Spontaneous hepatocarcinogenesis in farnesoid X receptor-null mice
Reads0
Chats0
TLDR
A potential role for FXR and BAs in hepatocarcinogenesis is revealed and increased cell proliferation is revealed as revealed by increased PCNA mRNA and BrdU incorporation.Abstract:
The farnesoid X receptor (FXR) controls the synthesis and transport of bile acids (BAs). Mice lacking expression of FXR, designated Fxr-null, have elevated levels of serum and hepatic BAs and an increase in BA pool size. Surprisingly, at 12 months of age, male and female Fxr-null mice had a high incidence of degenerative hepatic lesions, altered cell foci and liver tumors including hepatocellular adenoma, carcinoma and hepatocholangiocellular carcinoma, the latter of which is rarely observed in mice. At 3 months, Fxr-null mice had increased expression of the proinflammatory cytokine IL-1beta mRNA and elevated beta-catenin and its target gene c-myc. They also had increased cell proliferation as revealed by increased PCNA mRNA and BrdU incorporation. These studies reveal a potential role for FXR and BAs in hepatocarcinogenesis.read more
Citations
More filters
Journal ArticleDOI
Role of Bile Acids and Bile Acid Receptors in Metabolic Regulation
TL;DR: Results suggest that modulation of FXR activity and BA metabolism may open new attractive pharmacological approaches for the treatment of the metabolic syndrome and type 2 diabetes.
Journal ArticleDOI
Recent advances in 2D and 3D in vitro systems using primary hepatocytes, alternative hepatocyte sources and non-parenchymal liver cells and their use in investigating mechanisms of hepatotoxicity, cell signaling and ADME.
Patricio Godoy,Nicola J. Hewitt,Ute Albrecht,Melvin E. Andersen,Nariman Ansari,Sudin Bhattacharya,Johannes G. Bode,Jennifer Bolleyn,Christoph Borner,J Böttger,Albert Braeuning,Robert A. Budinsky,Britta Burkhardt,Neil R. Cameron,Giovanni Camussi,Chong Su Cho,Yun Jaie Choi,J. Craig Rowlands,Uta Dahmen,Georg Damm,Olaf Dirsch,María Teresa Donato,Jian Dong,Steven Dooley,Dirk Drasdo,Dirk Drasdo,Dirk Drasdo,Rowena Eakins,Karine Sá Ferreira,Valentina Fonsato,Joanna Fraczek,Rolf Gebhardt,Andrew Gibson,Matthias Glanemann,Christopher E. Goldring,María José Gómez-Lechón,Geny M. M. Groothuis,Lena Gustavsson,Christelle Guyot,David Hallifax,Seddik Hammad,Adam S. Hayward,Dieter Häussinger,Claus Hellerbrand,Philip Hewitt,Stefan Hoehme,Hermann-Georg Holzhütter,J. Brian Houston,Jens Hrach,Kiyomi Ito,Hartmut Jaeschke,Verena Keitel,Jens M. Kelm,B. Kevin Park,Claus Kordes,Gerd A. Kullak-Ublick,Edward L. LeCluyse,Peng Lu,Jennifer Luebke-Wheeler,Anna Lutz,Daniel J. Maltman,Madlen Matz-Soja,Patrick D. McMullen,Irmgard Merfort,Simon Messner,Christoph Meyer,Jessica Mwinyi,Dean J. Naisbitt,Andreas K. Nussler,Peter Olinga,Francesco Pampaloni,Jingbo Pi,Linda J. Pluta,Stefan Przyborski,Anup Ramachandran,Vera Rogiers,Cliff Rowe,Celine Schelcher,Kathrin Schmich,Michael Schwarz,Bijay Singh,Ernst H. K. Stelzer,Bruno Stieger,Regina Stöber,Yuichi Sugiyama,Ciro Tetta,Wolfgang E. Thasler,Tamara Vanhaecke,Mathieu Vinken,Thomas S. Weiss,Agata Widera,Courtney G. Woods,Jinghai James Xu,Kathy Yarborough,Jan G. Hengstler +94 more
TL;DR: This review encompasses the most important advances in liver functions and hepatotoxicity and analyzes which mechanisms can be studied in vitro and how closely hepatoma, stem cell and iPS cell–derived hepatocyte-like-cells resemble real hepatocytes.
