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Ursula J Lemberger, Claudia Fuchs, Matthias Karer, Stefanie Haas, Tatjana Stojakovic, Christian Schöfer, Hanns-Ulrich Marschall, Fritz Wrba, Makoto M Taketo, Gerda Egger, Michael Trauner, Christoph H Österreicher
BACKGROUND: The Wnt/β-catenin signaling pathway plays a crucial role in embryonic development, tissue homeostasis, wound healing and malignant transformation in different organs including the liver. The consequences of continuous β-catenin signaling in hepatocytes remain elusive. RESULTS: Livers of Ctnnb1CA hep mice were characterized by disturbed liver architecture, proliferating cholangiocytes and biliary type of fibrosis. Serum ALT and bile acid levels were significantly increased in Ctnnb1CA hep mice...
November 23, 2016: Oncotarget
Edwin C Y Chow, Holly P Quach, Yueping Zhang, Jason Z Y Wang, David C Evan, Albert P Li, Jose Silva, Rommel G Tirona, Yurong Lai, K Sandy Pang
The humanized liver mouse model is increasingly being exploited for human drug metabolism studies. However, its model stability, inter-communication between human hepatocytes and mouse non-parenchymal cells in liver and murine intestine, and changes in extrahepatic transporter and enzyme expression has not been investigated. We examined these issues in FRGN [Fah(-/-), Rag2(-/-), and IL-2rg(-/-) on NOD background] and chimeric mice: mFRGN, and hFRGN (repopulated with mouse or human hepatocytes, respectively)...
October 27, 2016: Journal of Pharmacology and Experimental Therapeutics
Supriya R Kulkarni, Carol J Soroka, Lee R Hagey, James L Boyer
: Sirtuin1 (Sirt1; mammalian homolog of Saccharomyces cerevisiae enzyme Sir2) is a transcriptional and transactivational regulator of murine farnesoid X receptor (Fxr), which is the primary bile acid (BA) sensor, and critical regulator of BA metabolism in physiological and pathophysiological conditions. Previous studies have suggested compromised Sirt1 expression in rodent models of cholestatic liver injury. We hypothesized that Sirt1 could be potentially targeted to alleviate cholestatic liver injury...
December 2016: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Jamie E Moscovitz, Bo Kong, Kyle Buckley, Brian Buckley, Grace L Guo, Lauren M Aleksunes
The farnesoid X receptor (Fxr) controls bile acid homeostasis by coordinately regulating the expression of synthesizing enzymes (Cyp7a1, Cyp8b1), conjugating enzymes (Bal, Baat) and transporters in the ileum (Asbt, Ostα/β) and liver (Ntcp, Bsep, Ostβ). Transcriptional regulation by Fxr can be direct, or through the ileal Fgf15/FGF19 and hepatic Shp pathways. Circulating bile acids are increased during pregnancy due to hormone-mediated disruption of Fxr signaling. While this adaptation enhances lipid absorption, elevated bile acids may predispose women to develop maternal cholestasis...
November 1, 2016: Toxicology and Applied Pharmacology
Monika Rau, Bruno Stieger, Maria J Monte, Johannes Schmitt, Daniel Jahn, Isabelle Frey-Wagner, Tina Raselli, Jose J G Marin, Beat Müllhaupt, Gerhard Rogler, Andreas Geier
BACKGROUND: Fibroblast growth factor (FGF) 15/19 is part of the gut-liver crosstalk accounting for bile acid (BA) metabolism regulation. Dysregulation of fibroblast growth factor 15/19 signaling is observed in different pathological conditions, for example, in gastrointestinal diseases such as inflammatory bowel disease (IBD). To understand the molecular bases, we analyzed the enterohepatic regulation of Fgf15-mediated pathway in 2 different inflammatory bowel disease mouse models. METHODS: Target genes of the BA-farnesoid-X-receptor (Fxr)-Ffg15 axis were quantified by RT-PCR or western blotting in gut and liver of dextran sulfate sodium (DSS)-treated and IL10 mice...
