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Alterations in bile...
Alterations in bile acid synthesis in carriers of HNF1α mutations.
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- Ekholm, Ella (author)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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Nilsson, Ralf (author)
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- Groop, Leif (author)
- Lund University,Lunds universitet,Genomik, diabetes och endokrinologi,Forskargrupper vid Lunds universitet,Genomics, Diabetes and Endocrinology,Lund University Research Groups
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Pramfalk, Camilla (author)
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(creator_code:org_t)
- 2013-05-06
- 2013
- English.
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In: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 274:3, s. 263-272
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Abstract
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- OBJECTIVES: Heterozygous mutations in hepatocyte nuclear factor 1α (HNF1α) cause maturity onset diabetes of the young 3 (MODY3), an autosomal dominant form of diabetes. Deficiency of HNF1α in mice results in diabetes, hypercholesterolaemia and increased bile acid (BA) and cholesterol synthesis. Little is known about alterations in lipid metabolism in patients with MODY3. The aim of this study was to investigate whether MODY3 patients have altered cholesterol and BA synthesis and intestinal cholesterol absorption. A secondary aim was to investigate the effects of HNF1α mutations on the transcriptional regulation of BA metabolism. METHODS: Plasma biomarkers of BA and cholesterol synthesis and intestinal cholesterol absorption were measured in patients with MODY3 (n = 19) and in matched healthy control subjects (n = 15). Co-transfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients. RESULTS: Plasma analysis showed higher levels of BA synthesis in MODY3 patients. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Co-transfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7α-hydroxylase promoter compared to HNF1α, without further differences in other studied promoters. By contrast, the other four mutations (L107I, T260M, P291fsinsC and R131Q) reduced the induction of the farnesoid X receptor promoter, which was followed by reduced repression of the small heterodimer partner promoter. In addition, these mutations also reduced the induction of the apical sodium-dependent bile salt transporter promoter. CONCLUSIONS: BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1α affect promoters involved in BA metabolism. This article is protected by copyright. All rights reserved.
Subject headings
- MEDICIN OCH HÄLSOVETENSKAP -- Klinisk medicin -- Endokrinologi och diabetes (hsv//swe)
- MEDICAL AND HEALTH SCIENCES -- Clinical Medicine -- Endocrinology and Diabetes (hsv//eng)
Publication and Content Type
- art (subject category)
- ref (subject category)
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