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Farnesoid x receptor

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https://www.readbyqxmd.com/read/28428116/cycloastragenol-improves-hepatic-steatosis-by-activating-farnesoid-x-receptor-signalling
#1
Ming Gu, Shiying Zhang, Yuanyuan Zhao, Jinwen Huang, Yahui Wang, Yin Li, Shengjie Fan, Li Yang, Guang Ji, Qingchun Tong, Cheng Huang
Non-alcoholic fatty liver disease (NAFLD) has become a global health problem. However, there is no approved therapy for NAFLD. Farnesoid X receptor (FXR) is a potential drug target for treatment of NAFLD. In an attempt to screen FXR agonists, we found that cycloastragenol (CAG), a natural occurring compound in Astragali Radix, stimulated FXR transcription activity. In animal studies, we demonstrated that CAG treatment resulted in obvious reduction of high-fat diet induced lipid accumulation in liver accompanied by lowered blood glucose, serum triglyceride levels and hepatic bile acid pool size...
April 17, 2017: Pharmacological Research: the Official Journal of the Italian Pharmacological Society
https://www.readbyqxmd.com/read/28424617/targeting-bile-acid-receptors-discovery-of-a-potent-and-selective-farnesoid-x-receptor-agonist-as-a-new-lead-in-the-pharmacological-approach-to-liver-diseases
#2
Carmen Festa, Simona De Marino, Adriana Carino, Valentina Sepe, Silvia Marchianò, Sabrina Cipriani, Francesco S Di Leva, Vittorio Limongelli, Maria C Monti, Angela Capolupo, Eleonora Distrutti, Stefano Fiorucci, Angela Zampella
Bile acid (BA) receptors represent well-defined targets for the development of novel therapeutic approaches to metabolic and inflammatory diseases. In the present study, we report the generation of novel C-3 modified 6-ethylcholane derivatives. The pharmacological characterization and molecular docking studies for the structure-activity rationalization, allowed the identification of 3β-azido-6α-ethyl-7α-hydroxy-5β-cholan-24-oic acid (compound 2), a potent and selective FXR agonist with a nanomolar potency in transactivation assay and high efficacy in the recruitment of SRC-1 co-activator peptide in Alfa Screen assay...
2017: Frontiers in Pharmacology
https://www.readbyqxmd.com/read/28411380/metabolic-profile-of-obeticholic-acid-and-endogenous-bile-acids-in-rats-with-decompensated-liver-cirrhosis
#3
Aldo Roda, Rita Aldini, Cecilia Camborata, Silvia Spinozzi, Placido Franco, Massimiliano Cont, Antonia D'Errico, Francesco Vasuri, Alessio Degiovanni, Lorenzo Maroni, Luciano Adorini
Obeticholic acid (OCA) is a semisynthetic bile acid (BA) analogue and potent farnesoid X receptor agonist approved to treat cholestasis. We evaluated the biodistribution and metabolism of OCA administered to CCl4 -induced cirrhotic rats. This was to ascertain if plasma and hepatic concentrations of OCA are potentially more harmful than those of endogenous BA. After administration of OCA (30 mg/kg), we used liquid chromatography-mass spectrometry to measure OCA, its metabolites, and BA at different time-points in various organs and fluids...
April 14, 2017: Clinical and Translational Science
https://www.readbyqxmd.com/read/28406477/mir-21-ablation-and-obeticholic-acid-ameliorate-nonalcoholic-steatohepatitis-in-mice
#4
Pedro M Rodrigues, Marta B Afonso, André L Simão, Catarina C Carvalho, Alexandre Trindade, António Duarte, Pedro M Borralho, Mariana V Machado, Helena Cortez-Pinto, Cecília Mp Rodrigues, Rui E Castro
microRNAs were recently suggested to contribute to the pathogenesis of nonalcoholic fatty liver disease (NAFLD), a disease lacking specific pharmacological treatments. In that regard, nuclear receptors are arising as key molecular targets for the treatment of nonalcoholic steatohepatitis (NASH). Here we show that, in a typical model of NASH-associated liver damage, microRNA-21 (miR-21) ablation results in a progressive decrease in steatosis, inflammation and lipoapoptosis, with impairment of fibrosis. In a complementary fast food (FF) diet NASH model, mimicking features of the metabolic syndrome, miR-21 levels increase in both liver and muscle, concomitantly with decreased expression of peroxisome proliferator-activated receptor α (PPARα), a key miR-21 target...
