Journal ArticleDOI
Vitamin D Receptor As an Intestinal Bile Acid Sensor
Makoto Makishima,Timothy T. Lu,Wen Xie,G. Kerr Whitfield,Hideharu Domoto,Ronald M. Evans,Mark R. Haussler,David J. Mangelsdorf +7 more
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TLDR
Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine offers a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.Abstract:
The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1alpha,25-dihydroxyvitamin D3 [1,25(OH)2D3]. We show that VDR also functions as a receptor for the secondary bile acid lithocholic acid (LCA), which is hepatotoxic and a potential enteric carcinogen. VDR is an order of magnitude more sensitive to LCA and its metabolites than are other nuclear receptors. Activation of VDR by LCA or vitamin D induced expression in vivo of CYP3A, a cytochrome P450 enzyme that detoxifies LCA in the liver and intestine. These studies offer a mechanism that may explain the proposed protective effects of vitamin D and its receptor against colon cancer.read more
Citations
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Bile salt biotransformations by human intestinal bacteria.
TL;DR: The potential exists for altering the bile acid pool by targeting key enzymes in the 7α/β-dehydroxylation pathway through the development of pharmaceuticals or sequestering bile acids biologically in probiotic bacteria, which may result in their effective removal from the host after excretion.
Journal ArticleDOI
The Enzymes, Regulation, and Genetics of Bile Acid Synthesis
TL;DR: The synthesis and excretion of bile acids comprise the major pathway of cholesterol catabolism in mammals and causes a spectrum of human disease; this ranges from liver failure in early childhood to progressive neuropathy in adults.
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
Bile acids: regulation of synthesis.
TL;DR: Bile acids are able to induce FGF 19 in human hepatocytes, and the FGF19 autocrine pathway may exist in the human livers, andThe mechanism by which FXR/FGF19/FGFR4 signaling inhibits CYP7A1 remains unknown.
Journal ArticleDOI
Targeting bile-acid signalling for metabolic diseases
TL;DR: How the signalling functions of bile acids can be exploited in the development of drugs for obesity, type 2 diabetes, hypertriglyceridaemia and atherosclerosis, as well as other associated chronic diseases such as non-alcoholic steatohepatitis are reviewed.
References
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Journal ArticleDOI
Identification of a Nuclear Receptor for Bile Acids
Makoto Makishima,Arthur Y. Okamoto,Joyce J. Repa,Hua Tu,R. Marc Learned,Alvin Luk,Mitchell V. Hull,Kevin D. Lustig,David J. Mangelsdorf,Bei Shan +9 more
TL;DR: Results presented here show that bile acids are physiological ligands for the farnesoid X receptor (FXR), an orphan nuclear receptor, which demonstrates a mechanism by which bile acid transcriptionally regulate their biosynthesis and enterohepatic transport.
Journal ArticleDOI
Nuclear receptors and lipid physiology: opening the X-files.
TL;DR: Some general principles that govern the actions of this class of bioactive lipids and their nuclear receptors are considered here, and the scheme that emerges reveals a complex molecular script at work.
Journal ArticleDOI
An Orphan Nuclear Receptor Activated by Pregnanes Defines a Novel Steroid Signaling Pathway
Steven A. Kliewer,John T. Moore,Laura E. Wade,Jeff L. Staudinger,Michael A. Watson,Stacey A. Jones,David D. McKee,Beverly B. Oliver,Timothy M. Willson,Rolf Zetterström,Thomas Perlmann,Jürgen M. Lehmann +11 more
TL;DR: The results provide evidence for the existence of a novel steroid hormone signaling pathway with potential implications in the regulation of steroid hormone and sterol homeostasis and the expression of the CYP3A family of steroid hydroxylases and modulates sterol and bile acid biosynthesis in vivo.
Journal ArticleDOI
Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors.
Timothy T. Lu,Makoto Makishima,Joyce J. Repa,Kristina Schoonjans,Thomas A. Kerr,Johan Auwerx,David J. Mangelsdorf +6 more
TL;DR: An elaborate autoregulatory cascade mediated by nuclear receptors for the maintenance of hepatic cholesterol catabolism is revealed, showing that repression is coordinately regulated by a triumvirate of nuclear receptors, including the bile acid receptor, FXR, and the promoter-specific repressor, SHP.
Journal ArticleDOI
The nuclear vitamin D receptor: biological and molecular regulatory properties revealed.
Mark R. Haussler,G. K. Whitfield,Carol A. Haussler,J. C. Hsieh,Paul Thompson,S. H. Selznick,Carlos Encinas Dominguez,Peter W. Jurutka +7 more
TL;DR: The scope of this review will be limited to highlighting the actions of 1,25(OH)2D3 mediated by nuclear VDR and discussing new developments in the structure/function analysis of the receptor, including the phenotype of VDR knockout mice and the biochemical classification of patients with point mutations in the receptor.