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Titolo:
The orphan nuclear receptor, shp, mediates bile acid-induced inhibition ofthe rat bile acid transporter, ntcp
Autore:
Denson, LA; Sturm, E; Echevarria, W; Zimmerman, TL; Makishima, M; Mangelsdorf, DJ; Karpen, SJ;
Indirizzi:
Baylor Coll Med, Dept Pediat, Houston, TX 77030 USA Baylor Coll Med Houston TX USA 77030 , Dept Pediat, Houston, TX 77030 USA Yale Univ, Sch Med, Dept Pediat, New Haven, CT 06510 USA Yale Univ New Haven CT USA 06510 ed, Dept Pediat, New Haven, CT 06510 USA Univ Texas, SW Med Ctr, Howard Hughes Med Inst, Dallas, TX USA Univ TexasDallas TX USA Med Ctr, Howard Hughes Med Inst, Dallas, TX USA Univ Texas, SW Med Ctr, Dept Pharmacol, Dallas, TX 75235 USA Univ Texas Dallas TX USA 75235 Ctr, Dept Pharmacol, Dallas, TX 75235 USA
Titolo Testata:
GASTROENTEROLOGY
fascicolo: 1, volume: 121, anno: 2001,
pagine: 140 - 147
SICI:
0016-5085(200107)121:1<140:TONRSM>2.0.ZU;2-S
Fonte:
ISI
Lingua:
ENG
Soggetto:
SALT EXPORT PUMP; GENE-EXPRESSION; DOWN-REGULATION; VITAMIN-A; LIVER; CHOLESTASIS; TRANSACTIVATION; COTRANSPORTER; MECHANISMS; DISEASE;
Tipo documento:
Article
Natura:
Periodico
Settore Disciplinare:
Clinical Medicine
Life Sciences
Citazioni:
27
Recensione:
Indirizzi per estratti:
Indirizzo: Karpen, SJ Baylor Coll Med, Dept Pediat, 1 Baylor Plaza, Houston, TX 77030USA Baylor Coll Med 1 Baylor Plaza Houston TX USA 77030 X 77030 USA
Citazione:
L.A. Denson et al., "The orphan nuclear receptor, shp, mediates bile acid-induced inhibition ofthe rat bile acid transporter, ntcp", GASTROENTY, 121(1), 2001, pp. 140-147

Abstract

Background & Aims: Hepatic bile acid homeostasis is regulated by negative feedback inhibition of genes involved in the uptake and synthesis of bile acids. Bile acids down-regulate the rate-limiting gene for bile acid synthesis, cholesterol 7 alpha -hydroxylase (cyp7a), via bile acid receptor (fxr) activation of an inhibitory nuclear receptor, shp. We hypothesized that shpwould also mediate negative feedback regulation of ntcp, the principal hepatic bile acid transporter. Methods: Primary rat hepatocytes or transfectedHepG2 and Cos cells were treated with retinoids with or without bile acids, and effects on bile acid transport and ntcp and shp gene expression and promoter activity were determined. Gel shift assays were performed using synthetic fry, rxr, and rar proteins. Results: Bile acid treatment of primary rat hepatocytes prevented retinoid activation of ntcp gene expression and function; this corresponded temporally with shp gene activation. Bile acid-mediated down-regulation occurred via fxr-dependent suppression of the ntcp RXR:RAR response element. Moreover, cotransfected shp directly inhibited retinoid activation of the ntcp promoter. Conclusions: These studies show negative feedback regulation of ntcp by bile acid-activated fxr via induction of shp. This novel regulatory pathway provides a means for coordinated down-regulation of bile acid import and synthesis, thereby protecting the hepatocyte from bile acid-mediated damage in cholestatic conditions.

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Documento generato il 04/07/20 alle ore 04:24:03