The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter

Freeman, Lita A.; Kennedy, Arion; Wu, Justina E.; Bark, Samantha E.; Remaley, Alan T.; Santamarina-Fojo, Silvia; Brewer, H. Bryan

doi:10.1194/jlr.c400002-jlr200

Cited by 92 publications

(86 citation statements)

References 59 publications

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“…It is interesting to note that this motif is not conserved in the rodent intergenic region. This is one of the differences between murine and human 'promoter' sequences in that the mouse not only has an identifiable TATA box, it also contains sequences that may bind HNF4 (both of which are absent from the human sequence) [12,40]. This may suggest that the human STSL locus may be fundamentally differently regulated relative to the murine locus, although most of the evidences are based upon the experimental data derived from murine models.…”

Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 98%

“…The strongest evidence that this is a direct effect is that the changes in RNA expression can be seen with as little as 12 h exposure to the ligands, both in vivo and in vitro [48]. The only direct evidence for both binding sites and an action on transcription has come from the investigation of the role of liver receptor homolog-1 (LRH-1), an orphan receptor, in the pathway that classically involves the FXR-SHP-LRH-1 [12]. The human intergenic sequence contains a LRH-1 binding site, this sequence has been shown to bind directly LRH-1 and activate expression of ABCG5 and ABCG8 in vitro [12].…”

Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 99%

“…The only direct evidence for both binding sites and an action on transcription has come from the investigation of the role of liver receptor homolog-1 (LRH-1), an orphan receptor, in the pathway that classically involves the FXR-SHP-LRH-1 [12]. The human intergenic sequence contains a LRH-1 binding site, this sequence has been shown to bind directly LRH-1 and activate expression of ABCG5 and ABCG8 in vitro [12]. It is interesting to note that this motif is not conserved in the rodent intergenic region.…”

Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 99%

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Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

Hazard

Patel

2006

Pflugers Arch - Eur J Physiol

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ABCG5 and ABCG8 are two ATP-binding cassette half-transporters that belong to the G family members. They were identified as proteins that are mutated in a rare human disorder, sitosterolemia, and their identification led to the completion of the physiological pathways by which dietary cholesterol, as well as noncholesterol sterols, traffics in the mammalian body. These proteins are likely to function as heterodimers, and current evidence suggests that these proteins are responsible for the majority of sterol secretions into bile, thus may define the long sought-after biliary sterol transporters. This review will focus on some of the backgrounds of this physiology, the genetics and regulation of these genes, as well as our current understanding of their functions. This review will also highlight the current limitations in our knowledge gap.

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Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 98%

Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 99%

Section: Regulation Of Abcg5 and Abcg8mentioning

confidence: 99%

See 1 more Smart Citation

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

Hazard

Patel

2006

Pflugers Arch - Eur J Physiol

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“…Previously recognized as an orphan receptor, phospholipids, including the phosphatidyl inositol second messengers, have been proposed as ligands for the human form (2)(3)(4). Although the role of LRH-1 in cholesterol and bile acid homeostasis is relatively well established (5)(6)(7)(8)(9)(10)(11)(12)(13)(14), unanticipated actions of LRH-1 in the intestine have emerged, including control of cell renewal (15). This finding was shown to be the result of cross-talk between LRH-1 and the ␤-catenin pathway (15), through which LRH-1 contributes to tumorigenesis under pathophysiological conditions (16).…”

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confidence: 99%

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Coste

Dubuquoy

Barnouin

et al. 2007

Proc. Natl. Acad. Sci. U.S.A.

141

205

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Liver receptor homolog-1 (LRH-1) is a nuclear receptor involved in intestinal lipid homeostasis and cell proliferation. Here we show that haploinsufficiency of LRH-1 predisposes mice to the development of intestinal inflammation. Besides the increased inflammatory response, LRH-1 heterozygous mice exposed to 2,4,6-trinitrobenzene sulfonic acid show lower local corticosterone production as a result of an impaired intestinal expression of the enzymes CYP11A1 and CYP11B1, which control the local synthesis of corticosterone in the intestine. Local glucocorticoid production is strictly enterocytedependent because it is robustly reduced in epithelium-specific LRH-1-deficient mice. Consistent with these findings, colon biopsies of patients with Crohn's disease and ulcerative colitis show reduced expression of LRH-1 and genes involved in the production of glucocorticoids. Hence, LRH-1 regulates intestinal immunity in response to immunological stress by triggering local glucocorticoid production. These findings underscore the importance of LRH-1 in the control of intestinal inflammation and the pathogenesis of inflammatory bowel disease.Crohn's disease ͉ inflammation ͉ nuclear receptors ͉ steroidogenesis ͉ ulcerative colitis

