR China
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27
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Zheng T, Kang JH, Sim JS, Kim JW, Koh JT, Shin CS, Lim H, Yim M. The farnesoid X receptor negatively regulates osteoclastogenesis in bone remodeling and pathological bone loss. Oncotarget 2017; 8:76558-76573. [PMID: 29100332 PMCID: PMC5652726 DOI: 10.18632/oncotarget.20576] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2017] [Accepted: 08/09/2017] [Indexed: 11/25/2022] Open
Abstract
Farnesoid X receptor (FXR, NR1H4) is a member of the nuclear receptor superfamily of ligand-activated transcription factors. Since the role of FXR in osteoclast differentiation remains ill-defined, we investigated the biological function of FXR on osteoclastogenesis, using FXR-deficient mice. We demonstrated that FXR deficiency increases osteoclast formation in vitro and in vivo. First, FXR deficiency was found to accelerate osteoclast formation via down-regulation of c-Jun N-terminal kinase (JNK) 1/2 expression. Increased expression of peroxisome proliferator-activated receptor (PPAR)γ and peroxisome proliferator-activated receptor gamma coactivator 1 (PGC-1)β seems to mediate the pro-osteoclastogenic effect of FXR deficiency via the JNK pathway. In addition, we found that FXR deficiency downregulated the expression of interferon-β (IFN-β), a strong inhibitor of osteoclastogenesis, via receptor activator of nuclear factor-kappaB ligand (RANKL). We further suggested that interference of IFN-β expression by FXR deficiency impaired the downstream JAK3-STAT1 signaling pathways, which in turn increased osteoclast formation. Finally, FXR deficiency accelerated unloading- or ovariectomy-induced bone loss in vivo. Thus, our findings demonstrate that FXR is a negative modulator in osteoclast differentiation and identify FXR as a potential therapeutic target for postmenopausal osteoporosis and unloading-induced bone loss.
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Affiliation(s)
- Ting Zheng
- College of Pharmacy, Sookmyung Women's University, Yongsan-ku, Seoul, Republic of Korea
| | - Ju-Hee Kang
- College of Pharmacy, Sookmyung Women's University, Yongsan-ku, Seoul, Republic of Korea
| | - Jung-Sun Sim
- College of Pharmacy, Sookmyung Women's University, Yongsan-ku, Seoul, Republic of Korea
| | - Jung-Woo Kim
- Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Jeong-Tae Koh
- Department of Pharmacology and Dental Therapeutics, Research Center for Biomineralization Disorders, School of Dentistry, Chonnam National University, Gwangju, Republic of Korea
| | - Chan Soo Shin
- Department of Internal Medicine, College of Medicine, Seoul National University, Seoul, Republic of Korea
| | - Hyungsik Lim
- Departments of Physics, Hunter College of the City University of New York, New York City, New York, USA
| | - Mijung Yim
- College of Pharmacy, Sookmyung Women's University, Yongsan-ku, Seoul, Republic of Korea
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28
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Di Leva FS, Festa C, Renga B, Sepe V, Novellino E, Fiorucci S, Zampella A, Limongelli V. Structure-based drug design targeting the cell membrane receptor GPBAR1: exploiting the bile acid scaffold towards selective agonism. Sci Rep 2015; 5:16605. [PMID: 26567894 PMCID: PMC4645117 DOI: 10.1038/srep16605] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2015] [Accepted: 10/16/2015] [Indexed: 12/21/2022] Open
Abstract
Bile acids can regulate nutrient metabolism through the activation of the cell membrane receptor GPBAR1 and the nuclear receptor FXR. Developing an exogenous control over these receptors represents an attractive strategy for the treatment of enterohepatic and metabolic disorders. A number of dual GPBAR1/FXR agonists are known, however their therapeutic use is limited by multiple unwanted effects due to activation of the diverse downstream signals controlled by the two receptors. On the other hand, designing selective GPBAR1 and FXR agonists is challenging since the two proteins share similar structural requisites for ligand binding. Here, taking advantage of our knowledge of the two targets, we have identified through a rational drug design study a series of amine lithocholic acid derivatives as selective GPBAR1 agonists. The presence of the 3α-NH2 group on the steroidal scaffold is responsible for the selectivity over FXR unveiling unprecedented structural insights into bile acid receptors activity modulation.
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Affiliation(s)
- Francesco Saverio Di Leva
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Carmen Festa
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Barbara Renga
- Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Valentina Sepe
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Ettore Novellino
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Stefano Fiorucci
- Department of Surgery and Biomedical Sciences, Nuova Facoltà di Medicina, P.zza L. Severi, I-06132 Perugia, Italy
| | - Angela Zampella
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy
| | - Vittorio Limongelli
- Department of Pharmacy, University of Naples "Federico II", Via D. Montesano 49, I-80131 Naples, Italy.,Università della Svizzera Italiana (USI), Faculty of Informatics, Institute of Computational Science, via G. Buffi 13, CH-6900 Lugano, Switzerland
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29
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NSAIDs Ibuprofen, Indometacin, and Diclofenac do not interact with Farnesoid X Receptor. Sci Rep 2015; 5:14782. [PMID: 26424593 PMCID: PMC4589779 DOI: 10.1038/srep14782] [Citation(s) in RCA: 43] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/23/2015] [Accepted: 09/10/2015] [Indexed: 02/01/2023] Open
Abstract
The nuclear farnesoid X receptor (FXR) is a ligand activated transcription factor and acts as cellular sensor for bile acids. In this role, FXR is a highly important liver protector and FXR inhibition by antagonists or knockout has shown several deleterious effects. A recent report characterized non-steroidal anti-rheumatic drugs (NSAIDs) such as ibuprofen or diclofenac as FXR antagonists and linked hepatotoxic effects of these drugs with antagonistic activity on FXR. Since this would guide a way to develop safer anti-inflammatory agents by sparing FXR, we intended to further characterize the reported antagonistic activity and intensively investigated ibuprofen, indometacin and diclofenac. However, we conclude that these agents do not interact with FXR and that the reported reduced FXR signaling induced by CDCA in presence of NSAIDs is merely a consequence than a cause of hepatotoxicity.