October 2016: Inflammatory Bowel Diseases
Ming-liang Chen, Long Yi, Yong Zhang, Xi Zhou, Li Ran, Jining Yang, Jun-dong Zhu, Qian-yong Zhang, Man-tian Mi
UNLABELLED: The gut microbiota is found to be strongly associated with atherosclerosis (AS). Resveratrol (RSV) is a natural phytoalexin with anti-AS effects; however, its mechanisms of action remain unclear. Therefore, we sought to determine whether the anti-AS effects of RSV were related to changes in the gut microbiota. We found that RSV attenuated trimethylamine-N-oxide (TMAO)-induced AS in ApoE(-/-) mice. Meanwhile, RSV decreased TMAO levels by inhibiting commensal microbial trimethylamine (TMA) production via gut microbiota remodeling in mice...
2016: MBio
Bobae Kim, Kun-Young Park, Yosep Ji, Soyoung Park, Wilhelm Holzapfel, Chang-Kee Hyun
Recent reports suggest that gut microbiota can be a major determinant of dyslipidemia and non-alcoholic fatty liver disease (NAFLD) and its modulation by treating probiotics is a valid strategy to exert a protective effect. In this study, high-fat diet (HFD)-fed mice were orally administrated with Lactobacillus rhamnosus GG (LGG) for 13 weeks. Significant reductions in the weights of the liver, mesenteric and subcutaneous adipose tissues were observed in LGG-treated HFD-fed mice compared to LGG-non-treated controls...
April 29, 2016: Biochemical and Biophysical Research Communications
Daniel Jahn, Dominic Sutor, Donata Dorbath, Johannes Weiß, Oliver Götze, Johannes Schmitt, Heike M Hermanns, Andreas Geier
Fibroblast growth factor 19 (FGF19) is a gut-derived hormone that controls bile acid (BA), carbohydrate and lipid metabolism. Whereas strong evidence supports a key role of BAs and farnesoid X receptor (FXR) for the control of FGF19 expression, information on other regulators is limited. In mice, FGF15 expression (ortholog of human FGF19) is induced by vitamin A (VitA) in an FXR-dependent manner. However, the significance of this finding for human FGF19 is currently unclear. Here, we demonstrate that VitA derivatives induce FGF19 in human intestinal cell lines by a direct transcriptional mechanism...
February 2016: Biochimica et Biophysica Acta
Rebecca M Heidker, Gianella C Caiozzi, Marie-Louise Ricketts
SCOPE: Understanding the molecular basis by which dietary procyanidins modulate triglyceride and cholesterol homeostasis has important implications for the use of natural products in the treatment and prevention of cardiovascular disease. METHODS: To determine whether modulation of bile acid (BA) homeostasis contributes to the hypotriglyceridemic action of grape seed procyanidin extract (GSPE) we examined the effect on genes regulating BA absorption, transport and synthesis in vitro, in Caco-2 cells, and in vivo, in wild type (C57BL/6) and farnesoid x receptor knockout (Fxr(-/-)) mice...
April 2016: Molecular Nutrition & Food Research
Ting Fu, Young-Chae Kim, Sangwon Byun, Dong-Hyun Kim, Sunmi Seok, Kelly Suino-Powell, H Eric Xu, Byron Kemper, Jongsook Kim Kemper
The bile acid (BA)-sensing nuclear receptor, farnesoid X receptor (FXR), regulates postprandial metabolic responses, including inhibition of BA synthesis, by inducing the intestinal hormone, fibroblast growth factor (FGF)15 (FGF19 in human). In this study, we tested a novel hypothesis that FXR not only induces intestinal FGF15 but also primes the liver for effectively responding to the signal by transcriptional induction of the obligate coreceptor for FGF15, β-Klotho (βKL). Activation of FXR by a synthetic agonist, GW4064, in mice increased occupancy of FXR and its DNA-binding partner, retinoid X receptor-α, at FGF15-signaling component genes, particularly βKL, and induced expression of these genes...