Journal ArticleDOI
Bile acid receptors as targets for drug development
TL;DR: The intracellular nuclear receptor farnesoid X receptor and the transmembrane G protein-coupled receptor TGR5 respond to bile acids by activating transcriptional networks and/or signalling cascades, and hold promise to become a new class of drugs for the treatment of chronic liver disease, hepatocellular cancer and extrahepatic inflammatory and metabolic diseases.
Journal ArticleDOI
Understanding the Holobiont: How Microbial Metabolites Affect Human Health and Shape the Immune System.
Thomas S. Postler,Sankar Ghosh +1 more
TL;DR: The role of the intestinal microbiome in human metabolic and inflammatory diseases is highlighted and the molecular mechanisms that govern the gut-immune axis are focused on.
Journal ArticleDOI
Differential regulation of bile acid homeostasis by the farnesoid X receptor in liver and intestine
Insook Kim,Sung-Hoon Ahn,Takeshi Inagaki,Mihwa Choi,Shinji Ito,Grace L. Guo,Grace L. Guo,Steven A. Kliewer,Frank J. Gonzalez +8 more
TL;DR: Evidence is provided that FXR-mediated repression of bile acid synthesis requires the complementary actions of FXR in both liver and intestine and mechanistic differences in feedback repression of CYP7A1 and CYP8B1 are revealed.
References
More filters
Journal ArticleDOI
Targeted Disruption of the Nuclear Receptor FXR/BAR Impairs Bile Acid and Lipid Homeostasis
Christopher J. Sinal,Masahiro Tohkin,Masaaki Miyata,Jerrold M. Ward,Gilles Lambert,Frank J. Gonzalez +5 more
TL;DR: It is demonstrated that FXR/BAR is critical for bile acid and lipid homeostasis by virtue of its role as an intracellular bile Acid sensor.
Journal ArticleDOI
In situ detection of fragmented dna (tunel assay) fails to discriminate among apoptosis, necrosis, and autolytic cell death: A cautionary note
Bettina Grasl-Kraupp,B. Ruttkay-Nedecky,Helga Koudelka,Krystyna Bukowska,Wilfried Bursch,Rolf Schulte-Hermann +5 more
TL;DR: DNA fragmentation is common to different kinds of cell death; its detection in situ should not be considered a specific marker of apoptosis.
Journal ArticleDOI
Activation of the nuclear receptor FXR improves hyperglycemia and hyperlipidemia in diabetic mice
Yanqiao Zhang,Florence Y. Lee,Gabriel C. Barrera,Hans Lee,Charisse Vales,Frank J. Gonzalez,Timothy M. Willson,Peter A. Edwards +7 more
TL;DR: It is proposed that FXR agonists are promising therapeutic agents for treatment of diabetes mellitus because of their central roles in coordinating regulation of both glucose and lipid metabolism.
Journal ArticleDOI
Nuclear receptor-dependent bile acid signaling is required for normal liver regeneration.
Wendong Huang,Ke Ma,Jun Zhang,Mohammed Qatanani,James M. Cuvillier,Jun Liu,Bingning Dong,Xiongfei Huang,David D. Moore +8 more
TL;DR: It is proposed that FXR activation by increased bile acid flux is a signal of decreased functional capacity of the liver, and may promote homeostasis not only by regulating expression of appropriate metabolic target genes but also by driving homeotrophic liver growth.
Journal ArticleDOI
Toxic bile salts induce rodent hepatocyte apoptosis via direct activation of Fas
William A. Faubion,M. Eugenia Guicciardi,Hideyuki Miyoshi,Steven F. Bronk,Patricia J. Roberts,Phyllis A. Svingen,Scott H. Kaufmann,Gregory J. Gores +7 more
TL;DR: Data suggest that GCDC-induced hepatocyte apoptosis involves ligand-independent oligomerization of Fas, recruitment of FADD, activation of caspase 8, and subsequent activation of effector proteases, including downstream caspases and cathepsin B.