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30
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Xu X, Xu X, Liu P, Zhu ZY, Chen J, Fu HA, Chen LL, Hu LH, Shen X. Structural Basis for Small Molecule NDB (N-Benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) Benzamide) as a Selective Antagonist of Farnesoid X Receptor α (FXRα) in Stabilizing the Homodimerization of the Receptor. J Biol Chem 2015; 290:19888-99. [PMID: 26100621 DOI: 10.1074/jbc.m114.630475] [Citation(s) in RCA: 44] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/17/2014] [Indexed: 01/27/2023] Open
Abstract
Farnesoid X receptor α (FXRα) as a bile acid sensor plays potent roles in multiple metabolic processes, and its antagonist has recently revealed special interests in the treatment of metabolic disorders, although the underlying mechanisms still remain unclear. Here, we identified that the small molecule N-benzyl-N-(3-(tert-butyl)-4-hydroxyphenyl)-2,6-dichloro-4-(dimethylamino) benzamide (NDB) functioned as a selective antagonist of human FXRα (hFXRα), and the crystal structure of hFXRα ligand binding domain (hFXRα-LBD) in complex with NDB was analyzed. It was unexpectedly discovered that NDB induced rearrangements of helix 11 (H11) and helix 12 (H12, AF-2) by forming a homodimer of hFXRα-LBD, totally different from the active conformation in monomer state, and the binding details were further supported by the mutation analysis. Moreover, functional studies demonstrated that NDB effectively antagonized the GW4064-stimulated FXR/RXR interaction and FXRα target gene expression in primary mouse hepatocytes, including the small heterodimer partner (SHP) and bile-salt export pump (BSEP); meanwhile, administration of NDB to db/db mice efficiently decreased the gene expressions of phosphoenolpyruvate carboxykinase (PEPCK), glucose 6-phosphatase (G6-pase), small heterodimer partner, and BSEP. It is expected that our first analyzed crystal structure of hFXRα-LBD·NDB will help expound the antagonistic mechanism of the receptor, and NDB may find its potential as a lead compound in anti-diabetes research.
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Affiliation(s)
- Xing Xu
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China, Shanghai Key Laboratory for Bone and Joint Diseases, Shanghai Institute of Traumatology and Orthopaedics, Shanghai Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai 200025, China
| | - Xin Xu
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Peng Liu
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Zhi-yuan Zhu
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Jing Chen
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China
| | - Hai-an Fu
- Department of Pharmacology, Emory University School of Medicine, Atlanta, Georgia 30322
| | - Li-li Chen
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China,
| | - Li-hong Hu
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China,
| | - Xu Shen
- From the CAS Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zuchongzhi Road, Shanghai 201203, China,
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31
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Tan Y, Bi W, Zhang GX. Role and molecular mechanism of farnesoid X receptor in obstructive jaundice. Shijie Huaren Xiaohua Zazhi 2015; 23:2574-2581. [DOI: 10.11569/wcjd.v23.i16.2574] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Obstructive jaundice is a common and frequently occurring disease, which can result in multiple organ dysfunction syndrome in serious conditions due to the abnormal accumulation of bile acids in blood. Farnesoid X receptor (FXR), a nuclear receptor for bile acid, plays a significant role in bile acid metabolism. Recent research demonstrates that FXR also participates in the regulation of the pathological and physiological processes during obstructive jaundice. In this article, we review the latest research about the role and molecular mechanism of FXR in obstructive jaundice, in order to explore new methods and strategies for curing the disease.
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32
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Mazuy C, Helleboid A, Staels B, Lefebvre P. Nuclear bile acid signaling through the farnesoid X receptor. Cell Mol Life Sci 2015; 72:1631-50. [PMID: 25511198 PMCID: PMC11113650 DOI: 10.1007/s00018-014-1805-y] [Citation(s) in RCA: 85] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2014] [Revised: 12/04/2014] [Accepted: 12/08/2014] [Indexed: 12/16/2022]
Abstract
Bile acids (BAs) are amphipathic molecules produced from cholesterol by the liver. Expelled from the gallbladder upon meal ingestion, BAs serve as fat solubilizers in the intestine. BAs are reabsorbed in the ileum and return via the portal vein to the liver where, together with nutrients, they provide signals to coordinate metabolic responses. BAs act on energy and metabolic homeostasis through the activation of membrane and nuclear receptors, among which the nuclear receptor farnesoid X receptor (FXR) is an important regulator of several metabolic pathways. Highly expressed in the liver and the small intestine, FXR contributes to BA effects on metabolism, inflammation and cell cycle control. The pharmacological modulation of its activity has emerged as a potential therapeutic strategy for liver and metabolic diseases. This review highlights recent advances regarding the mechanisms by which the BA sensor FXR contributes to global signaling effects of BAs, and how FXR activity may be regulated by nutrient-sensitive signaling pathways.