April 13, 2017: Cell Death & Disease
https://www.readbyqxmd.com/read/28400425/the-logic-of-transcriptional-regulator-recruitment-architecture-at-cis-regulatory-modules-controlling-liver-functions
#5
Julie Dubois-Chevalier, Vanessa Dubois, Hélène Dehondt, Parisa Mazrooei, Claire Mazuy, Aurélien A Sérandour, Céline Gheeraert, Guillaume Penderia, Eric Baugé, Bruno Derudas, Nathalie Hennuyer, Réjane Paumelle, Guillemette Marot, Jason S Carroll, Mathieu Lupien, Bart Staels, Philippe Lefebvre, Jérôme Eeckhoute
Control of gene transcription relies on concomitant regulation by multiple transcriptional regulators (TR). However, how recruitment of a myriad of TR is orchestrated at cis-regulatory modules (CRM) to account for co-regulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRM involved in regulatory activities of the hepatic TR, NR1H4 (FXR; farnesoid X receptor), as our model system to tackle this question. Using integrative cistromic, epigenomic, transcriptomic and interactomic analyses, we reveal a logical organization where trans-regulatory modules (TRM), which consist of subsets of preferentially and co-ordinately co-recruited TR, assemble into hierarchical combinations at hepatic CRM...
April 11, 2017: Genome Research
https://www.readbyqxmd.com/read/28400119/bile-acids-and-colon-cancer-is-fxr-the-solution-of-the-conundrum
#6
REVIEW
Raffaella Maria Gadaleta, Oihane Garcia-Irigoyen, Antonio Moschetta
Diet and lifestyle habits have a profound impact on the pathophysiology of many diseases. Colorectal cancer (CRC) is the third most common cancer worldwide and its etiology is strongly influenced by nutrition and high fat/high carbohydrate Western-style diet. Human epidemiological and animal studies have shown that colonic cancer risk is also related to faecal bile acid concentration. Abnormally high levels of bile acids (BA) trigger the colonic mucosa with a plethora of detrimental effects such as DNA oxidative damage, inflammation and hyperproliferation that highly promote CRC progression in post-initiation phase...
April 8, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28394474/proteomic-identification-of-rainbow-trout-blood-plasma-proteins-and-their-relationship-to-seminal-plasma-proteins
#7
Joanna Nynca, G J Arnold, T Fröhlich, A Ciereszko
The characterization of fish blood proteomes is important for comparative studies of seminal and blood proteins as well as for the analysis of fish immune mechanisms and pathways. In this study LC-MS/MS and 2D DIGE were applied to compare rainbow trout seminal (SP) and blood plasma (BP) proteomes. The 54 differentially abundant proteins identified in SP are involved in a variety of signalling pathways, including protein ubiquitination, liver X receptor/retinoid X receptor (LXR/RXR) and farnesoid X receptor (FXR)/RXR activation, cell cycle and acute phase signalling...
April 10, 2017: Proteomics
https://www.readbyqxmd.com/read/28390813/bile-acids-and-bariatric-surgery
#8
REVIEW
Vance L Albaugh, Babak Banan, Hana Ajouz, Naji N Abumrad, Charles R Flynn
Bariatric surgery, specifically Roux-en-Y gastric bypass (RYGB) and vertical sleeve gastrectomy (VSG), are the most effective and durable treatments for morbid obesity and potentially a viable treatment for type 2 diabetes (T2D). The resolution rate of T2D following these procedures is between 40 and 80% and far surpasses that achieved by medical management alone. The molecular basis for this improvement is not entirely understood, but has been attributed in part to the altered enterohepatic circulation of bile acids...
April 5, 2017: Molecular Aspects of Medicine
https://www.readbyqxmd.com/read/28381740/the-associations-between-circulating-bile-acids-and-the-muscle-volume-in-patients-with-non-alcoholic-fatty-liver-disease-nafld
#9
Yoshinao Kobayashi, Nagisa Hara, Ryosuke Sugimoto, Rumi Mifuji-Moroka, Hideaki Tanaka, Akiko Eguchi, Motoh Iwasa, Hiroshi Hasegawa, Kazuko Iwata, Yoshiyuki Takei, Osamu Taguchi
Objective Non-alcoholic fatty liver disease (NAFLD) is frequently associated with obesity, dyslipidemia and type-2 diabetes mellitus. Bile acids (BAs) bind to the farnesoid X receptor (FXR) and G protein-coupled receptor 5 (TGR5), which are involved in lipid and glucose metabolism and energy expenditure. The present study aimed to determine associations between the circulating BAs and the skeletal muscle volume (SMV), and lipid and glucose metabolism in patients with NAFLD. Methods Serum BAs and metabolic parameters were measured in 55 patients with NAFLD (median age, 55 years)...
