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https://www.readbyqxmd.com/read/29771182/ciliogenesis-is-reciprocally-regulated-by-ppara-and-nr1h4-fxr-through-controlling-autophagy-in-vitro-and-in-vivo
#1
Zhi-Qiang Liu, Joon No Lee, Myeongjoo Son, Jae-Young Lim, Raghbendra Kumar Dutta, Yunash Maharjan, SeongAe Kwak, Goo Taeg Oh, Kyunghee Byun, Seong-Kyu Choe, Raekil Park
The primary cilia are evolutionarily conserved microtubule-based cellular organelles that perceive metabolic status and thus link the sensory system to cellular signaling pathways. Therefore, ciliogenesis is thought to be tightly linked to autophagy, which is also regulated by nutrient-sensing transcription factors, such as PPARA (peroxisome proliferator activated receptor alpha) and NR1H4/FXR (nuclear receptor subfamily 1, group H, member 4). However, the relationship between these factors and ciliogenesis has not been clearly demonstrated...
May 17, 2018: Autophagy
https://www.readbyqxmd.com/read/29743187/the-effects-of-farnesoid-x-receptor-activation-on-arachidonic-acid-metabolism-nf-kb-signaling-and-hepatic-inflammation
#2
Zhibo Gai, Michele Visentin, Ting Gui, Lin Zhao, Wolfgang E Thasler, Stephanie Hausler, Ivan Hartling, Alessio Cremonesi, Christian Hiller, Gerd A Kullak-Ublick
Inflammation has a recognized role in non-alcoholic fatty liver disease (NAFLD) progression. The present work studied the effect of high fat diet (HFD) on arachidonic acid metabolism in the liver and investigated the role of the farnesoid X receptor (FXR, NR1H4) in eicosanoid biosynthetic pathways and NF-kB signaling, major modulators of the inflammatory cascade. Mice were fed a HFD to induce NAFLD, then, treated with the FXR ligand obeticholic acid (OCA). Histology and gene expression analysis were performed on liver tissue...
May 9, 2018: Molecular Pharmacology
https://www.readbyqxmd.com/read/29718219/xenobiotic-nuclear-receptor-signaling-determines-molecular-pathogenesis-of-progressive-familial-intrahepatic-cholestasis
#3
Kang Ho Kim, Jong Min Choi, Feng Li, Armando Arizpe, Clavia Ruth Wooton-Kee, Sayeepriyadarshini Anakk, Sung Yun Jung, Milton J Finegold, David D Moore
Progressive familial intrahepatic cholestasis (PFIC) is a genetically heterogeneous disorder of bile flow disruption due to abnormal canalicular transport or impaired bile acid (BA) metabolism, causing excess BA accumulation and liver failure. We reported an intrahepatic cholestasis mouse model based on loss of function of both farnesoid X receptor (FXR; NR1H4) and small heterodimer partner (SHP, NR0B2) (DKO), which has strong similarities to human PFIC type 5. Here, we compare the pathogenesis of the DKO liver to that of another intrahepatic cholestasis model, Bsep-/-, which represents human PFIC2...
April 26, 2018: Endocrinology
https://www.readbyqxmd.com/read/29177335/molecular-actions-of-hypocholesterolaemic-compounds-from-edible-mushrooms
#4
REVIEW
Alicia Gil-Ramírez, Diego Morales, Cristina Soler-Rivas
Cholesterol levels are strictly regulated to maintain its homeostasis; therefore, if it is not absorbed with the diet, the cholesterol biosynthetic pathway is enhanced and vice versa. Nowadays, the commonly prescribed therapeutic treatments for hypocholesterolemic patients are targeted toward the reduction of both cholesterol intestinal absorption and/or its endogenous biosynthesis. But, when hypercholesterolemia is still moderate the consumption of food products with cholesterol-lowering capacities is more desirable than using drugs...
January 24, 2018: Food & Function
https://www.readbyqxmd.com/read/29100332/the-farnesoid-x-receptor-negatively-regulates-osteoclastogenesis-in-bone-remodeling-and-pathological-bone-loss
#5
Ting Zheng, Ju-Hee Kang, Jung-Sun Sim, Jung-Woo Kim, Jeong-Tae Koh, Chan Soo Shin, Hyungsik Lim, Mijung Yim
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...