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Affiliation(s)
- Claire Mazuy
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Audrey Helleboid
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Bart Staels
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
| | - Philippe Lefebvre
- European Genomic Institute for Diabetes (EGID), 59000 Lille, France
- INSERM UMR1011-Bâtiment J&K, 59000 Lille, France
- University Lille 2, 59000 Lille, France
- Institut Pasteur de Lille, 59019 Lille, France
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33
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Abstract
Members of the nuclear receptor superfamily of ligand-dependent transcription factors carry out vital cellular functions and are highly druggable therapeutic targets. Liver X receptors (LXRs) are nuclear receptor family members that function in cholesterol transport, glucose metabolism and the modulation of inflammatory responses. There is now accumulating evidence to support the involvement of LXRs in a variety of malignancies and the potential efficacy of their ligands in these diseases. This Review summarizes the discovery and characterization of LXRs and their ligands, their effects and mechanisms in preclinical cancer models, and the future directions of basic and translational LXR research in cancer therapeutics.
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Affiliation(s)
- Chin-Yo Lin
- Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5056, USA
| | - Jan-Åke Gustafsson
- 1] Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, Texas 77204-5056, USA. [2] Department of Biosciences and Nutrition at NOVUM, Karolinska Institutet, Huddinge SE-141 83, Sweden
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Huang F, Wang T, Lan Y, Yang L, Pan W, Zhu Y, Lv B, Wei Y, Shi H, Wu H, Zhang B, Wang J, Duan X, Hu Z, Wu X. Deletion of mouse FXR gene disturbs multiple neurotransmitter systems and alters neurobehavior. Front Behav Neurosci 2015; 9:70. [PMID: 25870546 PMCID: PMC4378301 DOI: 10.3389/fnbeh.2015.00070] [Citation(s) in RCA: 71] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2014] [Accepted: 03/03/2015] [Indexed: 12/14/2022] Open
Abstract
Farnesoid X receptor (FXR) is a nuclear hormone receptor involved in bile acid synthesis and homeostasis. Dysfunction of FXR is involved in cholestasis and atherosclerosis. FXR is prevalent in liver, gallbladder, and intestine, but it is not yet clear whether it modulates neurobehavior. In the current study, we tested the hypothesis that mouse FXR deficiency affects a specific subset of neurotransmitters and results in an unique behavioral phenotype. The FXR knockout mice showed less depressive-like and anxiety-related behavior, but increased motor activity. They had impaired memory and reduced motor coordination. There were changes of glutamatergic, GABAergic, serotoninergic, and norepinephrinergic neurotransmission in either hippocampus or cerebellum. FXR deletion decreased the amount of the GABA synthesis enzyme GAD65 in hippocampus but increased GABA transporter GAT1 in cerebral cortex. FXR deletion increased serum concentrations of many bile acids, including taurodehydrocholic acid, taurocholic acid, deoxycholic acid (DCA), glycocholic acid (GCA), tauro-α-muricholic acid, tauro-ω-muricholic acid, and hyodeoxycholic acid (HDCA). There were also changes in brain concentrations of taurocholic acid, taurodehydrocholic acid, tauro-ω-muricholic acid, tauro-β-muricholic acid, deoxycholic acid, and lithocholic acid (LCA). Taken together, the results from studies with FXR knockout mice suggest that FXR contributes to the homeostasis of multiple neurotransmitter systems in different brain regions and modulates neurobehavior. The effect appears to be at least partially mediated by bile acids that are known to cross the blood-brain barrier (BBB) inducing potential neurotoxicity.
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Affiliation(s)
- Fei Huang
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Tingting Wang
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Yunyi Lan
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Li Yang
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Weihong Pan
- Blood-Brain Barrier Group, Pennington Biomedical Research Center Baton Rouge, LA, USA
| | - Yonghui Zhu
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Boyang Lv
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Yuting Wei
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Hailian Shi
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Hui Wu
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Beibei Zhang
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Jie Wang
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Xiaofeng Duan
- Pharmacy Department, Shanghai East Hospital Shanghai, China
| | - Zhibi Hu
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
| | - Xiaojun Wu
- The Ministry of Education Key Laboratory for Standardization of Chinese Medicines, the State Administration of TCM Key Laboratory for New Resources and Quality Evaluation of Chinese Medicine, Shanghai Key Laboratory of Complex Prescriptions, Institute of Chinese Materia Medica, Shanghai University of Traditional Chinese Medicine Shanghai, China
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Manley S, Ding W. Role of farnesoid X receptor and bile acids in alcoholic liver disease. Acta Pharm Sin B 2015; 5:158-67. [PMID: 26579442 PMCID: PMC4629219 DOI: 10.1016/j.apsb.2014.12.011] [Citation(s) in RCA: 81] [Impact Index Per Article: 8.1] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2014] [Revised: 12/20/2014] [Accepted: 12/29/2014] [Indexed: 02/07/2023] Open
Abstract
Alcoholic liver disease (ALD) is one of the major causes of liver morbidity and mortality worldwide. Chronic alcohol consumption leads to development of liver pathogenesis encompassing steatosis, inflammation, fibrosis, cirrhosis, and in extreme cases, hepatocellular carcinoma. Moreover, ALD may also associate with cholestasis. Emerging evidence now suggests that farnesoid X receptor (FXR) and bile acids also play important roles in ALD. In this review, we discuss the effects of alcohol consumption on FXR, bile acids and gut microbiome as well as their impacts on ALD. Moreover, we summarize the findings on FXR, FoxO3a (forkhead box-containing protein class O3a) and PPARα (peroxisome proliferator-activated receptor alpha) in regulation of autophagy-related gene transcription program and liver injury in response to alcohol exposure.