2017: Internal Medicine
https://www.readbyqxmd.com/read/28380377/farnesoid-x-receptor-regulation-of-the-nlrp3-inflammasome-underlies-cholestasis-associated-sepsis
#10
Haiping Hao, Lijuan Cao, Changtao Jiang, Yuan Che, Songyang Zhang, Shogo Takahashi, Guangji Wang, Frank J Gonzalez
Cholestasis is a common complication of sepsis, and the increased plasma levels of bile acids are predictive of sepsis-associated mortality. However, the exact mechanism by which cholestasis aggravates sepsis development remains elusive. Here, we show that bile acids are danger-associated molecular patterns (DAMPs) that can activate both signal 1 and 2 of the NLRP3 inflammasome in inflammatory macrophages. Mechanistically, bile acids induce a prolonged calcium influx and activate the NLRP3 inflammasome synergistically with ATP...
April 4, 2017: Cell Metabolism
https://www.readbyqxmd.com/read/28378930/hepatic-fxr-shp-axis-modulates-systemic-glucose-and-fatty-acid-homeostasis-in-aged-mice
#11
Kang Ho Kim, Sungwoo Choi, Ying Zhou, Eun Young Kim, Jae Man Lee, Pradip K Saha, Sayeepriyadarshini Anakk, David D Moore
The nuclear receptors farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP; NR0B2) play crucial roles in bile acid homeostasis. Global disruption of both FXR and SHP signaling (DKO) causes severe cholestasis and liver injury at early ages. Here, we report an unexpected beneficial impact on glucose and fatty acid metabolism in aged DKO mice, which show suppressed body weight gain and adiposity when maintained on normal chow. This phenotype was not observed in single Fxr or Shp knockouts. Liver-specific Fxr/Shp double knockout (FS(LK) °) mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance and accelerated fatty acid utilization...
April 5, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28377627/farnesoid-x-receptor-a-novel-proto-oncogene-in-non-small-cell-lung-cancer-promotes-tumor-growth-via-directly-transactivating-ccnd1
#12
Wenjie You, Bi Chen, Xueqing Liu, Shan Xue, Hui Qin, Handong Jiang
Farnesoid X receptor (FXR), a nuclear receptor for maintaining bile acid homeostasis, has been recognized as a tumor suppressor in enterohepatic tissues. However, its expression and functional role in non-small cell lung cancer (NSCLC) remain unclear. We report that FXR is significantly increased in NSCLC and that it predicts poor clinical outcomes in NSCLC patients. FXR knockdown in NSCLC cells inhibited in vitro cell proliferation, blocked xenograft growth in nude mice, and delayed the G1/S transition of the cell cycle, whereas ectopic overexpression of FXR promoted NSCLC cell proliferation...
April 4, 2017: Scientific Reports
https://www.readbyqxmd.com/read/28351411/activation-of-fxr-pathway-does-not-alter-glial-cell-function
#13
Stefanie Albrecht, Ann-Katrin Fleck, Ina Kirchberg, Stephanie Hucke, Marie Liebmann, Luisa Klotz, Tanja Kuhlmann
BACKGROUND: The nuclear receptor farnesoid-X-receptor (FXR; NR1H4) is expressed not only in the liver, gut, kidney and adipose tissue but also in the immune cells. FXR has been shown to confer protection in several animal models of inflammation, including experimental autoimmune encephalomyelitis (EAE), an animal model of multiple sclerosis (MS). FXR agonists are currently tested in clinical trials for treatment of human metabolic diseases. The beneficial effect of FXR agonists in EAE suggests that FXR might represent a potential target in inflammatory-demyelinating CNS diseases, such as MS...
March 28, 2017: Journal of Neuroinflammation
https://www.readbyqxmd.com/read/28346237/current-and-future-pharmacologic-treatment-of-nonalcoholic-steatohepatitis
#14
Bubu A Banini, Arun J Sanyal
PURPOSE OF REVIEW: Nonalcoholic steatohepatitis (NASH), the aggressive form of nonalcoholic fatty liver disease (NAFLD), can progress to cirrhosis and hepatocellular cancer in 5-15% of patients and is rapidly becoming the leading cause for end-stage liver disease. Dietary caloric restriction and exercise, currently the cornerstone of therapy for NAFLD, can be difficult to achieve and maintain, underscoring the dire need for pharmacotherapy. This review presents the agents currently used in managing NAFLD and their pharmacologic targets...
May 2017: Current Opinion in Gastroenterology
https://www.readbyqxmd.com/read/28341659/chronic-microaspiration-of-bile-acids-induces-lung-fibrosis-through-multiple-mechanisms-in-rats
#15
Bi Chen, Wen Jie You, Xue Qing Liu, Shan Xue, Hui Qin, Han Dong Jiang
Gastroesophageal reflux (GER) and microaspiration of duodenogastric refluxate have been recognized as a risk factor for pulmonary fibrosis. Recent evidence implicates that bile acid microaspiration may contribute to the development of lung fibrosis. However, the molecular evidences are scarce and the underlying mechanisms remain to be elucidated. We have recently demonstrated that bile acids induce activation of alveolar epithelial cells and lung fibroblasts in vitro In this study, a rat model of bile acid microaspiration was established by weekly intratracheal instillation of three major bile acids including chenodeoxycholic acid (CDCA), deoxycholic acid (DCA) and lithocholic acid (LCA) ...