September 29, 2017: Oncotarget
https://www.readbyqxmd.com/read/28951211/microrna-194-inhibition-improves-dietary-induced-non-alcoholic-fatty-liver-disease-in-mice-through-targeting-on-fxr
#6
Hezhongrong Nie, Chunli Song, Daming Wang, Shengjin Cui, Tingyu Ren, Zhaopeng Cao, Qing Liu, Zeyan Chen, Xiaoyong Chen, Yiwen Zhou
Non-alcoholic fatty liver disease (NAFLD) affects obesity-associated metabolic syndrome, which exhibits hepatic steatosis, insulin insensitivity and glucose intolerance. Previous studies indicated that hepatic microRNAs (miRs) play critical roles in the development of NAFLD. In this study, we aim to explore the pathophysiological role of miR-194 in obesity-mediated metabolic dysfunction. Our findings show that the high fat diet or palmitic acid treatment significantly increase hepatic miR-194 levels in vivo and in vitro...
September 22, 2017: Biochimica et Biophysica Acta
https://www.readbyqxmd.com/read/28935756/perinatal-hypercholesterolemia-exacerbates-atherosclerosis-lesions-in-offspring-by-altering-metabolism-of-trimethylamine-n-oxide-and-bile-acids
#7
Charlotte Trenteseaux, Anh-Thu Gaston, Audrey Aguesse, Guillaume Poupeau, Pierre de Coppet, Ramaroson Andriantsitohaina, Jamila Laschet, Valérie Amarger, Michel Krempf, Estelle Nobecourt-Dupuy, Khadija Ouguerram
OBJECTIVE: Experimental studies suggest that maternal hypercholesterolemia may be relevant for the early onset of cardiovascular disease in offspring. We investigated the effect of perinatal hypercholesterolemia on the atherosclerosis development in the offspring of apolipoprotein E-deficient mice and the underlying mechanism. APPROACH AND RESULTS: Atherosclerosis and related parameters were studied in adult male or female apolipoprotein E-deficient mice offspring from either normocholesterolemic or hypercholesterolemic mothers and normocholesterolemic fathers...
November 2017: Arteriosclerosis, Thrombosis, and Vascular Biology
https://www.readbyqxmd.com/read/28692147/persisting-hyperbilirubinemia-in-patients-with-paroxysmal-nocturnal-hemoglobinuria-pnh-chronically-treated-with-eculizumab-the-role-of-hepatocanalicular-transporter-variants
#8
Ferras Alashkar, Susanne N Weber, Colin Vance, Dörte Herich-Terhürne, Ulrich Dührsen, Frank Lammert, Alexander Röth
BACKGROUND: Eculizumab-treated paroxysmal nocturnal hemoglobinuria (PNH) patients (pts) show a dramatic decrease in serum lactate dehydrogenase (LDH) activities and bilirubin concentrations. However, some pts remain hyperbilirubinemic, possibly indicating an inadequate response due to extravascular hemolysis. METHODS: Mutation analyses of hepatocanalicular transporter/nuclear receptor variants (ABCB4, ABCB11, ATP8B1, NR1H4) were performed in eight (five of eight males; mean age 38 years [range 26-68 years]) out of the 174 pts with PNH/-clone at our department due to a persistent increase in total bilirubin concentrations (median 3...
October 2017: European Journal of Haematology
https://www.readbyqxmd.com/read/28507058/hepatocyte-nuclear-factor-1-%C3%AE-regulates-urinary-concentration-and-response-to-hypertonicity
#9
Karam Aboudehen, Lama Noureddine, Patricia Cobo-Stark, Svetlana Avdulov, Shayan Farahani, Micah D Gearhart, Daniel G Bichet, Marco Pontoglio, Vishal Patel, Peter Igarashi
The transcription factor hepatocyte nuclear factor-1 β (HNF-1 β ) is essential for normal kidney development and function. Inactivation of HNF-1 β in mouse kidney tubules leads to early-onset cyst formation and postnatal lethality. Here, we used Pkhd1/Cre mice to delete HNF-1 β specifically in renal collecting ducts (CDs). CD-specific HNF-1 β mutant mice survived long term and developed slowly progressive cystic kidney disease, renal fibrosis, and hydronephrosis. Compared with wild-type littermates, HNF-1 β mutant mice exhibited polyuria and polydipsia...
October 2017: Journal of the American Society of Nephrology: JASN
https://www.readbyqxmd.com/read/28400425/the-logic-of-transcriptional-regulator-recruitment-architecture-at-cis-regulatory-modules-controlling-liver-functions
#10
Julie Dubois-Chevalier, Vanessa Dubois, Hélène Dehondt, Parisa Mazrooei, Claire Mazuy, Aurélien A Sérandour, Céline Gheeraert, Penderia Guillaume, 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 (TRs). However, how recruitment of a myriad of TRs is orchestrated at cis -regulatory modules (CRMs) to account for coregulation of specific biological pathways is only partially understood. Here, we have used mouse liver CRMs 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 (TRMs), which consist of subsets of preferentially and coordinately corecruited TRs, assemble into hierarchical combinations at hepatic CRMs...