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Key Words
- 6ECDCA, 6α-ethyl-chenodeoxycholic acid
- ADH, alcohol dehydrogenase
- AF, activation function
- AKT, protein kinase B
- ALD, alcoholic liver disease
- ALT, alanine aminotransferase
- ASBT, apical sodium dependent bile acid transporter
- Alcoholic liver disease
- Atg, autophagy-related
- Autophagy
- BAAT, bile acid CoA:amino acid N-acyltransferase
- BACS, bile acid CoA synthetase
- BSEP, bile salt export pump
- Bile acids
- CA, cholic acid
- CB1R, cannabinoid receptor type 1
- CDCA, chenodeoxycholic acid
- CREB, cAMP response element-binding protein
- CREBH, cAMP response element-binding protein, hepatocyte specific
- CRTC2, CREB regulated transcription coactivator 2
- CYP, cytochrome P450
- DCA, deoxycholic acid
- DR1, direct repeat 1
- FGF15/19, fibroblast growth factor 15/19
- FGFR4, fibroblast growth factor receptor 4
- FXR, farnesoid X receptor
- Farnesoid X receptor
- FoxO3
- FoxO3a, forkhead box-containing protein class O3a
- GGT, gamma-glutamyltranspeptidase
- HCC, hepatocellular carcinoma
- IR-1, inverted repeat-1
- KO, knockout
- LC3, light chain 3
- LRH-1, liver receptor homolog 1
- LXR, liver X receptor
- MRP4, multidrug resistance protein 4
- NAD+, nicotinamide adenine dinucleotide
- NTCP, sodium taurocholate cotransporting polypeptide
- OSTα/β, organic solute transporter α/β
- PE, phosphatidylethanolamine
- PPARα, peroxisome proliferator-activated receptor alpha
- ROS, reactive oxygen species
- RXRα, retinoid X receptor-alpha
- SHP, small heterodimer partner
- SQSTM, sequestome-1
- SREBP1, sterol regulatory element-binding protein 1
- Sirt1, sirtuin 1
- TCA, taurocholic acid
- TFEB, transcription factor EB
- TLR4, toll-like receptor 4
- TUDCA, tauro-ursodeoxycholic acid
- UDCA, ursodeoxycholic acid
- WAY, WAY-362450
- WT, wild type
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Affiliation(s)
| | - Wenxing Ding
- Corresponding author. Tel.: +1 913 5889813; fax: +1 913 5887501.
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Li G, L. Guo G. Farnesoid X receptor, the bile acid sensing nuclear receptor, in liver regeneration. Acta Pharm Sin B 2015; 5:93-8. [PMID: 26579433 PMCID: PMC4629218 DOI: 10.1016/j.apsb.2015.01.005] [Citation(s) in RCA: 58] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/02/2014] [Revised: 01/02/2015] [Accepted: 01/05/2015] [Indexed: 01/19/2023] Open
Abstract
The liver is unique in regenerative potential, which could recover the lost mass and function after injury from ischemia and resection. The underlying molecular mechanisms of liver regeneration have been extensively studied in the past using the partial hepatectomy (PH) model in rodents, where 2/3 PH is carried out by removing two lobes. The whole process of liver regeneration is complicated, orchestrated event involving a network of connected interactions, which still remain fully elusive. Bile acids (BAs) are ligands of farnesoid X receptor (FXR), a nuclear receptor of ligand-activated transcription factor. FXR has been shown to be highly involved in liver regeneration. BAs and FXR not only interact with each other but also regulate various downstream targets independently during liver regeneration. Moreover, recent findings suggest that tissue-specific FXR also contributes to liver regeneration significantly. These novel findings suggest that FXR has much broader role than regulating BA, cholesterol, lipid and glucose metabolism. Therefore, these researches highlight FXR as an important pharmaceutical target for potential use of FXR ligands to regulate liver regeneration in clinic. This review focuses on the roles of BAs and FXR in liver regeneration and the current underlying molecular mechanisms which contribute to liver regeneration.
