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Cyndya A Shibao, Jorge E Celedonio, Robyn Tamboli, Reem Sidani, Latisha Love-Gregory, Terri Pietka, Yanhua Xiong, Yan Wei, Naji N Abumrad, Nada A Abumrad, Charles Robb Flynn
Context: Abnormal fatty acid (FA) metabolism contributes to diabetes and cardiovascular disease. The FA receptor CD36 has been linked to risk of metabolic syndrome. In rodents CD36 regulates various aspects of fat metabolism but whether it has similar actions in humans is unknown. We examined impact of a coding single-nucleotide polymorphism in CD36 on post-prandial hormone and bile acid (BA) responses. Objective: To examine if the minor allele (G) of coding CD36 variant rs3211938 (G/T) which reduces CD36 level by approximately 50% influences hormonal responses to a high-fat meal (HFM)...
March 12, 2018: Journal of Clinical Endocrinology and Metabolism
Stephen A Harrison, Mary E Rinella, Manal F Abdelmalek, James F Trotter, Angelo H Paredes, Hays L Arnold, Marcelo Kugelmas, Mustafa R Bashir, Mark J Jaros, Lei Ling, Stephen J Rossi, Alex M DePaoli, Rohit Loomba
BACKGROUND: Non-alcoholic steatohepatitis is a chronic liver disease characterised by the presence of hepatic steatosis, inflammation, and hepatocellular injury, for which no Food and Drug Administration (FDA)-approved treatment exists. FGF19 is a hormone that regulates bile acid synthesis and glucose homoeostasis. We aimed to assess the safety and efficacy of NGM282, an engineered FGF19 analogue, for the treatment of non-alcoholic steatohepatitis. METHODS: In this randomised, double-blind, placebo-controlled, phase 2 study, we recruited patients aged 18-75 years with biopsy-confirmed non-alcoholic steatohepatitis as defined by the non-alcoholic steatohepatitis clinical research network histological scoring system, from hospitals and gastroenterology and liver clinics in Australia and the USA...
March 5, 2018: Lancet
Hanliang He, Chunqing Wang, Qifeng Tang, Fan Yang, Youjia Xu
Estrogen can affect the cartilage development of zebrafish; however, the mechanism underlying its effects is not completely understood. Four-day-old zebrafish larvae were treated with 0.8 μM estrogen, the 5 days post fertilization (dpf) zebrafish larvae did not demonstrate obvious abnormalities during development; however, the 6 dpf and 7 dpf larvae exhibited abnormal craniofacial bone development along with craniofacial bone degradation. RNA deep sequencing was performed to elucidate the mechanism involved...
February 27, 2018: Toxicology Letters
Qiang Li, Qiang Zhao, Chuanzhao Zhang, Peng Zhang, Anbin Hu, Longjuan Zhang, Paul M Schroder, Yi Ma, Zhiyong Guo, Xiaofeng Zhu, Xiaoshun He
Fibroblast growth factor (FGF) has been considered to modulate liver regeneration (LR) after partial hepatectomy (PH) at the tissue level. Previous studies have demonstrated that FGF15 and FGF19 induce the activation of its receptor, FGF receptor 4 (FGFR4), which can promote hepatocellular carcinoma progression and regulate liver lipid metabolism. In this study, we aimed to explore the role of the ileal FGF15/19- hepatic FGFR4 axis in the LR after PH. Male C57BL/6 mice aged 8-12 weeks were partially hepatectomized and assessed for expression of ileal FGF15/19 to hepatic FGFR4 signaling...
February 22, 2018: Journal of Physiology and Biochemistry
Thomas T DeLeon, Daniel H Ahn, James M Bogenberger, Panos Z Anastasiadis, Mansi Arora, Ramesh K Ramanathan, Bashar A Aqel, George Vasmatzis, Mark J Truty, Rahmi Oklu, Tanios S Bekaii-Saab, Mitesh J Borad
Worldwide hepatobiliary cancers are the second leading cause of cancer related death. Despite their relevance, hepatobiliary cancers have a paucity of approved systemic therapy options. However, there are a number of emerging therapeutic biomarkers and therapeutic concepts that show promise. In hepatocellular carcinoma, nivolumab appears particularly promising and recently received US FDA approval. In intrahepatic cholangiocarcinoma, therapies targeting FGFR2 and IDH1 and immune checkpoint inhibitors are the furthest along and generating the most excitement...