January 2016: Molecular Endocrinology
Charles Robb Flynn, Vance L Albaugh, Steven Cai, Joyce Cheung-Flynn, Phillip E Williams, Robert M Brucker, Seth R Bordenstein, Yan Guo, David H Wasserman, Naji N Abumrad
Roux-en-Y gastric bypass (RYGB) is highly effective in reversing obesity and associated diabetes. Recent observations in humans suggest a contributing role of increased circulating bile acids in mediating such effects. Here we use a diet-induced obesity (DIO) mouse model and compare metabolic remission when bile flow is diverted through a gallbladder anastomosis to jejunum, ileum or duodenum (sham control). We find that only bile diversion to the ileum results in physiologic changes similar to RYGB, including sustained improvements in weight, glucose tolerance and hepatic steatosis despite differential effects on hepatic gene expression...
2015: Nature Communications
Makoto Shimizu, Hitomi Morimoto, Ryuto Maruyama, Jun Inoue, Ryuichiro Sato
Fibroblast growth factor 19 (FGF19) and FGF21 are members of a subfamily of the FGFs called endocrine FGFs. FGF19 regulates the bile acid synthetic pathway. FGF19 expression is induced by farnesoid X receptor (FXR), a nuclear hormone receptor activated by bile acids in the small intestine. FGF21 plays an important role in lipolysis that occurs in white adipose tissue. FGF21 expression is stimulated by the nuclear fatty acid receptor peroxisome proliferator-activated receptor α (PPARα) in the liver. FGF19 and FGF21 were recently identified as targets of activating transcription factor 4 (ATF4), which is activated in response to endoplasmic reticulum (ER) stress...
2015: Journal of Nutritional Science and Vitaminology
Steven A Kliewer, David J Mangelsdorf
While it has long been recognized that bile acids are essential for solubilizing lipophilic nutrients in the small intestine, the discovery in 1999 that bile acids serve as ligands for the nuclear receptor farnesoid X receptor (FXR) opened the floodgates in terms of characterizing their actions as selective signaling molecules. Bile acids act on FXR in ileal enterocytes to induce the expression of fibroblast growth factor (FGF)15/19, an atypical FGF that functions as a hormone. FGF15/19 subsequently acts on a cell surface receptor complex in hepatocytes to repress bile acid synthesis and gluconeogenesis, and to stimulate glycogen and protein synthesis...
2015: Digestive Diseases
Takeshi Katafuchi, Daria Esterházy, Andrew Lemoff, Xunshan Ding, Varun Sondhi, Steven A Kliewer, Hamid Mirzaei, David J Mangelsdorf
Fibroblast growth factor 15 (FGF15) has been proposed as a postprandial hormone that signals from intestine to liver to regulate bile acid and carbohydrate homeostasis. However, detecting FGF15 in blood using conventional techniques has proven difficult. Here, we describe a stable isotope standards and capture by anti-peptide antibodies (SISCAPA) assay that combines immuno-enrichment with selected reaction monitoring (SRM) mass spectrometry to overcome this issue. Using this assay, we show that FGF15 circulates in plasma in an FXR and circadian rhythm-dependent manner at concentrations that activate its receptor...
June 2, 2015: Cell Metabolism
Reija Silvennoinen, Helena Quesada, Ilona Kareinen, Josep Julve, Leena Kaipiainen, Helena Gylling, Francisco Blanco-Vaca, Joan Carles Escola-Gil, Petri T Kovanen, Miriam Lee-Rueckert
Psychological stress is a risk factor for atherosclerosis, yet the pathophysiological mechanisms involved remain elusive. The transfer of cholesterol from macrophage foam cells to liver and feces (the macrophage-specific reverse cholesterol transport, m-RCT) is an important antiatherogenic pathway. Because exposure of mice to physical restraint, a model of psychological stress, increases serum levels of corticosterone, and as bile acid homeostasis is disrupted in glucocorticoid-treated animals, we investigated if chronic intermittent restraint stress would modify m-RCT by altering the enterohepatic circulation of bile acids...