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Key Words
- ABC, ATP-binding cassette
- AMPK, AMP-activated protein kinase
- BA, bile acid
- Bile acids
- C/EBPβ, CCAAT-enhancer binding protein β
- CA, cholic acid
- CDCA, chenodeoxycholic acid
- CTX, cerebrotendinous xanthomatosis
- CYP7A1, cholesterol 7alpha-hydroxylase
- CYP8B1, sterol 12α-hydroxylase
- Cyp27-KO, sterol 27-hydroxylase–knockout
- DDAH-1, dimethylarginineaminohydrolase-1
- ERK1/2, extracellular signal-regulated kinase 1/2
- FGF-15, fibroblast growth factor 15
- FGFR4, FGF receptor 4
- FOXM1b, forkhead boxm1b
- FXR, farnesoid X receptor
- Farnesoid X receptor
- Fibroblast growth factor 15
- Fxr-KO, Fxr-knockout
- GPBAR1 or TGR5, G protein-coupled BA receptor 1
- HEX, hematopoietically expressed homeobox
- JNK, c-Jun N-terminal kinase
- KC, Kupffer cells
- KO, knockout
- Liver regeneration
- Liver-intestine croass talk
- MAPK, mitogen-activated protein kinase
- MRP3, multidrug resistance associated protein 3
- NASH, nonalcoholic steatohepatitis
- NF-κB, nuclear factor-κB
- PH, partial hepatectomy
- Rb, retinoblastoma
- SHP, small heterodimer partner
- STAT3, signal transducer and activator of transcription 3
- TH, thyroid hormone
- THR, TH receptor
- Transmembrane G protein coupled receptor 5
- WT, wild type
- cAMP, cyclic adenosine monophosphate
- hepFxr-KO, hepatocyte-specific Fxr knockout
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Abstract
Farnesoid X receptor (FXR) is a member of the nuclear receptor family and a ligand-modulated transcription factor. In the liver, FXR has been considered a multi-functional cell protector and a tumor suppressor. FXR can suppress liver carcinogenesis via different mechanisms: 1) FXR maintains the normal liver metabolism of bile acids, glucose and lipids; 2) FXR promotes liver regeneration and repair after injury; 3) FXR protects liver cells from death and enhances cell survival; 4) FXR suppresses hepatic inflammation, thereby preventing inflammatory damage; and 5) FXR can directly increase the expression of some tumor-suppressor genes and repress the transcription of several oncogenes. However, inflammation and epigenetic silencing are known to decrease FXR expression during tumorigenesis. The reactivation of FXR function in the liver may be a potential therapeutic approach for patients with liver cancer.
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Jiao Y, Lu Y, Li XY. Farnesoid X receptor: a master regulator of hepatic triglyceride and glucose homeostasis. Acta Pharmacol Sin 2015; 36:44-50. [PMID: 25500875 DOI: 10.1038/aps.2014.116] [Citation(s) in RCA: 132] [Impact Index Per Article: 13.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2014] [Accepted: 09/01/2014] [Indexed: 12/12/2022]
Abstract
Non-alcoholic fatty liver disease (NAFLD) is characterized by the aberrant accumulation of triglycerides in hepatocytes in the absence of significant alcohol consumption, viral infection or other specific causes of liver disease. NAFLD has become a burgeoning health problem both worldwide and in China, but its pathogenesis remains poorly understood. Farnesoid X receptor (FXR), a member of the nuclear receptor (NR) superfamily, has been demonstrated to be the primary sensor for endogenous bile acids, and play a crucial role in hepatic triglyceride homeostasis. Deciphering the synergistic contributions of FXR to triglyceride metabolism is critical for discovering therapeutic agents in the treatment of NAFLD and hypertriglyceridemia.
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Shaik FB, Prasad DVR, Narala VR. Role of farnesoid X receptor in inflammation and resolution. Inflamm Res 2014; 64:9-20. [PMID: 25376338 DOI: 10.1007/s00011-014-0780-y] [Citation(s) in RCA: 56] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2014] [Revised: 10/10/2014] [Accepted: 10/27/2014] [Indexed: 12/20/2022] Open
Abstract
OBJECTIVE The aim of this paper is to review the developments of farnesoid X receptor (FXR) biology, its ligands, and various functions, in particular we discuss the anti-inflammatory and anti-fibrotic role in chronic inflammatory diseases. INTRODUCTION FXR is a ligand-dependent transcription factor belonging to the nuclear hormone receptor superfamily. The accrued data have shown that the FXR plays important roles not only in bile acid, lipid metabolism, and carbohydrate homeostasis, but also in inflammatory responses. The anti-inflammatory and anti-fibrotic effects of FXR on chronic inflammatory diseases are not well documented. METHODS A literature survey was performed using PubMed database search to gather complete information regarding FXR and its role in inflammation. RESULTS AND DISCUSSION FXR is highly expressed in liver, intestine, kidney and adrenals, but with lower expression in fat tissue, heart and recently it has been found to express in lungs too. Primary bile acids, cholic acid and chenodeoxycholic acid are the natural endogenous ligands for FXR. GW4064 and 6α-ethyl-chenodeoxycholic acid are the synthetic high-affinity agonists. An exhaustive literature survey revealed that FXR acts as a key metabolic regulator and potential drug target for many metabolic syndromes that include chronic inflammatory diseases.
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Yang H, Jiang J, Xu X, He J, He C, Ma H. Molecular characterization, tissue expression profile and SNP analysis of the porcine NR1H4 gene. Mol Biol Rep 2014; 41:7009-14. [PMID: 25034892 DOI: 10.1007/s11033-014-3588-5] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/06/2013] [Accepted: 07/05/2014] [Indexed: 01/06/2023]
Abstract
Nuclear Receptor subfamily 1, group H, member 4 (NR1H4) is a receptor for bile acids and has an important role in regulating energy metabolism in liver, muscle and adipose tissues in humans and animals. In this study, we cloned the full coding region of NR1H4 gene from porcine Longissimus dorsi by Rapid amplification of cDNA end (RACE). Results indicated that the open reading frame of NR1H4 covered 1461 bp encoding 486 amino acid residues and the deduced amino acid sequence was 91-94 % identical to that of Homo sapiens, Bos taurus, Macaca mulatta, Gorilla gorilla, and Ovis aries. Bioinformatic analysis indicated that NR1H4 contained 31 phosphorylation sites with 14 serine, 6 threonine and 11 tyrosine. One single nucleotide polymorphism (SNP) was detected by PCR-RFLP in 3' untranslated region of exon 9 (NR1H4) and the allele frequency analysis showed that A allele frequency was low among 396 pigs from five breeds. The NR1H4 mRNA expression pattern showed that NR1H4 gene was expressed highly in live and Longissimus dorsi. This work provided an important experimental basis for further research on mechanism of lipid metabolism and fat deposition in pigs.