February 20, 2018: Future Oncology
Aleix Gavaldà-Navarro, Jose J Pastor, Alessandro Mereu, Francesc Villarroya, Ignacio R Ipharraguerre
Fibroblast growth factor-19 (FGF19) is an emerging endocrine factor involved in the regulation of bile acid homeostasis and energy metabolism in rodents and humans. In pigs, however, the FGF19 system remains largely unexplored. This study was designed to investigate the developmental regulation of the FGF19 system in domestic pigs. Samples of intestinal sections, liver, and plasma were collected from 24 pigs (n = 6) at four developmental stages (birth, pre-weaning, post-weaning, and adulthood). In the intestine, expression of the farnesoid X receptor (FXR) and FGF19 showed a congruent time- and region-dependent regulation, beginning soon after birth to achieve maximal expression in ileum during adulthood...
February 15, 2018: American Journal of Physiology. Gastrointestinal and Liver Physiology
Ewelina Motylewska, Tomasz Stępień, Magdalena Borkowska, Krzysztof Kuzdak, Agnieszka Siejka, Jan Komorowski, Henryk Stępień, Hanna Ławnicka
INTRODUCTION: βKlotho (βKL) is known to act as co-receptor for fibroblast growth factor receptor 4 (FGFR4) which is the main cognate receptor for fibroblast growth factor 19 (FGF19). Dysregulation of this FGF19/FGFR4/βKL signaling axis has been implicated in the pathogenesis of several cancers. However, its role in the pathogenesis of thyroid cancer has not been determined. MATERIALS AND METHODS: The aim of this study was to assess FGF19, FGFR4 and βKL concentrations in a group of 36 patients with papillary thyroid cancer (PTC), 11 patients with follicular thyroid cancer (FTC), 9 patients with anaplastic thyroid cancer (ATC) and a group of 19 subjects with multinodular nontoxic goiter (MNG)...
February 10, 2018: Cytokine
Heiko S Schadt, Armin Wolf, Joerg Andreas Mahl, Kuno Wuersch, Philippe Couttet, Marianne Schwald, Audrey Fischer, Mathilde Lienard, Corinne Emotte, Chi-Hse Teng, Elizabeth Skuba, Terrilyn A Richardson, Luigi Manenti, Andreas Weiss, Diana Graus Porta, Robin A Fairhurst, Gerd A Kullak-Ublick, Salah-Dine Chibout, Francois Pognan, William Kluwe, Jacqueline Kinyamu-Akunda
The FGF19-FGFR4-βKlotho (KLB) pathway plays an important role in the regulation of bile acid (BA) homeostasis. Aberrant activation of this pathway has been described in the development and progression of a subset of liver cancers including hepatocellular carcinoma (HCC), establishing FGFR4 as an attractive therapeutic target for such solid tumors. FGF401 is a highly selective FGFR4 kinase inhibitor being developed for HCC, currently in Phase I/II clinical studies. In preclinical studies in mice and dogs, oral administration of FGF401 led to induction of Cyp7a1, elevation of its peripheral marker 7alpha-hydroxy-4-cholesten-3-one (C4), increased BA pool size, decreased serum cholesterol and diarrhea in dogs...
February 8, 2018: Toxicological Sciences: An Official Journal of the Society of Toxicology
Mei Zhou, R Marc Learned, Stephen J Rossi, Alex M DePaoli, Hui Tian, Lei Ling
Nonalcoholic fatty liver disease (NAFLD) is an increasingly prevalent chronic liver disease for which no approved therapies are available. Despite intensive research, the cellular mechanisms that mediate NAFLD pathogenesis and progression are poorly understood. Although obesity, diabetes, insulin resistance, and related metabolic syndrome, all consequences of a Western diet lifestyle, are well-recognized risk factors for NAFLD development, dysregulated bile acid metabolism is emerging as a novel mechanism contributing to NAFLD pathogenesis...
December 2017: Hepatology Communications
Sangwon Lee, Jungyuen Choi, Jyotidarsini Mohanty, Leiliane P Sousa, Francisco Tome, Els Pardon, Jan Steyaert, Mark A Lemmon, Irit Lax, Joseph Schlessinger
Canonical fibroblast growth factors (FGFs) activate FGF receptors (FGFRs) through paracrine or autocrine mechanisms in a process that requires cooperation with heparan sulfate proteoglycans, which function as co-receptors for FGFR activation. By contrast, endocrine FGFs (FGF19, FGF21 and FGF23) are circulating hormones that regulate critical metabolic processes in a variety of tissues. FGF19 regulates bile acid synthesis and lipogenesis, whereas FGF21 stimulates insulin sensitivity, energy expenditure and weight loss...
