Article

Ost -Ost is required for bile acid and conjugated steroid disposition in the intestine, kidney, and liver

Department of Environmental Medicine, University of Rochester School of Medicine, 575 Elmwood Ave., Rochester, NY 14642, USA.
AJP Gastrointestinal and Liver Physiology (Impact Factor: 3.8). 08/2008; 295(1):G179-G186. DOI: 10.1152/ajpgi.90319.2008
Source: PubMed

ABSTRACT

Mice deficient in the organic solute transporter (Ost)-alpha subunit of the heteromeric organic solute and steroid transporter, Ostalpha-Ostbeta, were generated and were found to be viable and fertile but exhibited small intestinal hypertrophy and growth retardation. Bile acid pool size and serum levels were decreased by more than 60% in Ostalpha-/- mice, whereas fecal bile acid excretion was unchanged, suggesting a defect in intestinal bile acid absorption. In support of this hypothesis, when [3H]taurocholic acid or [3H]estrone 3-sulfate were administered into the ileal lumen, absorption was lower in Ostalpha-/- mice. Interestingly, serum cholesterol and triglyceride levels were also approximately 15% lower in Ostalpha-/- mice, an effect that may be related to the impaired intestinal bile acid absorption. After intraperitoneal administration of [3H]estrone 3-sulfate or [3H]dehydroepiandrosterone sulfate, Ostalpha-/- mice had higher levels of radioactivity in their liver and urinary bladder and less in the duodenum, indicating altered hepatic, renal, and intestinal disposition. Loss of Ostalpha was associated with compensatory changes in the expression of several genes involved in bile acid homeostasis, including an increase in the multidrug resistance-associated protein 3, (Mrp3)/Abcc3, an alternate basolateral bile acid export pump, and a decrease in cholesterol 7alpha-hydroxylase, Cyp7a1, the rate-limiting enzyme in bile acid synthesis. The latter finding may be explained by increased ileal expression of fibroblast growth factor 15 (Fgf15), a negative regulator of hepatic Cyp7a1 transcription. Overall, these findings provide direct support for the hypothesis that Ostalpha-Ostbeta is a major basolateral transporter of bile acids and conjugated steroids in the intestine, kidney, and liver.

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    • "This highly efficient process ensures that the majority of bile acids are recycled [24]. SLC51A/B (OSTa/b) a heteromeric complex, functions as a major basolateral transporter of bile acids [25], and is essential for intestinal bile acid transportation as well [26]. FXR not only regulates bile acid homeostasis, it also has a role in controlling insulin resistance and glucose homeostasis [27]. "
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    ABSTRACT: Retinoic acid (RA) and bile acids share common roles in regulating lipid homeostasis and insulin sensitivity. In addition, the receptor for RA (retinoid x receptor) is a permissive partner of the receptor for bile acids, farnesoid x receptor (FXR/NR1H4). Thus, RA can activate the FXR-mediated pathway as well. The current study was designed to understand the effect of all-trans RA on bile acid homeostasis. Mice were fed an all-trans RA-supplemented diet and the expression of 46 genes that participate in regulating bile acid homeostasis was studied. The data showed that all-trans RA has a profound effect in regulating genes involved in synthesis and transport of bile acids. All-trans RA treatment reduced the gene expression levels of Cyp7a1, Cyp8b1, and Akr1d1, which are involved in bile acid synthesis. All-trans RA also decreased the hepatic mRNA levels of Lrh-1 (Nr5a2) and Hnf4α (Nr2a1), which positively regulate the gene expression of Cyp7a1 and Cyp8b1. Moreover, all-trans RA induced the gene expression levels of negative regulators of bile acid synthesis including hepatic Fgfr4, Fxr, and Shp (Nr0b2) as well as ileal Fgf15. All-trans RA also decreased the expression of Abcb11 and Slc51b, which have a role in bile acid transport. Consistently, all-trans RA reduced hepatic bile acid levels and the ratio of CA/CDCA, as demonstrated by liquid chromatography-mass spectrometry. The data suggest that all-trans RA-induced SHP may contribute to the inhibition of CYP7A1 and CYP8B1, which in turn reduces bile acid synthesis and affects lipid absorption in the gastrointestinal tract.
    Full-text · Article · Aug 2014 · Biochemical Pharmacology
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    • "This highly efficient process ensures that the majority of bile acids are recycled [24]. SLC51A/B (OSTa/b) a heteromeric complex, functions as a major basolateral transporter of bile acids [25], and is essential for intestinal bile acid transportation as well [26]. FXR not only regulates bile acid homeostasis, it also has a role in controlling insulin resistance and glucose homeostasis [27]. "

    Full-text · Article · Aug 2014 · Biochemical Pharmacology
  • Source
    • "This highly efficient process ensures that the majority of bile acids are recycled [24]. SLC51A/B (OSTa/b) a heteromeric complex, functions as a major basolateral transporter of bile acids [25], and is essential for intestinal bile acid transportation as well [26]. FXR not only regulates bile acid homeostasis, it also has a role in controlling insulin resistance and glucose homeostasis [27]. "

    Full-text · Article · Aug 2014 · Biochemical pharmacology
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