Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

Li-Hawkins, Jia; Gåfvels, Mats; Olin, Maria; Lund, Erik; Andersson, Ulla; Schuster, Gertrud U.; Björkhem, Ingemar; Russell, David W.; Eggertsen, Gösta

doi:10.1172/jci0216309

Cited by 216 publications

(176 citation statements)

References 47 publications

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“…SHP mRNA levels were significantly increased with the synthetic FXR agonist GW4064, whereas an increase of ϳ2-fold was seen with CDCA compared with vehicle-treated cells (Fig. 1A) consistent with studies indicating that CDCA is a weak activator of SHP in vivo (20). BSEP mRNA levels were also induced by GW4064, and a 2-fold induction was seen with CDCA ( Fig.…”

Section: Identification Of Bat As a Fxr Targetsupporting

confidence: 87%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

168

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Section: Identification Of Bat As a Fxr Targetsupporting

confidence: 87%

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Pircher

Kitto

Petrowski

et al. 2003

Journal of Biological Chemistry

168

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“…Ibabp mRNA expression is upregulated by bile acids via FXR (12,13,19,20) and was used as a positive control for the cholic acid feeding. Ibabp expression increased in the ileum, cecum, and proximal colon of cholic acid-fed mice (Fig.…”

Section: Resultsmentioning

confidence: 99%

Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids

Frankenberg¹,

Rao²,

Chen³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

104

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Regulation of the mouse organic solute transporter ␣-␤, Ost␣-Ost␤, by bile acids. Am J Physiol Gastrointest Liver Physiol 290: G912-G922, 2006. First published December 15, 2005 doi:10.1152/ajpgi.00479.2005.-The mechanisms responsible for bile acid regulation of mouse intestinal organic solute transporter ␣-␤ (Ost␣-Ost␤) expression were investigated. Expression of Ost␣-Ost␤ mRNA was increased in cecum and proximal colon of cholic acid-fed mice and in chenodeoxycholatetreated mouse CT26 colon adenocarcinoma cells. Sequence analysis revealed potential cis-acting elements for farnesoid X receptor (FXR) and liver receptor homolog-1 (LRH-1) in the mouse Ost␣ and Ost␤ promoters and reporter constructs containing Ost␣ and Ost␤ 5Ј-flanking sequences were positively regulated by bile acids. Expression of a dominant-negative FXR, reduction of FXR with interfering small RNA (siRNA), or mutation of the potential FXR elements decreased Ost␣ and Ost␤ promoter activity and abolished the induction by chenodeoxycolic acid. Negative regulation of the Ost␣ and Ost␤ promoters by bile acids was mediated through LRH-1 elements. Ost␣ and Ost␤ promoter activities were increased by coexpression of LRH-1 and decreased by coexpression of SHP. Mutation of the potential LRH-1 elements and siRNA-mediated reduction of LRH-1 expression decreased basal promoter activity. As predicted from the promoter analyses, ileal Ost␣ and Ost␤ mRNA expressions were increased in wild-type mice administered the FXR agonist GW4064 and decreased in FXR-null mice. Immunoblotting analysis revealed that Ost␣ and Ost␤ intestinal protein expressions correlated with mRNA expression. The mouse Ost␣ and Ost␤ promoters are unusual in that they contain functional FXR and LRH elements, which mediate, respectively, positive and negative feedback regulation by bile acids. Although the positive regulatory pathway appears to be dominant, this arrangement provides a mechanism to finely titrate Ost␣-Ost␤ expression to the bile acid flux.

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“…The expression level of Cyp8b1, which is an important enzyme to determine cholic acid/chenodeoxycholic acid ratio (Bjorkhem & Eggertsen 2001, Li-Hawkins et al 2002, was significantly increased by 81% in male homozygous mice compared with that of the wild-type mice, while the others remained unchanged in male homozygous mice (Fig. 4A).…”

Section: Targeted Disruption Of the Gpbar1 Genementioning

confidence: 99%

Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice

Maruyama¹,

Tanaka²,

Suzuki³

et al. 2006

Journal of Endocrinology

255

199

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G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) is a novel G protein-coupled receptor for bile acid. Tissue distribution and cell-type specificity of Gpbar1 mRNA suggest a potential role for the receptor in the endocrine system; however, the precise physiological role of Gpbar1 still remains to be elucidated. To investigate the role of Gpbar1 in vivo, the Gpbar1 gene was disrupted in mice. In homozygous mice, total bile acid pool size was significantly decreased by 21-25% compared with that of the wild-type mice, suggesting that Gpbar1 contributes to bile acid homeostasis. In order to assess the impact of Gpbar1 deficiency in bile acid homeostasis more precisely, Gpbar1 homozygous mice were fed a high-fat diet for 2 months. As a result, female Gpbar1 homozygous mice showed significant fat accumulation with body weight gain compared with that of the wild-type mice. These findings were also observed in heterozygous mice to the same extent. Although the precise mechanism for fat accumulation in female Gpbar1 homozygous mice remains to be addressed, these data indicate that Gpbar1 is a potential new player in energy homeostasis. Thus, Gpbar1-deficient mice are useful in elucidating new physiological roles for Gpbar1.

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Cholic acid mediates negative feedback regulation of bile acid synthesis in mice

Cited by 216 publications

References 47 publications

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Farnesoid X Receptor Regulates Bile Acid-Amino Acid Conjugation

Regulation of the mouse organic solute transporter α-β, Ostα-Ostβ, by bile acids

Targeted disruption of G protein-coupled bile acid receptor 1 (Gpbar1/M-Bar) in mice

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