January 25, 2018: Nature
Gabriella Garruti, David Q-H Wang, Agostino Di Ciaula, Piero Portincasa
The gallbladder provides rhythmic secretion of concentrated bile acids (BAs) during fasting and postprandially contributes to digestion of dietary lipids. In addition, BAs activate metabolic pathways governing gluco-lipid homeostasis and energy expenditure via the farnesoid X nuclear receptor (FXR), G protein-coupled BA receptor 1 (GPBAR-1), and fibroblast growth factor 19 (FGF19) in the liver, intestine, brown fat, and muscle. Cholecystectomy is standard treatment worldwide for symptomatic gallstone patients...
January 2018: Laboratory Investigation; a Journal of Technical Methods and Pathology
Jessica M Lee, Jessica R Ong, Laurent Vergnes, Thomas Q de Aguiar Vallim, Jonathan Nolan, Rita M Cantor, Julian R F Walters, Karen Reue
Diet1 modulates intestinal production of the hormone fibroblast growth factor 15 (FGF15), which signals in liver to regulate bile acid synthesis. C57BL/6ByJ mice with a spontaneous Diet1 null mutation are resistant to hypercholesterolemia compared to wild-type C57BL/6J mice through enhanced cholesterol conversion to bile acids. To further characterize the role of Diet1 in metabolism, we generated Diet1-/- mice on the C57BL6/J genetic background. C57BL/6J Diet1-/- mice had elevated bile acid levels, reduced Fgf15 expression, and increased gastrointestinal motility and intestinal luminal water content, which are symptoms of bile acid diarrhea (BAD) in humans...
January 2, 2018: Journal of Lipid Research
Shunmei Liu, Genevieve Marcelin, Clemence Blouet, Jae Hoon Jeong, Young-Hwan Jo, Gary J Schwartz, Streamson Chua
OBJECTIVE: Bile acids have been implicated as important regulators of glucose metabolism via activation of FXR and GPBAR1. We have previously shown that FGF19 can modulate glucose handling by suppressing the activity of hypothalamic AGRP/NPY neurons. As bile acids stimulate the release of FGF19/FGF15 into the circulation, we pursued the potential of bile acids to improve glucose tolerance via a gut-brain axis involving FXR and FGF15/FGF19 within enterocytes and FGF receptors on hypothalamic AGRP/NPY neurons...
December 9, 2017: Molecular Metabolism
Jaya Julie Joshi, Heather Coffey, Erik Corcoran, Jennifer Tsai, Chia-Ling Huang, Kana Ichikawa, Sudeep Prajapati, Ming-Hong Hao, Suzanna Bailey, Jeremy Wu, Victoria Rimkunas, Craig Karr, Vanitha Subramanian, Pavan Kumar, Crystal MacKenzie, Raelene Hurley, Takashi Satoh, Kun Yu, Eunice Park, Nathalie Rioux, Amy Kim, Weidong G Lai, Lihua Yu, Ping Zhu, Silvia Buonamici, Nicholas Larsen, Peter Fekkes, John Wang, Markus Warmuth, Dominic J Reynolds, Peter G Smith, Anand Selvaraj
Activation of the fibroblast growth factor receptor FGFR4 by FGF19 drives hepatocellular carcinoma (HCC), a disease with few, if any, effective treatment options. While a number of pan-FGFR inhibitors are being clinically evaluated, their application to FGF19-driven HCC may be limited by dose-limiting toxicities mediated by FGFR1-3 receptors. To evade the potential limitations of pan-FGFR inhibitors, we generated H3B-6527, a highly selective covalent FGFR4 inhibitor, through structure-guided drug design. Studies in a panel of 40 HCC cell lines and 30 HCC PDX models showed that FGF19 expression is a predictive biomarker for H3B-6527 response...
