지원사업
학술연구/단체지원/교육 등 연구자 활동을 지속하도록 DBpia가 지원하고 있어요.
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논문 기본 정보
- 자료유형
- 학술저널
- 저자정보
- 발행연도
- 2011.1
- 수록면
- 571 - 579 (9page)
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Cholesterol 7α-hydroxylase (CYP7A1) regulates the balance between cholesterol supply and metabolism by catalyzing the rate-limiting step of bile acid biosynthesis. The transcriptional activity of CYP7A1 is tightly controlled by various nuclear receptors. A forkhead transcription factor O1 (FOXO1) plays a critical role in metabolism, and insulin inactivates FOXO1 through Akt-dependent phosphorylation and nuclear exclusion. We investigated the role of insulin-Akt-FOXO1 signaling pathway in CYP7A1 transcriptional regulation since we found putative insulin-response elements, FOXO1 binding sequences, in both rat and human CYP7A1 promoters. However, ectopic expression of FOXO1 increased the rat CYP7A1-, but mildly reduced human CYP7A1-promoter activities in a dose-dependent manner. Similarly to bile acids,insulin treatment increased small heterodimer partner (SHP) mRNA rapidly and transiently, leading to the suppression of CYP7A1 transcription in both human and rodents. Chromatin immunoprecipitation showed that FOXO1 directly bound to rat CYP1A1 promoter in the absence of insulin. FOXO1 binding to the rat promoter was diminished by insulin treatment as well as by expression of SHP. Our results suggest that the stimulation of insulin- signaling pathway of Akt-FOXO1and SHP expression may regulate cholesterol/bile acid metabolisms in liver, linking carbohydrate and cholesterol metabolic pathways. A prolonged exposure of insulin in hyperinsulinemic insulin resistance or diabetic status represses CYP7A1 transcription and bile acid biosynthesis through SHP induction and FOXO1 inactivation, leading to impairment of the hepatic cholesterol/bile acid metabolisms.
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참고문헌 (22)
참고문헌 신청
Altomonte J / 2004 / Foxo1 mediates insulin action on apoC-III and triglyceride metabolism / J Clin Invest 114 : 1493 ~ 1503
Barthel A / 2005 / FoxO proteins in insulin action and metabolism / Trends Endocrinol Metab 16 : 183 ~ 189
Biggs WH / 1999 / Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1 / Proc Natl Acad Sci 96 : 7421 ~ 742
Chen JY / 2002 / Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased
Chen W / 2001 / Nuclear receptor-mediated repression of human cholesterol 7alpha-hydroxylase gene transcription by bile acids / J Lipid Res 42 : 1402 ~ 1412
Barthel A / 2005 / FoxO proteins in insulin action and metabolism / Trends Endocrinol Metab 16 : 183 ~ 189
Biggs WH / 1999 / Protein kinase B/Akt-mediated phosphorylation promotes nuclear exclusion of the winged helix transcription factor FKHR1 / Proc Natl Acad Sci 96 : 7421 ~ 742
Chen JY / 2002 / Mice expressing the human CYP7A1 gene in the mouse CYP7A1 knock-out background lack induction of CYP7A1 expression by cholesterol feeding and have increased
Chen W / 2001 / Nuclear receptor-mediated repression of human cholesterol 7alpha-hydroxylase gene transcription by bile acids / J Lipid Res 42 : 1402 ~ 1412
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