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Affiliation(s)
- Hu Yang
- College of Animal Science and Technology, Hunan Agricultural University, Changsha, 410128, People's Republic of China
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41
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Singh N, Yadav M, Singh AK, Kumar H, Dwivedi SKD, Mishra JS, Gurjar A, Manhas A, Chandra S, Yadav PN, Jagavelu K, Siddiqi MI, Trivedi AK, Chattopadhyay N, Sanyal S. Synthetic FXR agonist GW4064 is a modulator of multiple G protein-coupled receptors. Mol Endocrinol 2014; 28:659-73. [PMID: 24597548 DOI: 10.1210/me.2013-1353] [Citation(s) in RCA: 22] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The synthetic nuclear bile acid receptor (farnesoid X receptor [FXR]) agonist GW4064 is extensively used as a specific pharmacological tool to illustrate FXR functions. We noticed that GW4064 activated empty luciferase reporters in FXR-deficient HEK-293T cells. We postulated that this activity of GW4064 might be routed through as yet unknown cellular targets and undertook an unbiased exploratory approach to identify these targets. Investigations revealed that GW4064 activated cAMP and nuclear factor for activated T-cell response elements (CRE and NFAT-RE, respectively) present on these empty reporters. Whereas GW4064-induced NFAT-RE activation involved rapid intracellular Ca(2+) accumulation and NFAT nuclear translocation, CRE activation involved soluble adenylyl cyclase-dependent cAMP accumulation and Ca(2+)-calcineurin-dependent nuclear translocation of transducers of regulated CRE-binding protein 2. Use of dominant negative heterotrimeric G-protein minigenes revealed that GW4064 caused activation of Gαi/o and Gq/11 G proteins. Sequential pharmacological inhibitor-based screening and radioligand-binding studies revealed that GW4064 interacted with multiple G protein-coupled receptors. Functional studies demonstrated that GW4064 robustly activated H1 and H4 and inhibited H2 histamine receptor signaling events. We also found that MCF-7 breast cancer cells, reported to undergo GW4064-induced apoptosis in an FXR-dependent manner, did not express FXR, and the GW4064-mediated apoptosis, also apparent in HEK-293T cells, could be blocked by selective histamine receptor regulators. Taken together, our results demonstrate identification of histamine receptors as alternate targets for GW4064, which not only necessitates cautious interpretation of the biological functions attributed to FXR using GW4064 as a pharmacological tool but also provides a basis for the rational designing of new pharmacophores for histamine receptor modulation.
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Affiliation(s)
- Nidhi Singh
- Division of Biochemistry (N.S., M.Y., A.K.S., H.K., J.S.M., A.G., S.S.), Division of Endocrinology and Center for Anabolic Skeletal Targets in Health and Illness (S.K.D.D., N.C.), Division of Pharmacology (A.M., P.N.Y., K.J.), and Division of Molecular and Structural Biology (S.C., M.I.S.), Council of Scientific and Industrial Research-Central Drug Research Institute, Lucknow 226031, Uttar Pradesh, India
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Ding L, Pang S, Sun Y, Tian Y, Yu L, Dang N. Coordinated Actions of FXR and LXR in Metabolism: From Pathogenesis to Pharmacological Targets for Type 2 Diabetes. Int J Endocrinol 2014; 2014:751859. [PMID: 24872814 PMCID: PMC4020365 DOI: 10.1155/2014/751859] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/02/2014] [Accepted: 04/09/2014] [Indexed: 12/13/2022] Open
Abstract
Type 2 diabetes (T2D) is the most prevalent metabolic disease, and many people are suffering from its complications driven by hyperglycaemia and dyslipidaemia. Nuclear receptors (NRs) are ligand-inducible transcription factors that mediate changes to metabolic pathways within the body. As metabolic regulators, the farnesoid X receptor (FXR) and the liver X receptor (LXR) play key roles in the pathogenesis of T2D, which remains to be clarified in detail. Here we review the recent progress concerning the physiological and pathophysiological roles of FXRs and LXRs in the regulation of bile acid, lipid and glucose metabolism and the implications in T2D, taking into account that these two nuclear receptors are potential pharmaceutical targets for the treatment of T2D and its complications.
