Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2006) 11 P307

ECE2006 Poster Presentations Diabetes, metabolism and cardiovascular (174 abstracts)

Altered cholesterol and bile acid homeostasis in the hexose-6-phosphate dehydrogenase (H6PDH) knockout mouse

KN Hewitt , IJ Bujalska , GG Lavery , PM Stewart & EA Walker

University of Birmingham, West Midlands, United Kingdom.

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. GCs are regulated at the prereceptor level by 11beta-hydroxysteroid dehydrogenases (11β-HSD). 11β-HSD type 1 (11β-HSD1) predominantly displays oxo-reductase activity, converting cortisone in man, 11-dehydrocorticosterone in rodents, to cortisol and corticosterone respectively – a reaction requiring the cofactor NADPH. The generation of a hexose-6-phosphate dehydrogenase (H6PDH) null mouse has shown that H6PDH is required for generating NADPH and thereby allowing oxo-reductase activity of 11β-HSD1. In this study, we used the H6PDH KO mice to assess the effects of altered GCs on lipid and carbohydrate metabolism in the liver. Histological examination of liver sections revealed no obvious difference between the KO and WT livers, although hepatic cholesterol levels were found to be lower in the KO mice compared with WT (n=4). Pooled liver RNA from 3 WT and 3 KO male mice were used to assess changes in expression of genes involved in a variety of metabolic pathways, using Affymetrix arrays. Peroxisomal acyl-CoA thioesterase 2A (PTE-2A), an enzyme involved in peroxisomal β-oxidation and proposed to regulate bile acid formation and excretion, was up regulated 7.4 fold in the H6PDH KO mice compared with WT controls (P< 0.001). This increase in expression was confirmed by real time PCR, where there was an 18.4 fold increase in the KO compared to WT (P<0.001). Cyp7a1, which encodes cholesterol-7a hydroxylase, the rate limiting step in bile acid formation, was increased 1.6 fold in the H6PDH KO male mice compared to WT mice (P<0.001), and the very low density lipoprotein receptor (VLDLR) was increased 2 fold in the KO mice compared with WT (P<0.001). These data suggest a potentially novel role for H6PDH and possibly GCs in the maintenance of cholesterol and/or bile acid homeostasis.

Volume 11

8th European Congress of Endocrinology incorporating the British Endocrine Societies

European Society of Endocrinology 
British Endocrine Societies 

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