Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters

Huber, Reid; Murphy, Kathleen; Miao, Bowman; Link, John R.; Cunningham, Mark R.; Rupar, Mark; Gunyuzlu, Paul L.; Haws, Thomas F; Kassam, Altaf; Powell, Francoise; Hollis, Gregory; Young, Peter R.; Mukherjee, Ranjan; Burn, Timothy C.

doi:10.1016/s0378-1119(02)00557-7

Cited by 187 publications

(149 citation statements)

References 27 publications

Supporting

Mentioning

137

Contrasting

Unclassified

Order By: Relevance

“…Alternative promoter usage and differential splicing have been observed for many transcription factor genes, and in several instances this alters the structure of an activation domain. Most similar to SREBP-1, alternative promoters that result in N-terminal heterogeneity are common in the nuclear receptor family where different versions of an N-terminal constitutive activation domain (AF1) are produced (Zhu et al 1995;Oberste-Berghaus et al 2000;Huber et al 2002). However, in most cases, the real physiological significance of these variants has not been fully explored because most studies have focused on the nuclear receptor AF2 activation domain, which is located close to the ligand-binding domain at the C terminus.…”

Section: Transcriptional Activation By Srebpsmentioning

confidence: 99%

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Osborne

Espenshade²

2009

Genes Dev.

234

249

View full text Add to dashboard Cite

Sterol regulatory element-binding proteins (SREBPs) are a subfamily of basic helix–loop–helix leucine zipper (bHLH-LZ) transcription factors that are conserved from fungi to humans and are defined by two key features: a signature tyrosine residue in the DNA-binding domain, and a membrane-tethering domain that is a target for regulated proteolysis. Recent studies including genome-wide and model organism approaches indicate SREBPs coordinate cellular lipid metabolism with other cellular physiologic processes. These functions are broadly related as cellular adaptation to environmental changes ranging from nutrient fluctuations to toxin exposure. This review integrates classic features of the SREBP pathway with newer information regarding the regulation and sensing mechanisms that serve to assimilate different cellular physiologic processes for optimal function and growth.

show abstract

Section: Transcriptional Activation By Srebpsmentioning

confidence: 99%

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Osborne

Espenshade²

2009

Genes Dev.

234

249

View full text Add to dashboard Cite

show abstract

“…The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).…”

mentioning

confidence: 99%

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Zhang

Huang

Гао

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

View full text Add to dashboard Cite

The farnesoid X receptor (FXR) is a ligand-activated transcription factor belonging to the nuclear receptor superfamily. FXR is mainly expressed in liver and small intestine, where it plays an important role in bile acid, lipid, and glucose metabolism. The kidney also has a high FXR expression level, with its physiological function unknown. Here we demonstrate that FXR is ubiquitously distributed in renal tubules. FXR agonist treatment significantly lowered urine volume and increased urine osmolality, whereas FXR knockout mice exhibited an impaired urine concentrating ability, which led to a polyuria phenotype. We further found that treatment of C57BL/6 mice with chenodeoxycholic acid, an FXR endogenous ligand, significantly up-regulated renal aquaporin 2 (AQP2) expression, whereas FXR gene deficiency markedly reduced AQP2 expression levels in the kidney. In vitro studies showed that the AQP2 gene promoter contained a putative FXR response element site, which can be bound and activated by FXR, resulting in a significant increase of AQP2 transcription in cultured primary inner medullary collecting duct cells. In conclusion, the present study demonstrates that FXR plays a critical role in the regulation of urine volume, and its activation increases urinary concentrating capacity mainly via up-regulating its target gene AQP2 expression in the collecting ducts.water homeostasis | bile acid receptor T he farnesoid X receptor (FXR) is a member of the nuclear receptor superfamily, with the typical functional domains including the DNA binding domain and the ligand binding domain. Upon binding to its ligands, FXR forms a heterodimer with another nuclear receptor, retinoid X receptor, whereupon the receptor dimer binds to the FXR response element (FXRE) located in the promoter regions of FXR target genes, thereby regulating the transcription of these genes (1-3). The single FXR gene gives rise to two isoforms, designated as FXRα and FXRβ, as a result of alternative use of the promoters (4). In addition, each FXR isoform has two variants (FXRα1/FXRβ1 and FXRα2/ β2), depending on the presence or absence of an insert of four amino acids (MYTG) immediately adjacent to the DNA binding domain in the hinge domain (5). Because FXRβ constitutes a pseudogene in humans and primates, all recent studies focus on FXRα (6).FXR is highly expressed in the liver and intestine, where it functions as an intracellular sensor of bile acids and is required for the negative feedback regulation of bile acid biosynthesis and its enterohepatic cycle (7,8). Most recently FXR has been found to be involved in the regulation of adrenal and vascular function, as well as hepatic glucose and lipid metabolism, which suggests an important role for FXR in many tissues beyond the hepatointestinal system (9-12). Among most tissues tested, the kidney exhibits the highest expression levels (13). However, the role of FXR in the kidney remains largely unknown. It has been previously reported that FXR may negatively regulate sterol regulatory element-binding protei...

show abstract

“…High levels of mRNA for FXR are also found in the kidney and adrenal gland, areas of the body not classically considered as being bile acid targets (1), whereas low levels of mRNA for FXR are present in a variety of tissues, including heart, ovary, thymus, eye, spleen, and testes (7,8). The roles of FXR in these tissues are not known, nor indeed is the potential of bile acids to act as its ligands.…”

mentioning

confidence: 99%

“…Furthermore, the expression of FXR protein, especially in human tissue, is poorly understood. In addition, splice variants of FXR have recently been identified that have different pharmacology (7) and͞or different expression patterns (8). The roles of these splice variants in man are also unknown.…”

mentioning

confidence: 99%

Expression and activation of the farnesoid X receptor in the vasculature

Bishop‐Bailey

Walsh

Warner

2004

Proc. Natl. Acad. Sci. U.S.A.

212

163

View full text Add to dashboard Cite

The farnesoid X receptor͞bile acid receptor (FXR) is a recently discovered member of the nuclear hormone superfamily. FXR ligands have been proposed as targets in cardiovascular disease, regulating cholesterol metabolism and bile acid transport and metabolism in the liver and gastrointestinal tract. When we used a human cardiovascular tissue array, we found that FXR is expressed in a variety of normal and pathological human tissue. Particularly high levels of FXR were found in the vasculature and in a number of different metastatic cancers, as well as the previously identified target tissues of the liver, small intestine, and kidney. In vitro, FXR is present in rat and human vascular smooth muscle cells. When treated with a range of FXR ligands, vascular smooth muscle cells undergo apoptosis in a manner that correlates with the ligands' ability to activate FXR. Furthermore, FXR activators induce mRNA for the FXR target genes, phospholipid transfer protein, and the small heterodimer partner. FXR therefore is a functional protein in the vasculature that may provide a direct target for the treatment of proliferative and dyslipidaemic diseases.

show abstract

Generation of multiple farnesoid-X-receptor isoforms through the use of alternative promoters

Cited by 187 publications

References 27 publications

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Evolutionary conservation and adaptation in the mechanism that regulates SREBP action: what a long, strange tRIP it's been

Farnesoid X receptor (FXR) gene deficiency impairs urine concentration in mice

Expression and activation of the farnesoid X receptor in the vasculature

Contact Info

Product

Resources

About