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

doi:10.1126/science.1070477

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

Research output: Contribution to journal › Article › peer-review

1122 Scopus citations

Abstract

The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,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.

Original language	English (US)
Pages (from-to)	1313-1316
Number of pages	4
Journal	Science
Volume	296
Issue number	5571
DOIs	https://doi.org/10.1126/science.1070477
State	Published - May 17 2002
Externally published	Yes

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title = "Vitamin D receptor as an intestinal bile acid sensor",

abstract = "The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,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.",

author = "Makoto Makishima and Lu, \{Timothy T.\} and Wen Xie and Whitfield, \{G. Kerr\} and Hideharu Domoto and Evans, \{Ronald M.\} and Haussler, \{Mark R.\} and Mangelsdorf, \{David J.\}",

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doi = "10.1126/science.1070477",

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T1 - Vitamin D receptor as an intestinal bile acid sensor

AU - Makishima, Makoto

AU - Lu, Timothy T.

AU - Xie, Wen

AU - Whitfield, G. Kerr

AU - Domoto, Hideharu

AU - Evans, Ronald M.

AU - Haussler, Mark R.

AU - Mangelsdorf, David J.

PY - 2002/5/17

Y1 - 2002/5/17

N2 - The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,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.

AB - The vitamin D receptor (VDR) mediates the effects of the calcemic hormone 1α,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.

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VL - 296

SP - 1313

EP - 1316

JO - Science

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ER -

Vitamin D receptor as an intestinal bile acid sensor

Abstract

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