May 11, 2015: Physiological Reports
Li Jiao, Hongying Gan-Schreier, Sabine Tuma-Kellner, Wolfgang Stremmel, Walee Chamulitrat
Chronic bowel disease can co-exist with severe autoimmune hepatitis (AIH) in an absence of primary sclerosing cholangitis. Genetic background may contribute to this overlap syndrome. We previously have shown that the deficiency of iPLA2β causes an accumulation of hepatocyte apoptosis, and renders susceptibility for acute liver injury. We here tested whether AIH induction in iPLA2β-null mice could result in intestinal injury, and whether bile acid metabolism was altered. Control wild-type (WT) and female iPLA2β-null (iPLA2β(-/-)) mice were intravenously injected with 10mg/kg concanavalinA (ConA) or saline for 24h...
August 2015: Biochimica et Biophysica Acta
Hyunsook Kim, Dong-Hyeon Kim, Kun-Ho Seo, Jung-Whan Chon, Seung-Yeol Nah, Glenn E Bartley, Torey Arvik, Rebecca Lipson, Wallace Yokoyama
The relationship between the intestinal microbiota and the hypocholesterolemic and antiobesity effects of whole grape seed flour from white and red winemaking was evaluated. Male Golden Syrian hamsters were fed a high-fat (HF) control diet or a HF diet supplemented with 10% partially defatted grape seed flours from either Chardonnay (ChrSd) or Cabernet Sauvignon (CabSd) grapes for 3 weeks. The numbers of total bacteria and relative abundances of Bifidobacterium spp., Lactobacillus spp., and Firmicutes in feces were significantly lower, while the relative abundance of Bacteroides fragilis was greater than the control from feeding the ChrSd diet...
February 11, 2015: Journal of Agricultural and Food Chemistry
Peizhen Song, Cheryl E Rockwell, Julia Yue Cui, Curtis D Klaassen
Bile acids (BAs) are known to regulate BA synthesis and transport by the farnesoid X receptor in the liver (FXR-SHP) and intestine (FXR-Fgf15). However, the relative importance of individual BAs in regulating these processes is not known. Therefore, mice were fed various doses of five individual BAs, including cholic acid (CA), chenodeoxycholic acid (CDCA), deoxoycholic acid (DCA), lithocholic acid (LCA), and ursodeoxycholic acid (UDCA) in their diets at various concentrations for one week to increase the concentration of one BA in the enterohepatic circulation...
February 15, 2015: Toxicology and Applied Pharmacology
Sungsoon Fang, Jae Myoung Suh, Shannon M Reilly, Elizabeth Yu, Olivia Osborn, Denise Lackey, Eiji Yoshihara, Alessia Perino, Sandra Jacinto, Yelizaveta Lukasheva, Annette R Atkins, Alexander Khvat, Bernd Schnabl, Ruth T Yu, David A Brenner, Sally Coulter, Christopher Liddle, Kristina Schoonjans, Jerrold M Olefsky, Alan R Saltiel, Michael Downes, Ronald M Evans
The systemic expression of the bile acid (BA) sensor farnesoid X receptor (FXR) has led to promising new therapies targeting cholesterol metabolism, triglyceride production, hepatic steatosis and biliary cholestasis. In contrast to systemic therapy, bile acid release during a meal selectively activates intestinal FXR. By mimicking this tissue-selective effect, the gut-restricted FXR agonist fexaramine (Fex) robustly induces enteric fibroblast growth factor 15 (FGF15), leading to alterations in BA composition, but does so without activating FXR target genes in the liver...
February 2015: Nature Medicine
Shuangwei Li, Andrew Ni, Gen-sheng Feng
Bile acids (BAs) are traditionally considered as "physiological detergents" for emulsifying hydrophobic lipids and vitamins due to their amphipathic nature. But accumulating clinical and experimental evidence shows an association between disrupted BA homeostasis and various liver disease conditions including hepatitis infection, diabetes and cancer. Consequently, BA homeostasis regulation has become a field of heavy interest and investigation. After identification of the Farnesoid X Receptor (FXR) as an endogenous receptor for BAs, several nuclear receptors (SHP, HNF4α, and LRH-1) were also found to be important in regulation of BA homeostasis...
January 2015: Acta Pharmacologica Sinica
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