December 15, 2017: Cancer Research
X Hu, Q Xiong, Y Xu, X Zhang, X Pan, X Ma, Y Bao, W Jia
BACKGROUND AND AIMS: Recent studies suggested that circulating fibroblast growth factor (FGF) 19 levels might be associated with the fat content and distribution, and varied with different glucose tolerance status. This study aimed to investigate the association of serum FGF19 levels with obesity and visceral fat accumulation in a Chinese population with differing glucose tolerance status. METHODS AND RESULTS: The 2383 participants were divided into subgroups of glucose tolerance status: normal glucose tolerance (NGT, n = 1754), impaired glucose regulation (IGR, n = 499), and newly diagnosed diabetes mellitus (DM, n = 130)...
February 2018: Nutrition, Metabolism, and Cardiovascular Diseases: NMCD
Kim L Mertens, Andries Kalsbeek, Maarten R Soeters, Hannah M Eggink
Bile acids are best known as detergents involved in the digestion of lipids. In addition, new data in the last decade have shown that bile acids also function as gut hormones capable of influencing metabolic processes via receptors such as FXR (farnesoid X receptor) and TGR5 (Takeda G protein-coupled receptor 5). These effects of bile acids are not restricted to the gastrointestinal tract, but can affect different tissues throughout the organism. It is still unclear whether these effects also involve signaling of bile acids to the central nervous system (CNS)...
2017: Frontiers in Neuroscience
Phillipp Hartmann, Katrin Hochrath, Angela Horvath, Peng Chen, Caroline T Seebauer, Cristina Llorente, Lirui Wang, Yazen Alnouti, Derrick E Fouts, Peter Stärkel, Rohit Loomba, Sally Coulter, Christopher Liddle, Ruth T Yu, Lei Ling, Stephen J Rossi, Alex M DePaoli, Michael Downes, Ronald M Evans, David A Brenner, Bernd Schnabl
Alcoholic liver disease is associated with changes in the intestinal microbiota. Functional consequences of alcohol-associated dysbiosis are largely unknown. The aim of this study was to identify a mechanism of how changes in the intestinal microbiota contribute to alcoholic liver disease. Metagenomic sequencing of intestinal contents demonstrated that chronic ethanol feeding in mice is associated with an overrepresentation of bacterial genomic DNA encoding choloylglycine hydrolase, which deconjugates bile acids in the intestine...
November 21, 2017: Hepatology: Official Journal of the American Association for the Study of Liver Diseases
Kenji Kozuka, Ying He, Samantha Koo-McCoy, Padmapriya Kumaraswamy, Baoming Nie, Karen Shaw, Priscilla Chan, Michael Leadbetter, Limin He, Jason G Lewis, Ziyang Zhong, Dominique Charmot, Marwan Balaa, Andrew J King, Jeremy S Caldwell, Matthew Siegel
We describe the development and characterization of a mouse and human epithelial cell monolayer platform of the small and large intestines, with a broad range of potential applications including the discovery and development of minimally systemic drug candidates. Culture conditions for each intestinal segment were optimized by correlating monolayer global gene expression with the corresponding tissue segment. The monolayers polarized, formed tight junctions, and contained a diversity of intestinal epithelial cell lineages...
November 7, 2017: Stem Cell Reports
Richard N Appleby, Jonathan D Nolan, Ian M Johnston, Sanjeev S Pattni, Jessica Fox, Julian Rf Walters
Background: Bile acid diarrhoea (BAD) is a common cause of chronic diarrhoea with a population prevalence of primary BAD around 1%. Previous studies have identified associations with low levels of the ileal hormone fibroblast growth factor 19 (FGF19), obesity and hypertriglyceridaemia. The aim of this study was to identify further associations of BAD. Methods: A cohort of patients with chronic diarrhoea who underwent 75selenohomocholic acid taurate (SeHCAT) testing for BAD was further analysed retrospectively...
2017: BMJ Open Gastroenterology
Min You, Zhou Zhou, Michael Daniels, Alvin Jogasuria
Alcoholic liver disease (ALD) is the most prevalent form of liver diseases, encompassing a spectrum of progressive pathological changes from steatosis to steatohepatitis to fibrosis/cirrhosis and hepatocellular carcinoma. Alcoholic steatosis/steatohepatitis is the initial stage of ALD and a major risk factor for advanced liver injuries. Adiponectin is a hormone secreted from adipocytes. Fibroblast growth factor (FGF) 15 (human homolog, FGF19) is an ileum-derived hormone. Adipocyte-derived adiponectin and gut-derived FGF15/19 regulate each other, share common signaling cascades and exert similar beneficial functions...
November 2, 2017: Gene Expression
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