A common polymorphism in the bile acid receptor farnesoid X receptor is associated with decreased hepatic target gene expression. Mol Endocrinol 2007 Aug;21(8):1769-80
Date
05/24/2007Pubmed ID
17519356DOI
10.1210/me.2007-0025Scopus ID
2-s2.0-34547431187 (requires institutional sign-in at Scopus site) 60 CitationsAbstract
The farnesoid X receptor (FXR or NR1H4) is an important bile-acid-activated, transcriptional regulator of genes involved in bile acid, lipid, and glucose homeostasis. Accordingly, interindividual variations in FXR expression and function could manifest as variable susceptibility to conditions such as cholesterol gallstone disease, atherosclerosis, and diabetes. We performed an FXR polymorphism discovery analysis of European-, African-, Chinese-, and Hispanic-Americans and identified two rare gain-of-function variants and a common single nucleotide polymorphism resulting in a G-1T substitution in the nucleotide adjacent to the translation initiation site (FXR*1B) with population allelic frequencies ranging from 2.5 to 12%. In cell-based transactivation assays, FXR*1B (-1T) activity was reduced compared with FXR*1A (-1G). This reduced activity for FXR*1B resulted from neither decreased translational efficiency nor the potential formation of a truncated translational variant. To further define the relevance of this polymorphism, gene expression was examined in a human liver bank to reveal that levels of the FXR target genes small heterodimer partner and organic anion transporting polypeptide 1B3 were significantly reduced in livers harboring an FXR*1B allele. These findings are the first to identify the presence of a common genetic variant in FXR with functional consequences that could contribute to disease risk or therapeutic outcomes.
Author List
Marzolini C, Tirona RG, Gervasini G, Poonkuzhali B, Assem M, Lee W, Leake BF, Schuetz JD, Schuetz EG, Kim RBAuthor
Mahfoud Assem PharmD Associate Professor in the School of Pharmacy Administration department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AllelesAmino Acid Sequence
Bile Acids and Salts
DNA-Binding Proteins
Gene Expression Regulation
Humans
Liver
Molecular Sequence Data
Polymorphism, Genetic
Protein Isoforms
Receptors, Cytoplasmic and Nuclear
Transcription Factors
