Thyroid hormone suppresses hepatic sterol 12α-hydroxylase (CYP8B1) activity and messenger ribonucleic acid in rat liver: Failure to define known thyroid hormone response elements in the gene

Andersson, Ulla; Yang, Yizeng; Björkhem, Ingemar; Einarsson, Curt; Eggertsen, Gösta; Gåfvels, Mats

doi:10.1016/s1388-1981(99)00036-0

Cited by 40 publications

(28 citation statements)

References 13 publications

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“…Through the study carried out in HYPOX and TX male rats, we provide further evidence that the interaction of EE with GH and/or thyroid hormones is relevant in the regulation of bile acid synthesis and transport. We showed that EE administration to TX rats did not decrease expression of CYP7A1 or CYP27A1, whereas CYP8B1 was down-regulated, an effect caused by T 3 (which is a known inhibitor of CYP8B1 expression in TX rats) as well (Andersson et al, 1999). The hormone response elements for ER␣ and thyroid hormones receptor are very similar (Zhu et al, 1996), suggesting that ER␣ may interact at the promoter region of the genes under regulation by thyroid hormones.…”

Section: Estrogen-induced Cholestasismentioning

confidence: 87%

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat

Hernández¹,

Flores‐Morales²,

Santana-Farré³

et al. 2006

J Pharmacol Exp Ther

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Estrogens cause intrahepatic cholestasis in susceptible women during pregnancy, after administration of oral contraceptives, or during postmenopausal hormone replacement therapy. 17␣-Ethinylestradiol (EE) is a synthetic estrogen widely used to cause experimental cholestasis in rodents with the aim of examining molecular mechanisms involved in this disease. EE actions on the liver are thought to be mediated by estrogen receptor ␣ (ER␣) and pituitary hormones. We tested this hypothesis by analyzing metabolic changes induced by EE in livers from hypophysectomized (HYPOX) and hypothyroid rats. Microarray studies revealed that the number of genes regulated by EE was increased almost 4-fold in HYPOX rat livers compared with intact males. Little overlap was apparent between the effects of EE in intact and HYPOX rats, demonstrating that pituitary hormones play a critical role in the hepatic effects of EE. Consistently, hypophysectomy protects the liver against induction by EE of serum bilirubin and alkaline phosphatase, two markers of cholestasis and hepatotoxicity and modulates the effects of EE on several genes involved in bile acid homeostasis (e.g., FXR, SHP, BSEP, and Cyp8b1). Finally, we demonstrate a novel mechanism of action of EE through binding and negative regulation of glucocorticoid receptor-mediated transcription. In summary, pituitary-and ER␣-independent mechanisms contribute to development of EE-induced changes in liver transcriptome. Such mechanisms may be relevant when this model of EE-induced cholestasis is evaluated. The observation that the pharmacological effects of estrogen in liver differ in the absence or presence of the pituitary could be clinically relevant, because different drugs that block actions of pituitary hormones are now available.

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Section: Estrogen-induced Cholestasismentioning

confidence: 87%

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat

Hernández¹,

Flores‐Morales²,

Santana-Farré³

et al. 2006

J Pharmacol Exp Ther

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“…Also, Cyp8b1, a 12α-hydroxylase responsible for the synthesis of cholic acid (CA), has been shown to be downregulated by TH and LXR agonists (17,31,32). The reduction in CYP8B1 activity leads to a decrease in synthesis of CA and a concomitant increase in production of more hydrophilic muricholic acid (MCA), a mechanism that is thought to underlie the LXR-mediated decrease in intestinal cholesterol absorption.…”

Section: Upregulation Of Expression Of Alternative Bile Acid Synthesimentioning

confidence: 99%

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Astapova¹,

Ramadoss²,

Costa-e-Sousa³

et al. 2014

J. Clin. Invest.

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Transcriptional coregulators are important components of nuclear receptor (NR) signaling machinery and provide additional mechanisms for modulation of NR activity. Expression of a mutated nuclear corepressor 1 (NCoR1) that lacks 2 NR interacting domains (NCoRΔID) in the liver leads to elevated expression of genes regulated by thyroid hormone receptor (TR) and liver X receptor (LXR), both of which control hepatic cholesterol metabolism. Here, we demonstrate that expression of NCoRΔID in mouse liver improves dietary cholesterol tolerance in an LXRα-independent manner. NCoRΔID-associated cholesterol tolerance was primarily due to diminished intestinal cholesterol absorption as the result of changes in the composition and hydrophobicity of the bile salt pool. Alterations of the bile salt pool were mediated by increased expression of genes encoding the bile acid metabolism enzymes CYP27A1 and CYP3A11 as well as canalicular bile salt pump ABCB11. We have determined that these genes are regulated by thyroid hormone and that TRβ1 is recruited to their regulatory regions. Together, these data indicate that interactions between NCoR1 and TR control a specific pathway involved in regulation of cholesterol metabolism and clearance. IntroductionCholesterol metabolism in the liver is critical for normal systemic regulation of serum cholesterol levels and eventual cardiac risk. Both the thyroid hormone receptor (TR) and liver X receptor (LXR) regulate multiple cholesterol clearance pathways and have been targeted as potential therapeutic avenues to improve cholesterol metabolism in humans (1-4). Thyroid hormone (TH) and its liver-specific analogs have been shown to lower serum cholesterol levels through increased expression of the LDL-R and/or HDL receptor SR-B1 in the liver (2, 5, 6), stimulate cholesterol elimination via conversion to bile acids (3, 5, 7-9), enhance biliary cholesterol excretion through ATP-binding cassette transporter G5 and G8 (ABCG5/G8), and decrease cholesterol absorption (10-12). The effects of TH on the cholesterol metabolism in the liver are mediated by the TRβ1 isoform (7, 13).LXRα and LXRβ are activated by oxysterols and act as intracellular cholesterol sensors (14). LXRα is the major isoform in the liver that plays a predominant role in maintaining hepatic cholesterol homeostasis. Global or liver-specific KO of Lxra leads to a dramatic hepatic cholesterol accumulation in mice fed diets with high cholesterol content (15-17). LXRα controls cholesterol clearance through regulation of intestinal cholesterol absorption and biliary cholesterol secretion as well as cholesterol conversion into bile acids (15,(17)(18)(19). Thus, TRβ1 and LXRα regulate both distinct and overlapping pathways to control cholesterol metabolism in the liver. Based on this, we hypothesized that targeting common nuclear receptor (NR) coregulators could amplify beneficial effects of both pathways on cholesterol metabolism.Previous work from our laboratory and others has demonstrated that the NR corepressor, nuclear corepressor 1 (N...