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Affiliation(s)
- Lin Ding
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Shuguang Pang
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
- *Shuguang Pang:
| | - Yongmei Sun
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Yuling Tian
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Li Yu
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
| | - Ningning Dang
- Endocrinology Department, Jinan Central Hospital Affiliated to Shandong University, No. 105 Jiefang Road, Jinan, Shandong 250013, China
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Abstract
Enterohepatic circulation is responsible for the capture of bile acids and other steroids produced or metabolized in the liver and secreted to the intestine, for reabsorption back into the circulation and transport back to the liver. Bile acids are secreted from the liver in the form of mixed micelles that also contain phosphatidylcholines and cholesterol that facilitate the uptake of fats and vitamins from the diet due to the surfactant properties of bile acids and lipids. Bile acids are synthesized in the liver from cholesterol by a cascade of enzymes that carry out oxidation and conjugation reactions, and transported to the bile duct and gall bladder where they are stored before being released into the intestine. Bile flow from the gall bladder to the small intestine is triggered by food intake in accordance with its role in lipid and vitamin absorption from the diet. Bile acids are further metabolized by gut bacteria and are transported back to the circulation. Metabolites produced in the liver are termed primary bile acids or primary conjugated bile salts, while the metabolites generated by bacterial are called secondary bile acids. About 95% of bile acids are reabsorbed in the proximal and distal ileum into the hepatic portal vein and then into the liver sinusoids, where they are efficiently transported into the liver with little remaining in circulation. Each bile acid is reabsorbed about 20 times on average before being eliminated. Enterohepatic circulation is under tight regulation by nuclear receptor signaling, notably by the farnesoid X receptor (FXR).
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Affiliation(s)
- Frank J Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA.
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Poly(ADP-ribose) polymerase 1 promotes oxidative-stress-induced liver cell death via suppressing farnesoid X receptor α. Mol Cell Biol 2013; 33:4492-503. [PMID: 24043304 DOI: 10.1128/mcb.00160-13] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023] Open
Abstract
Farnesoid X receptor α (FXR) is highly expressed in the liver and regulates the expression of various genes involved in liver repair. In this study, we demonstrated that activated poly(ADP-ribose) polymerase 1 (PARP1) promoted hepatic cell death by inhibiting the expression of FXR-dependent hepatoprotective genes. PARP1 could bind to and poly(ADP-ribosyl)ate FXR. Poly(ADP-ribosyl)ation dissociated FXR from the FXR response element (FXRE), present in the promoters of target genes, and suppressed FXR-mediated gene transcription. Moreover, treatment with a FXR agonist attenuated poly(ADP-ribosyl)ation of FXR and promoted FXR-dependent gene expression. We further established the CCl4-induced acute liver injury model in wild-type and FXR-knockout mice and identified an essential role of FXR poly(ADP-ribosyl)ation in CCl4-induced liver injury. Thus, our results identified poly(ADP-ribosyl)ation of FXR by PARP1 as a key step in oxidative-stress-induced hepatic cell death. The molecular association between PARP1 and FXR provides new insight into the mechanism, suggesting that inhibition of PARP1 could prevent liver injury.
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Abstract
Enzymatic oxidation of cholesterol generates numerous distinct bile acids that function both as detergents that facilitate digestion and absorption of dietary lipids, and as hormones that activate four distinct receptors. Activation of these receptors alters gene expression in multiple tissues, leading to changes not only in bile acid metabolism but also in glucose homeostasis, lipid and lipoprotein metabolism, energy expenditure, intestinal motility and bacterial growth, inflammation, liver regeneration, and hepatocarcinogenesis. This review covers the roles of specific bile acids, synthetic agonists, and their cognate receptors in controlling these diverse functions, as well as their current use in treating human diseases.
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Affiliation(s)
- Thomas Q de Aguiar Vallim
- Department of Biological Chemistry, University of California, Los Angeles, Los Angeles, CA 90095, USA
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Matsubara T, Li F, Gonzalez FJ. FXR signaling in the enterohepatic system. Mol Cell Endocrinol 2013; 368:17-29. [PMID: 22609541 PMCID: PMC3491147 DOI: 10.1016/j.mce.2012.05.004] [Citation(s) in RCA: 294] [Impact Index Per Article: 24.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/11/2012] [Revised: 04/18/2012] [Accepted: 05/08/2012] [Indexed: 02/07/2023]
Abstract
Enterohepatic circulation serves to capture bile acids and other steroid metabolites produced in the liver and secreted to the intestine, for reabsorption back into the circulation and reuptake to the liver. This process is under tight regulation by nuclear receptor signaling. Bile acids, produced from cholesterol, can alter gene expression in the liver and small intestine via activating the nuclear receptors farnesoid X receptor (FXR; NR1H4), pregnane X receptor (PXR; NR1I2), vitamin D receptor (VDR; NR1I1), G protein coupled receptor TGR5, and other cell signaling pathways (JNK1/2, AKT and ERK1/2). Among these controls, FXR is known to be a major bile acid-responsive ligand-activated transcription factor and a crucial control element for maintaining bile acid homeostasis. FXR has a high affinity for several major endogenous bile acids, notably cholic acid, deoxycholic acid, chenodeoxycholic acid, and lithocholic acid. By responding to excess bile acids, FXR is a bridge between the liver and small intestine to control bile acid levels and regulate bile acid synthesis and enterohepatic flow. FXR is highly expressed in the liver and gut, relative to other tissues, and contributes to the maintenance of cholesterol/bile acid homeostasis by regulating a variety of metabolic enzymes and transporters. FXR activation also affects lipid and glucose metabolism, and can influence drug metabolism.
