Regulation of the Hamster Cholesterol 7α-Hydroxylase Gene (CYP7A): Prevalence of Negative over Positive Transcriptional Control

Fabiani, Emma De; Crestani, Maurizio; Marrapodi, Maria; Pinelli, A; Chiang, John Y.L.; Galli, Giovanni

doi:10.1006/bbrc.1996.1412

Cited by 11 publications

(9 citation statements)

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“…The cholesterol 7␣-hydroxylase gene promoter also contains binding sites for peroxisome proliferator activated receptor-␣ (PPAR-␣) and retinoid X receptor (RXR) (46). It has also been shown that the proximal promoter region of hamster cholesterol 7␣-hydroxylase gene contains HNF-3 and HNF-4 response elements (47). We have recently shown that LPS acutely decreases the mRNA and protein levels of RXR isoforms (␣, ␤, and ␥), LXR-␣, and PPAR-␣ in the liver of Syrian hamsters (24).…”

Section: Fig 8 Effect Of Lps Treatment On Hnf-1 Mrna Expression (A)mentioning

confidence: 94%

In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response

Memon

Moser

Shigenaga

et al. 2001

Journal of Biological Chemistry

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The host response to infection is associated with several alterations in lipid metabolism that promote lipoprotein production. These changes can be reproduced by lipopolysaccharide (LPS) administration. LPS stimulates hepatic cholesterol synthesis and suppresses the conversion of cholesterol to bile acids. LPS down-regulates hepatic cholesterol 7␣-hydroxylase, the rate-limiting enzyme in the classic pathway of bile acid synthesis. We now demonstrate that LPS markedly decreases the activity of sterol 27-hydroxylase, the rate-limiting enzyme in the alternate pathway of bile acid synthesis, in the liver of Syrian hamsters. Moreover, LPS progressively decreases hepatic sterol 27-hydroxylase mRNA levels by 75% compared with controls over a 24-h treatment period. LPS also decreases oxysterol 7␣-hydroxylase mRNA levels in mouse liver. In vitro studies in HepG2 cells demonstrate that tumor necrosis factor and interleukin (IL)-1 decrease sterol 27-hydroxylase mRNA levels by 48 and 80%, respectively, whereas IL-6 has no such effect. The IL-1-induced decrease in sterol 27-hydroxylase mRNA expression occurs early, is sustained for 48 h, and requires very low doses. In vivo IL-1 treatment also lowers hepatic sterol 27-hydroxylase mRNA levels in Syrian hamsters. Studies investigating the molecular mechanisms of LPS-induced decrease in sterol 27-hydroxylase show that LPS markedly decreases mRNA and protein levels of hepatocyte nuclear factor-1 (HNF-1), a transcription factor that regulates sterol 27-hydroxylase, in the liver. Moreover, LPS decreases the binding activity of HNF-1 by 70% in nuclear extracts in hamster liver, suggesting that LPS may down-regulate sterol 27-hydroxylase by decreasing the binding of HNF-1 to its promoter. Coupled with our earlier studies on cholesterol 7␣-hydroxylase, these data indicate that LPS suppresses both the classic and alternate pathways of bile acid synthesis. A decrease in bile acid synthesis in liver would reduce cholesterol catabolism and thereby contribute to the increase in hepatic lipoprotein production that is induced by LPS and cytokines.

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Section: Fig 8 Effect Of Lps Treatment On Hnf-1 Mrna Expression (A)mentioning

confidence: 94%

In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response

Memon

Moser

Shigenaga

et al. 2001

Journal of Biological Chemistry

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“…It has been shown that insulin inhibits cholesterol 7α-hydroxylase expression by acting at the transcriptional level [16]. In previous studies we demonstrated that the responsiveness of hamster CYP7A1 to insulin is due to one or more elements present in the proximal promoter [23]. To define these elements, we performed a functional study of the hamster CYP7A1 promoter, focusing on putative response sequences represented in Figure 1.…”

Section: Discussionmentioning

confidence: 99%

“…HepG2 were purchased from A. T. C. C. (Manassas, VA, U.S.A.) and grown in 12-well cluster plates as described previously [23,27].…”

Section: Cell Culture and Transient Transfection Assaysmentioning

confidence: 99%

“…Confluent cells were transfected by the calcium phosphate precipitation technique [17,23,28]. pCMVβ expression vector for bacterial β-galactosidase (Clontech, Palo Alto, CA, U.S.A.) was used to normalize for transfection efficiency.…”

Section: Cell Culture and Transient Transfection Assaysmentioning

confidence: 99%

“…In previous studies we reported that insulin and glucocorticoids regulate CYP7A1 transcription in opposite directions by interacting with the proximal promoter of the rat [17], human [18] and hamster [23] genes, although putative responsive sequences mediating hormone action seem to be located differently in the three promoters [23].…”

Section: Introductionmentioning

confidence: 99%

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Identification and characterization of cis-acting elements conferring insulin responsiveness on hamster cholesterol 7α-hydroxylase gene promoter

et al. 2000

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Bile acid biosynthesis occurs primarily through a pathway initiated by the 7alpha-hydroxylation of cholesterol, catalysed by cholesterol 7alpha-hydroxylase (encoded by CYP7A1). Insulin down-regulates CYP7A1 transcription. The aim of our study was to characterize the sequences of hamster CYP7A1 promoter, mediating the response to insulin. We therefore performed transient transfection assays with CYP7A1 promoter/luciferase chimaeras mutated at putative response elements and studied protein-DNA interactions by means of gel electrophoresis mobility-shift assay. Here we show that two sequences confer insulin responsiveness on hamster CYP7A1 promoter: a canonical insulin response sequence TGTTTTG overlapping a binding site for hepatocyte nuclear factor 3 (HNF-3) (at nt -235 to -224) and a binding site for HNF-4 at nt -203 to -191. In particular we show that the hamster CYP7A1 insulin response sequence is part of a complex unit involved in specific interactions with multiple transcription factors such as members of the HNF-3 family; this region does not bind very strongly to HNF-3 and as a consequence partly contributes to the transactivation of the gene. Another sequence located at nt -138 to -128 binds to HNF-3 and is involved in the tissue-specific regulation of hamster CYP7A1. The sequence at nt -203 to -191 is not only essential for insulin effect but also has a major role in the liver-specific expression of CYP7A1; it is the target of HNF-4. Therefore the binding sites for liver-enriched factors, present in the hamster CYP7A1 proximal promoter in close vicinity and conserved between species, constitute a regulatory unit important for basal hepatic expression and tissue restriction of the action of hormones such as insulin.

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Species-specific mechanisms for cholesterol 7α-hydroxylase (CYP7A1) regulation by drugs and bile acids

Handschin

Gnerre

Fraser

et al. 2005

Archives of Biochemistry and Biophysics

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Regulation of the Hamster Cholesterol 7α-Hydroxylase Gene (CYP7A): Prevalence of Negative over Positive Transcriptional Control

Cited by 11 publications

References 0 publications

In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response

In Vivo and in Vitro Regulation of Sterol 27-Hydroxylase in the Liver during the Acute Phase Response

Identification and characterization of cis-acting elements conferring insulin responsiveness on hamster cholesterol 7α-hydroxylase gene promoter

Species-specific mechanisms for cholesterol 7α-hydroxylase (CYP7A1) regulation by drugs and bile acids

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