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“…ABCG5/ABCG8 mediates the efflux of plant sterols from enterocytes back into the intestinal lumen and their excretion into bile, thus limiting their accumulation in the body (3,15). The expression of the Abcg5 and Abcg8 genes is controlled by the liver X receptor (LXR-␣/NR1H3) and possibly by liver receptor homolog (LRH)-1 (8,43). LXR is activated by oxysterols and hence is considered as a cellular "cholesterol sensor" (16).…”

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confidence: 99%

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

Plösch¹,

Veen²,

Havinga³

et al. 2006

American Journal of Physiology-Gastrointestinal and Liver Physi

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Plö sch, Torsten, Jelske N. van der Veen, Rick Havinga, Nicolette C. A. Huijkman, Vincent W. Bloks, and Folkert Kuipers. Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice. Am J Physiol Gastrointest Liver Physiol 291: G414 -G423, 2006. First published April 13, 2006; doi:10.1152/ajpgi.00557.2005.-The ATP-binding cassette (ABC) half-transporters ABCG5 and ABCG8 heterodimerize into a functional complex that mediates the secretion of plant sterols and cholesterol by hepatocytes into bile and their apical efflux from enterocytes. We addressed the putative rate-controlling role of Abcg5/Abcg8 in hepatobiliary cholesterol excretion in mice during (maximal) stimulation of this process. Despite similar bile salt (BS) excretion rates, basal total sterol and phospholipid (PL) output rates were reduced by 82% and 35%, respectively, in chow-fed Abcg5 Ϫ/Ϫ mice compared with wild-type mice. When mice were infused with the hydrophilic BS tauroursodeoxycholate, similar relative increases in bile flow, BS output, PL output, and total sterol output were observed in wild-type, Abcg5 ϩ/Ϫ , and Abcg5 Ϫ/Ϫ mice. Maximal cholesterol and PL output rates in Abcg5 Ϫ/Ϫ mice were only 15% and 69%, respectively, of wild-type values. An infusion of increasing amounts of the hydrophobic BS taurodeoxycholate increased cholesterol excretion by 3.0-and 2.4-fold in wild-type and Abcg5 Ϫ/Ϫ mice but rapidly induced cholestasis in Abcg5 Ϫ/Ϫ mice. Treatment with the liver X receptor (LXR) agonist T0901317 increased the maximal sterol excretion capacity in wild-type mice (fourfold), concomitant with the induction of Abcg5/Abcg8 expression, but not in Abcg5 Ϫ/Ϫ mice. In a separate study, mice were fed chow containing 1% (wt/wt) cholesterol. As expected, hepatic expression of Abcg5 and Abcg8 was strongly induced (fivefold and fourfold) in wild-type but not LXR-␣-deficient (Lxra Ϫ/Ϫ ) mice. Surprisingly, hepatobiliary cholesterol excretion was increased to the same extent, i.e., 2.2-fold in wild-type mice and 2.0-fold in Lxra Ϫ/Ϫ mice, upon cholesterol feeding. Our data confirm that Abcg5, as part of the Abcg5/Abcg8 heterodimer, strongly controls hepatobiliary cholesterol secretion in mice. However, our data demonstrate that Abcg5/Abcg8 heterodimer-independent, inducible routes exist that can significantly contribute to total hepatobiliary cholesterol output.ATP-binding cassette transporter; bile formation; biliary lipids; canalicular transport MUTATIONS in the ATP binding-cassette (ABC) half-transporters ABCG5 and ABCG8 cause sitosterolemia (3, 23), which is characterized by the accumulation of plant sterols in the body (4). Data indicate that ABCG5 and ABCG8, which are highly expressed in the liver and small intestine, heterodimerize into a functional complex (3,12). Mutations in either one of the genes cause the biochemical hallmarks of the disease in humans (3, 23) as well as in mouse models (18,27). The daily intake of plant sterols, i.e., sitosterol and campesterol, from a "Western-type" diet is in the same o...

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The orphan nuclear receptor LRH-1 activates the ABCG5/ABCG8 intergenic promoter

Cited by 92 publications

References 59 publications

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

Sterolins ABCG5 and ABCG8: regulators of whole body dietary sterols

LRH-1-mediated glucocorticoid synthesis in enterocytes protects against inflammatory bowel disease

Abcg5/Abcg8-independent pathways contribute to hepatobiliary cholesterol secretion in mice

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