Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations
Article first published online: 5 MAY 2013
© 2013 The Association for the Publication of the Journal of Internal Medicine
Journal of Internal Medicine
Volume 274, Issue 3, pages 263–272, September 2013
How to Cite
Department of Clinical Sciences, Diabetes and Endocrinology, Malmö University Hospital, Malmö, Sweden; AstraZeneca Research & Development, Mölndal, Sweden; Division of Clinical Chemistry, Department of Laboratory Medicine, NOVUM, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden; Molecular Nutrition Unit, Department of Biosciences and Nutrition, Centre for Nutrition and Toxicology, NOVUM, Karolinska Institutet at Karolinska University Hospital Huddinge, Stockholm, Sweden). Alterations in bile acid synthesis in carriers of hepatocyte nuclear factor 1α mutations. J Intern Med 2013; 274: 263–272., , , (
- Issue published online: 10 AUG 2013
- Article first published online: 5 MAY 2013
- Accepted manuscript online: 23 APR 2013 02:16AM EST
- Swedish Heart-Lung Foundation
- Henning and Johan Throne-Holst Foundation
- cholesterol metabolism;
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 patients with MODY3 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.
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). Cotransfection experiments were performed with several promoters involved in BA metabolism along with expression vectors carrying the mutations found in these patients.
Plasma analysis showed higher levels of BA synthesis in patients with MODY3. No differences were observed in cholesterol synthesis or intestinal cholesterol absorption. Cotransfection experiments showed that one of the mutations (P379A) increased the induction of the cholesterol 7α-hydroxylase promoter compared with 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 (FXR) 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.
BA synthesis is increased in patients with MODY3 compared with control subjects. Mutations in HNF1α affect promoters involved in BA metabolism.