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

1039 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

ASJC Scopus subject areas

General

Access to Document

10.1126/science.1070477

Cite this

@article{e3082d690f1345c2910f91aa42b69b49,

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.}",

year = "2002",

month = may,

day = "17",

doi = "10.1126/science.1070477",

language = "English (US)",

volume = "296",

pages = "1313--1316",

journal = "Science",

issn = "0036-8075",

publisher = "American Association for the Advancement of Science",

number = "5571",

}

TY - JOUR

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.

UR - http://www.scopus.com/inward/record.url?scp=0037123667&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037123667&partnerID=8YFLogxK

U2 - 10.1126/science.1070477

DO - 10.1126/science.1070477

M3 - Article

C2 - 12016314

AN - SCOPUS:0037123667

SN - 0036-8075

VL - 296

SP - 1313

EP - 1316

JO - Science

JF - Science

IS - 5571

ER -

Vitamin D receptor as an intestinal bile acid sensor

Abstract

ASJC Scopus subject areas

Access to Document

Other files and links

Fingerprint

Cite this