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https://www.readbyqxmd.com/read/28434196/role-of-gut-microbiota-bile-acids-and-their-crosstalk-in-the-effects-of-bariatric-surgery-on-obesity-and-type-2-diabetes
#1
Haijun Liu, Cheng Hu, Xueli Zhang, Weiping Jia
Type 2 diabetes mellitus is becoming increasingly prevalent worldwide and has become one of the greatest threats to global health. Bariatric surgery was initially designed to achieve weight loss and subsequently was noted to induce improvements or remission of type 2 diabetes. Currently, these bariatric operations such as Roux-en-Y gastric bypass (RYGB) and sleeve gastrectomy (SG) are the most effective procedures for the treatment of obesity and type 2 diabetes mellitus worldwide. However, the specific mechanism mediating the beneficial effects of metabolic surgery has remained largely unknown...
April 23, 2017: Journal of Diabetes Investigation
https://www.readbyqxmd.com/read/28428116/cycloastragenol-improves-hepatic-steatosis-by-activating-farnesoid-x-receptor-signalling
#2
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
#3
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/28416481/western-diet-deregulates-bile-acid-homeostasis-cell-proliferation-and-tumorigenesis-in-colon
#4
Denis Dermadi, Satu Valo, Saara Ollila, Rabah Soliymani, Nina Sipari, Marjaana Pussila, Laura Sarantaus, Jere Linden, Marc Baumann, Minna Nyström
Western-style diets (WD) high in fat and scarce in fiber and vitamin D increase risks of colorectal cancer (CRC). Here we performed a long-term diet study in mice to follow tumorigenesis and characterize structural and metabolic changes in colon mucosa associated with WD and predisposition to CRC. WD increased colon tumor numbers and mucosa proteomic analysis indicated severe deregulation of intracellular bile acid (BA) homeostasis and activation of cell proliferation. WD also increased crypt depth and colon cell proliferation...
April 17, 2017: Cancer Research
https://www.readbyqxmd.com/read/28406477/mir-21-ablation-and-obeticholic-acid-ameliorate-nonalcoholic-steatohepatitis-in-mice
#5
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/28402278/correlated-high-expression-of-fxr-and-sp1-of-the-cancer-cells-confers-a-poor-prognosis-for-pancreatic-cancer-a-study-based-on-tcga-and-tissue-microarray
#6
Hai Hu, Lei-Lei Wu, Ting Han, Meng Zhuo, Wang Lei, Jiu-Jie Cui, Feng Jiao, Li-Wei Wang
Bile acids (BAs) was critical in the initiation and progression of various tumors. However, their prognostic significance in pancreatic cancer was still illusive. In the present study, the expression and biological significance of FXR, a major receptor of BAs, in the lethal disease were evaluated in mRNA and protein levels. We found that FXR protein was elevated in the cancerous tissues, which was significantly higher than the adjacent tissues (p < 0.05). Meanwhile, our data showed that FXR was positively correlated with primary tumor location (p = 0...
March 28, 2017: Oncotarget
https://www.readbyqxmd.com/read/28400425/the-logic-of-transcriptional-regulator-recruitment-architecture-at-cis-regulatory-modules-controlling-liver-functions
#7
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
#8
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
#9
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/28391356/rat-precision-cut-liver-slices-predict-drug-induced-cholestatic-injury
#10
Viktoriia Starokozhko, Rick Greupink, Petra van de Broek, Nashwa Soliman, Samiksha Ghimire, Inge A M de Graaf, Geny M M Groothuis
Drug-induced cholestasis (DIC) is one of the leading manifestations of drug-induced liver injury (DILI). As the underlying mechanisms for DIC are not fully known and specific and predictive biomarkers and pre-clinical models are lacking, the occurrence of DIC is often only reported when the drug has been approved for registration. Therefore, appropriate models that predict the cholestatic potential of drug candidates and/or provide insight into the mechanism of DIC are highly needed. We investigated the application of rat precision-cut liver slices (PCLS) to predict DIC, using several biomarkers of cholestasis: hepatocyte viability, intracellular accumulation of total as well as individual bile acids and changes in the expression of genes known to play a role in cholestasis...
April 8, 2017: Archives of Toxicology
https://www.readbyqxmd.com/read/28390813/bile-acids-and-bariatric-surgery
#11
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
#12
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
#13
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/28380370/a-novel-protective-role-for-fxr-against-inflammasome-activation-and-endotoxemia
#14
Oihane Garcia-Irigoyen, Antonio Moschetta
During conditions of impaired bile flow (cholestasis), increased serum bile acids (BAs) are prognostic markers of sepsis. In this issue, Hao et al. (2017) show that the BA receptor FXR binds NLRP3 inflammasome in macrophages and inhibits activation of inflammasome components, thus reducing endotoxemia in cholestasis.
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
#15
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
#16
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
#17
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/28348052/bile-acid-administration-elicits-an-intestinal-antimicrobial-program-and-reduces-the-bacterial-burden-in-two-mouse-models-of-enteric-infection
#18
Sarah Tremblay, Guillaume Romain, Mélisange Roux, Xi-Lin Chen, Kirsty Brown, Deanna L Gibson, Sheela Ramanathan, Alfredo Menendez
In addition to their chemical antimicrobial nature, bile acids (BA) are thought to have other functions in the homeostatic control of gastrointestinal immunity. However, those functions have remained largely undefined. In this work, we used ileal explants and mouse models of BA administration to investigate the role of BA in the regulation of the intestinal antimicrobial response. Mice fed on a diet supplemented with 0.1% chenodeoxycholic acid (CDCA) showed an upregulated expression of Paneth cell α-defensins as well as an increased synthesis of the type-C lectins Reg3b and Reg3g by the ileal epithelium...
March 27, 2017: Infection and Immunity
https://www.readbyqxmd.com/read/28341659/chronic-microaspiration-of-bile-acids-induces-lung-fibrosis-through-multiple-mechanisms-in-rats
#19
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/28324023/long-chain-free-fatty-acid-receptor-gpr120-mediates-oil-induced-gip-secretion-through-cck-in-male-mice
#20
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
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