June 2017: Genome Research
https://www.readbyqxmd.com/read/28378930/hepatic-fxr-shp-axis-modulates-systemic-glucose-and-fatty-acid-homeostasis-in-aged-mice
#11
COMPARATIVE STUDY
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 double knockout of 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 mice fully phenocopied the DKO mice, with lower hepatic triglyceride accumulation, improved glucose/insulin tolerance, and accelerated fatty acid use...
August 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
https://www.readbyqxmd.com/read/28351411/activation-of-fxr-pathway-does-not-alter-glial-cell-function
#12
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/28287408/nutrient-sensing-nuclear-receptors-ppar%C3%AE-and-fxr-control-liver-energy-balance
#13
REVIEW
Geoffrey A Preidis, Kang Ho Kim, David D Moore
The nuclear receptors PPARα (encoded by NR1C1) and farnesoid X receptor (FXR, encoded by NR1H4) are activated in the liver in the fasted and fed state, respectively. PPARα activation induces fatty acid oxidation, while FXR controls bile acid homeostasis, but both nuclear receptors also regulate numerous other metabolic pathways relevant to liver energy balance. Here we review evidence that they function coordinately to control key nutrient pathways, including fatty acid oxidation and gluconeogenesis in the fasted state and lipogenesis and glycolysis in the fed state...
April 3, 2017: Journal of Clinical Investigation
https://www.readbyqxmd.com/read/28130067/farnesoid-x-receptor-activation-promotes-hepatic-amino-acid-catabolism-and-ammonium-clearance-in-mice
#14
Vittoria Massafra, Alexandra Milona, Harmjan R Vos, Rúben J J Ramos, Johan Gerrits, Ellen C L Willemsen, José M Ramos Pittol, Noortje Ijssennagger, Martin Houweling, Hubertus C M T Prinsen, Nanda M Verhoeven-Duif, Boudewijn M T Burgering, Saskia W C van Mil
BACKGROUND & AIMS: The nuclear receptor subfamily 1 group H member 4 (NR1H4 or farnesoid X receptor [FXR]) regulates bile acid synthesis, transport, and catabolism. FXR also regulates postprandial lipid and glucose metabolism. We performed quantitative proteomic analyses of liver tissues from mice to evaluate these functions and investigate whether FXR regulates amino acid metabolism. METHODS: To study the role of FXR in mouse liver, we used mice with a disruption of Nr1h4 (FXR-knockout mice) and compared them with floxed control mice...
May 2017: Gastroenterology
https://www.readbyqxmd.com/read/27557342/effects-of-polymorphisms-in-nr1h4-nr1i2-slco1b1-and-abcg2-on-the-pharmacokinetics-of-rosuvastatin-in-healthy-chinese-volunteers
#15
Mei Liu, Xiu-Jun Wu, Gui-Lian Zhao, Ti Zhang, Shan-Sen Xu, Ya-Xin Sun, Feng Qiu, Li-Mei Zhao
The nuclear receptors (NR)-farnesoid X receptor (FXR, NR1H4) and pregnane X receptor (PXR, NR1I2)-have important effects on the expression of genes related to the pharmacokinetics (PKs) of rosuvastatin. This study was designed to investigate whether the genetic variants in drug disposition genes (SLCO1B1 and ABCG2) combined with their upstream regulators (NR1H4 and NR1I2) would affect the PKs of rosuvastatin in a Chinese population. Sixty-one healthy male volunteers were enrolled and the plasma concentrations of rosuvastatin were measured using the liquid chromatographic-tandem mass spectrometry/MS method...
November 2016: Journal of Cardiovascular Pharmacology
https://www.readbyqxmd.com/read/27383204/the-farnesoid-x-receptor-in-myeloid-cells-controls-cns-autoimmunity-in-an-il-10-dependent-fashion
#16
Stephanie Hucke, Martin Herold, Marie Liebmann, Nicole Freise, Maren Lindner, Ann-Katrin Fleck, Stefanie Zenker, Stephanie Thiebes, Juncal Fernandez-Orth, Dorothea Buck, Felix Luessi, Sven G Meuth, Frauke Zipp, Bernhard Hemmer, Daniel Robert Engel, Johannes Roth, Tanja Kuhlmann, Heinz Wiendl, Luisa Klotz
Innate immune responses by myeloid cells decisively contribute to perpetuation of central nervous system (CNS) autoimmunity and their pharmacologic modulation represents a promising strategy to prevent disease progression in Multiple Sclerosis (MS). Based on our observation that peripheral immune cells from relapsing-remitting and primary progressive MS patients exhibited strongly decreased levels of the bile acid receptor FXR (farnesoid-X-receptor, NR1H4), we evaluated its potential relevance as therapeutic target for control of established CNS autoimmunity...