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Affiliation(s)
- Tsutomu Matsubara
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Fei Li
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
| | - Frank J. Gonzalez
- Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892
- Correspondence: Frank J. Gonzalez, Laboratory of Metabolism, National Cancer Institute, Building 37, Room 3106, Bethesda, MD 20892, Tel: 301-496-9067, Fax: 301-496-8419,
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Hepatocyte nuclear factor 4 alpha and farnesoid X receptor co-regulates gene transcription in mouse livers on a genome-wide scale. Pharm Res 2013; 30:2188-98. [PMID: 23462932 DOI: 10.1007/s11095-013-1006-7] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2012] [Accepted: 02/06/2013] [Indexed: 01/06/2023]
Abstract
PURPOSE Farnesoid X receptor (Fxr) is a ligand-activated nuclear receptor critical for liver function. Reports indicate that the functions of Fxr in the liver may overlap with those of hepatocyte nuclear factor 4α (Hnf4α), but studies of their precise genome-wide interaction to regulate gene transcription in the liver are lacking. Thus, we compared the genome-wide binding of Fxr and Hnf4α in the liver of mice and characterized their cooperative activity on binding to and activating target gene transcription. METHODS Genome-wide ChIP-Seq data of Fxr and Hnf4α in mouse liver were analyzed by MACS, BEDTools, and DAVID. Co-immunoprecipitation, ChIP-qPCR, and luciferase assays were done to test for protein-protein interaction and cooperative binding. RESULTS ChIP-seq analysis showed nearly 50% binding sites of Fxr and Hnf4α in mouse liver overlap and Hnf4α bound to shared target sites upstream and in close proximity to Fxr. Moreover, genes co-bound by Fxr and Hnf4α are enriched in complement and coagulation cascades and drug metabolism. A direct Fxr-Hnf4α protein interaction dependent on Fxr activity was detected and transcriptional assays suggest that Hnf4α can increase Fxr transcriptional activity. Conversely, binding assays showed Hnf4α can be either Fxr-dependent or -independent at different shared binding sites. CONCLUSION Our results showed that Fxr cooperates with Hnf4α in the liver to modulate gene transcription. This study provides the first evidence on a genome-wide scale of both cooperative and independent interactions between Fxr and Hnf4α in regulating gene transcription in the liver.
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Plant sterols as anticancer nutrients: evidence for their role in breast cancer. Nutrients 2013; 5:359-87. [PMID: 23434903 PMCID: PMC3635199 DOI: 10.3390/nu5020359] [Citation(s) in RCA: 56] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2012] [Revised: 11/30/2012] [Accepted: 01/24/2013] [Indexed: 12/12/2022] Open
Abstract
While many factors are involved in the etiology of cancer, it has been clearly established that diet significantly impacts one’s risk for this disease. More recently, specific food components have been identified which are uniquely beneficial in mitigating the risk of specific cancer subtypes. Plant sterols are well known for their effects on blood cholesterol levels, however research into their potential role in mitigating cancer risk remains in its infancy. As outlined in this review, the cholesterol modulating actions of plant sterols may overlap with their anti-cancer actions. Breast cancer is the most common malignancy affecting women and there remains a need for effective adjuvant therapies for this disease, for which plant sterols may play a distinctive role.
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Abstract
Liver X receptors (LXRs) are members of the nuclear receptor family and are present in two isoforms, α and β, encoded by two separate genes. Originally described in the liver, LXRs have in the last 15 years been implicated in central metabolic pathways, including bile acid synthesis, lipid and glucose homeostasis. Although the vast majority of studies have been performed in non-adipose cells/tissues, results in recent years suggest that LXRs may have important modulatory roles in adipose tissue and adipocytes. Although several authors have published reviews on LXR, there have been no attempts to summarize the effects reported specifically in adipose systems. This overview gives a brief introduction to LXR and describes the sometimes-contradictory results obtained in murine cell systems and in rodent adipose tissue. The so far very limited number of studies performed in human adipocytes and adipose tissue are also presented. It should be apparent that although LXR may impact on several different pathways in metabolism, the clinical role of LXR modulation in adipose tissue is still not clear.
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Genome-wide profiling of liver X receptor, retinoid X receptor, and peroxisome proliferator-activated receptor α in mouse liver reveals extensive sharing of binding sites. Mol Cell Biol 2011; 32:852-67. [PMID: 22158963 DOI: 10.1128/mcb.06175-11] [Citation(s) in RCA: 200] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
The liver X receptors (LXRs) are nuclear receptors that form permissive heterodimers with retinoid X receptor (RXR) and are important regulators of lipid metabolism in the liver. We have recently shown that RXR agonist-induced hypertriglyceridemia and hepatic steatosis in mice are dependent on LXRs and correlate with an LXR-dependent hepatic induction of lipogenic genes. To further investigate the roles of RXR and LXR in the regulation of hepatic gene expression, we have mapped the ligand-regulated genome-wide binding of these factors in mouse liver. We find that the RXR agonist bexarotene primarily increases the genomic binding of RXR, whereas the LXR agonist T0901317 greatly increases both LXR and RXR binding. Functional annotation of putative direct LXR target genes revealed a significant association with classical LXR-regulated pathways as well as peroxisome proliferator-activated receptor (PPAR) signaling pathways, and subsequent chromatin immunoprecipitation-sequencing (ChIP-seq) mapping of PPARα binding demonstrated binding of PPARα to 71 to 88% of the identified LXR-RXR binding sites. The combination of sequence analysis of shared binding regions and sequential ChIP on selected sites indicate that LXR-RXR and PPARα-RXR bind to degenerate response elements in a mutually exclusive manner. Together, our findings suggest extensive and unexpected cross talk between hepatic LXR and PPARα at the level of binding to shared genomic sites.
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