March 24, 2017: Clinical Science (1979-)
https://www.readbyqxmd.com/read/28338522/developments-in-intestinal-cholesterol-transport-and-triglyceride-absorption
#16
Yared Paalvast, Jan Freark de Boer, Albert K Groen
PURPOSE OF REVIEW: To discuss recent advances in research focused on intestinal lipid handling. RECENT FINDINGS: An important strategy in reducing atherosclerosis and risk of cardiovascular events is to increase the rate of reverse cholesterol transport, including its final step; cholesterol excretion from the body. The rate of removal is determined by a complex interplay between the factors involved in regulation of intestinal cholesterol absorption. One of these factors is a process known as transintestinal cholesterol excretion...
March 23, 2017: Current Opinion in Lipidology
https://www.readbyqxmd.com/read/28333693/pediatric-intestinal-failure-associated-liver-disease
#17
Cathleen M Courtney, Brad W Warner
PURPOSE OF REVIEW: The goal of this review is to provide updates on the definition, pathophysiology, treatment, and prevention of intestinal failure-associated liver disease (IFALD) that are relevant to care of pediatric patients. RECENT FINDINGS: Current literature emphasizes the multifactorial nature of IFALD. The pathogenesis is still largely unknown; however, molecular pathways have been identified. Key to these pathways are proinflammatory cytokines involved in hepatic inflammation and bile acids synthesis such as Toll-like receptor 4 and farnesoid X receptor, respectively...
March 22, 2017: Current Opinion in Pediatrics
https://www.readbyqxmd.com/read/28324023/long-chain-free-fatty-acid-receptor-gpr120-mediates-oil-induced-gip-secretion-through-cck-in-male-mice
#18
Akiko Sankoda, Norio Harada, Kanako Iwasaki, Shunsuke Yamane, Yuki Murata, Kimitaka Shibue, Yotsapon Thewjitcharoen, Kazuyo Suzuki, Takanari Harada, Yoshinori Kanemaru, Satoko Shimazu-Kuwahara, Akira Hirasawa, Nobuya Inagaki
Free fatty acid receptors GPR120 and GPR40 are involved in the secretion of gut hormones. GPR120 and GPR40 are expressed in enteroendocrine K-cells and their activation induces the secretion of the incretin glucose-dependent insulinotropic polypeptide (GIP). However, the role of these receptors in fat-induced GIP secretion in vivo and the associated mechanisms are unclear. In this study, we investigated corn oil-induced GIP secretion in GPR120-knockout (GPR120-/-) and GPR40-knockout (GPR40-/-) mice. Oil-induced GIP secretion was reduced by 50% and 80% in GPR120-/- and GPR40-/- mice compared to that in wild-type (WT) mice, respectively...
March 15, 2017: Endocrinology
https://www.readbyqxmd.com/read/28315136/ursodeoxycholic-acid-suppresses-lipogenesis-in-mouse-liver-possible-role-of-the-decrease-in-%C3%AE-muricholic-acid-a-farnesoid-x-receptor-antagonist
#19
Kyosuke Fujita, Yusuke Iguchi, Mizuho Une, Shiro Watanabe
The farnesoid X receptor (FXR) is a major nuclear receptor of bile acids; its activation suppresses sterol regulatory element-binding protein 1c (SREBP1c)-mediated lipogenesis and decreases the lipid contents in the liver. There are many reports showing that the administration of ursodeoxycholic acid (UDCA) suppresses lipogenesis and reduces the lipid contents in the liver of experimental animals. Since UDCA is not recognized as an FXR agonist, these effects of UDCA cannot be readily explained by its direct activation of FXR...
March 17, 2017: Lipids
https://www.readbyqxmd.com/read/28304141/evidence-connecting-old-new-and-neglected-glucose-lowering-drugs-to-bile-acid-induced-glp-1-secretion-a-review
#20
REVIEW
Martin L Kårhus, Andreas Brønden, David P Sonne, Tina Vilsbøll, Fillip K Knop
Bile acids are amphipathic water-soluble steroid-based molecules best known for their important lipid-solubilizing role in the assimilation of fat. Recently, bile acids have emerged as metabolic integrators with glucose-lowering potential. Among a variety of gluco-metabolic effects, bile acids have been demonstrated to modulate the secretion of the gut-derived incretin hormone glucagon-like peptide-1 (GLP-1), possibly via the transmembrane receptor Takeda G protein-coupled receptor 5 (TGR5) and the nuclear farnesoid X receptor (FXR), in intestinal L cell...
March 17, 2017: Diabetes, Obesity & Metabolism
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