September 2016: Acta Neuropathologica
https://www.readbyqxmd.com/read/27079614/microrna-192-suppresses-the-expression-of-the-farnesoid-x-receptor
#17
Regina Krattinger, Adrian Boström, Helgi B Schiöth, Wolfgang E Thasler, Jessica Mwinyi, Gerd A Kullak-Ublick
Farnesoid X receptor (FXR, NR1H4) plays an important role in the regulation of bile acid homeostasis in liver and intestine and may exert protective effects against certain forms of cancer such as colon carcinoma. However, the role of FXR in cell growth regulation, apoptosis, and carcinogenesis is still controversial. Similar to FXR, microRNA-192 (miR-192) is mainly expressed in the liver and colon and plays an important role in the pathogenesis of colon carcinoma. In this study, we investigated the extent to which FXR is regulated by miR-192...
June 1, 2016: American Journal of Physiology. Gastrointestinal and Liver Physiology
https://www.readbyqxmd.com/read/26946349/phenotypic-and-biomarker-evaluation-of-zebrafish-larvae-as-an-alternative-model-to-predict-mammalian-hepatotoxicity
#18
Sandra Verstraelen, Bernard Peers, Walid Maho, Karen Hollanders, Sylvie Remy, Pascale Berckmans, Adrian Covaci, Hilda Witters
Zebrafish phenotypic assays have shown promise to assess human hepatotoxicity, though scoring of liver morphology remains subjective and difficult to standardize. Liver toxicity in zebrafish larvae at 5 days was assessed using gene expression as the biomarker approach, complementary to phenotypic analysis and analytical data on compound uptake. This approach aimed to contribute to improved hepatotoxicity prediction, with the goal of identifying biomarker(s) as a step towards the development of transgenic models for prioritization...
September 2016: Journal of Applied Toxicology: JAT
https://www.readbyqxmd.com/read/26888176/mutations-in-the-nuclear-bile-acid-receptor-fxr-cause-progressive-familial-intrahepatic-cholestasis
#19
Natalia Gomez-Ospina, Carol J Potter, Rui Xiao, Kandamurugu Manickam, Mi-Sun Kim, Kang Ho Kim, Benjamin L Shneider, Jennifer L Picarsic, Theodora A Jacobson, Jing Zhang, Weimin He, Pengfei Liu, A S Knisely, Milton J Finegold, Donna M Muzny, Eric Boerwinkle, James R Lupski, Sharon E Plon, Richard A Gibbs, Christine M Eng, Yaping Yang, Gabriel C Washington, Matthew H Porteus, William E Berquist, Neeraja Kambham, Ravinder J Singh, Fan Xia, Gregory M Enns, David D Moore
Neonatal cholestasis is a potentially life-threatening condition requiring prompt diagnosis. Mutations in several different genes can cause progressive familial intrahepatic cholestasis, but known genes cannot account for all familial cases. Here we report four individuals from two unrelated families with neonatal cholestasis and mutations in NR1H4, which encodes the farnesoid X receptor (FXR), a bile acid-activated nuclear hormone receptor that regulates bile acid metabolism. Clinical features of severe, persistent NR1H4-related cholestasis include neonatal onset with rapid progression to end-stage liver disease, vitamin K-independent coagulopathy, low-to-normal serum gamma-glutamyl transferase activity, elevated serum alpha-fetoprotein and undetectable liver bile salt export pump (ABCB11) expression...
February 18, 2016: Nature Communications
https://www.readbyqxmd.com/read/26878262/recent-progress-on-bile-acid-receptor-modulators-for-treatment-of-metabolic-diseases
#20
Yanping Xu
Bile acids are steroid-derived molecules synthesized in the liver, secreted from hepatocytes into the bile canaliculi, and subsequently stored in the gall bladder. During the feeding, bile flows into the duodenum, where it contributes to the solubilization and digestion of lipid-soluble nutrients. After a meal, bile-acid levels increase in the intestine, liver, and also in the systemic circulation. Therefore, serum bile-acid levels serve as an important sensing mechanism for nutrient and energy. Recent studies have described bile acids as versatile signaling molecules endowed with systemic endocrine functions...
July 28, 2016: Journal of Medicinal Chemistry
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