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“…Liver tissue was snap-frozen and stored at 2808C. Liver microsomes were isolated and assayed for 12a-hydroxylase activity as described previously using a mass spectrometric determination of the ratio between the substrate, 7a-hydroxy-4-cholesten-3-one, and the product, 7a,12a-dihydroxy-4-cholesten-3-one (14).…”

Section: Cyp8b1 Activitymentioning

confidence: 99%

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culprit

Sehayek

Hagey

Fung

et al. 2006

Journal of Lipid Research

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An intercross between C57BL/6J and CASA/Rk mice was used to study the genetics of biliary bile acid composition. In parental strains, male C57BL/6J mice had significantly higher cholic acid (CA; 14%) and lower b-muricholic acid (bMC; 27%) than CASA/Rk mice, whereas females did not differ. However, quantitative trait locus analysis of F2 mice revealed no significant chromosome 9 loci in males but loci in females on chromosome 9 for percentage CA (%CA) at 72 centimorgan (cM) [logarithm of the odds (LOD) 5.89] and %bMC at 54 cM (LOD 4.09). Chromosome 9 congenic and subcongenic strains representing CASA/Rk intervals 38-73 cM (9KK) and 68-73 cM (9DKK) on the C57BL/6J background were made. In 9KK and 9DKK males, %CA was increased and %bMC was unchanged, whereas in 9KK but not 9DKK females, %CA was increased and %bMC was decreased. Sterol 12a-hydroxylase (Cyp8b1) channels bile acid precursors into CA and maps at chromosome 9 (73 cM). However, there was no significant difference in Cyp8b1 mRNA or enzymatic activity between parental mice, parental-congenic-subcongenic mice, or highlow biliary %CA F2 mice. In summary, two chromosome 9 loci control sexually dimorphic effects on biliary bile acid composition: a distal (68-73 cM) major determinant in males, and a more proximal (38-68 cM) major determinant in females. In this intercross, Cyp8b1, a strong candidate, does not appear to be responsible. In humans and mice, biliary bile acid composition affects the enterohepatic metabolism of lipids, including the synthesis and transport of bile acids across hepatocytes, the excretion of biliary lipids, and the absorption of sterols from the intestines (1-6). In humans, the two major primary bile acids are chenodeoxycholic acid (CDCA), a dihydroxy bile acid, and cholic acid (CA), a trihydroxy bile acid. The difference between them is hydroxylation of the 12 carbon of the sterol ring, which is carried out by the enzyme sterol 12a-hydroxylase (CYP8B1). As a result, CDCA is more hydrophobic and CA is more hydrophilic. In mice, CA is one of the major primary bile acids; it is formed by CYP8B1-mediated 12 hydroxylation. Muricholic acids comprise the other major murine bile acids, and they are formed from CDCA by 6 hydroxylation and 7 epimerization to generate a-and b-muricholic acid (bMC), with bMC predominating. bMC is even more hydrophilic than CA. Although the mouse does not have CDCA as a major species, it is possible to use this model to identify genes that influence the 12 hydroxylation pathway and uptake of bile acids from the intestines by studying the proportions of CA and bMC in bile. Identifying the genes that influence 12 hydroxylation and bile acid uptake from the intestines is particularly important because they determine the proportions of CA and CDCA and hence the hydrophobicity of the bile acid pool in humans.In humans, the proportions of CA and CDCA vary between individuals (7, 8), and there is some evidence for genetic control. For example, studies in monozygotic and dizygotic twins found a significant pair-...

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Thyroid hormone suppresses hepatic sterol 12α-hydroxylase (CYP8B1) activity and messenger ribonucleic acid in rat liver: Failure to define known thyroid hormone response elements in the gene

Cited by 40 publications

References 13 publications

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat

Role of Pituitary Hormones on 17α-Ethinylestradiol-Induced Cholestasis in Rat

Hepatic nuclear corepressor 1 regulates cholesterol absorption through a TRβ1-governed pathway

Two loci on chromosome 9 control bile acid composition: evidence that a strong candidate gene, Cyp8b1, is not the culprit

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