The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp

Lee A. Denson, Ekkehard Sturm, Wihelma Echevarria, Tracy L. Zimmerman, Makoto Makishima, David J. Mangelsdorf, Saul J. Karpen

Research output: Contribution to journalArticle

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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 7α-hydroxylase (cyp7a), via bile acid receptor (fxr) activation of an inhibitory nuclear receptor, shp. We hypothesized that shp would also mediate negative feedback regulation of ntcp, the principal hepatic bile acid transporter. Methods: Primary rat hepatocytes or transfected HepG2 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 fxr, 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.

Original languageEnglish (US)
Pages (from-to)140-147
Number of pages8
JournalGastroenterology
Volume121
Issue number1
StatePublished - 2001

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Orphan Nuclear Receptors
Bile Acids and Salts
Retinoids
Hepatocytes
Down-Regulation
bile acid binding proteins
Cholesterol 7-alpha-Hydroxylase
Gene Expression
Liver
Hep G2 Cells
Response Elements
Cytoplasmic and Nuclear Receptors
Transcriptional Activation
Genes

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Denson, L. A., Sturm, E., Echevarria, W., Zimmerman, T. L., Makishima, M., Mangelsdorf, D. J., & Karpen, S. J. (2001). The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology, 121(1), 140-147.

The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. / Denson, Lee A.; Sturm, Ekkehard; Echevarria, Wihelma; Zimmerman, Tracy L.; Makishima, Makoto; Mangelsdorf, David J.; Karpen, Saul J.

In: Gastroenterology, Vol. 121, No. 1, 2001, p. 140-147.

Research output: Contribution to journalArticle

Denson, LA, Sturm, E, Echevarria, W, Zimmerman, TL, Makishima, M, Mangelsdorf, DJ & Karpen, SJ 2001, 'The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp', Gastroenterology, vol. 121, no. 1, pp. 140-147.
Denson, Lee A. ; Sturm, Ekkehard ; Echevarria, Wihelma ; Zimmerman, Tracy L. ; Makishima, Makoto ; Mangelsdorf, David J. ; Karpen, Saul J. / The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. In: Gastroenterology. 2001 ; Vol. 121, No. 1. pp. 140-147.
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