Biomedical subjects

Gareth G Lavery

Publications and source records attributed to Gareth G Lavery.

6 recordsLinked to original sources

PubMed2005

Hexose-6-phosphate dehydrogenase knock-out mice lack 11 beta-hydroxysteroid dehydrogenase type 1-mediated glucocorticoid generation.

The local generation of active glucocorticoid by NADPH-dependent, 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) oxoreductase activity, has emerged as an important factor in regulating hepatic glucose output and visceral adiposity. We have proposed that this NADPH is generated within the endoplasmic reticulum by the enzyme hexose-6-phosphate dehydrogenase. To address this hypothesis, we generated mice with a targeted inactivation of the H6PD gene. These mice were unable to convert 11-dehydrocorticosterone (11-DHC) to corticosterone but demonstrated increased corticosterone to 11-DHC conversion consistent with lack of 11beta-HSD1 oxoreductase and a concomitant increase in dehydrogenase activity. This increased corticosterone clearance in the knock-out mice resulted in a reduction in circulating corticosterone levels. Our studies define the critical requirement of hexose-6-phosphate dehydrogenase for 11beta-HSD1 oxoreductase activity and add a new dimension to the investigation of 11beta-HSD1 as a therapeutic target in patients with the metabolic syndrome.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2004

11beta-hydroxysteroid dehydrogenase type 1: a tissue-specific regulator of glucocorticoid response.

11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1) interconverts inactive cortisone and active cortisol. Although bidirectional, in vivo it is believed to function as a reductase generating active glucocorticoid at a prereceptor level, enhancing glucocorticoid receptor activation. In this review, we discuss both the genetic and enzymatic characterization of 11beta-HSD1, as well as describing its role in physiology and pathology in a tissue-specific manner. The molecular basis of cortisone reductase deficiency, the putative "11beta-HSD1 knockout state" in humans, has been defined and is caused by intronic mutations in HSD11B1 that decrease gene transcription together with mutations in hexose-6-phosphate dehydrogenase, an endoluminal enzyme that provides reduced nicotinamide-adenine dinucleotide phosphate as cofactor to 11beta-HSD1 to permit reductase activity. We speculate that hexose-6-phosphate dehydrogenase activity and therefore reduced nicotinamide-adenine dinucleotide phosphate supply may be crucial in determining the directionality of 11beta-HSD1 activity. Therapeutic inhibition of 11beta-HSD1 reductase activity in patients with obesity and the metabolic syndrome, as well as in glaucoma and osteoporosis, remains an exciting prospect.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2003

Late-onset apparent mineralocorticoid excess caused by novel compound heterozygous mutations in the HSD11B2 gene.

Mutations in the gene encoding 11beta-hydroxysteroid dehydrogenase type 2, 11beta-HSD2 (HSD11B2), explain the molecular basis for the syndrome of apparent mineralocorticoid excess (AME), characterized by severe hypertension and hypokalemic alkalosis. Cortisol is the offending mineralocorticoid in AME, as the result of a lack of 11beta-HSD2-mediated cortisol to cortisone inactivation. In this study, we describe mutations in the HSD11B2 gene in 3 additional AME kindreds in which probands presented in adult life, with milder phenotypes including the original seminal case reported by Stewart and Edwards. Genetic analysis of the HSD11B2 gene revealed that all probands were compound heterozygotes, for a total of 7 novel coding and noncoding mutations. Of the 7 mutations detected, 6 were investigated for their effects on gene expression and enzyme activity by the use of mutant cDNA and minigene constructs transfected into HEK 293 cells. Four missense mutations resulted in enzymes with varying degrees of activity, all <10% of wild type. A further 2 mutations generated incorrectly spliced mRNA and predicted severely truncated, inactive enzyme. The mothers of 2 probands heterozygous for missense mutations have presented with a phenotype indistinguishable from "essential" hypertension. These genetic and biochemical data emphasize the heterogeneous nature of AME and the effects that heterozygosity at the HSD11B2 locus can have on blood pressure in later life.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2003

Mutations in the genes encoding 11beta-hydroxysteroid dehydrogenase type 1 and hexose-6-phosphate dehydrogenase interact to cause cortisone reductase deficiency.

In cortisone reductase deficiency (CRD), activation of cortisone to cortisol does not occur, resulting in adrenocorticotropin-mediated androgen excess and a phenotype resembling polycystic ovary syndrome (PCOS; refs. 1,2). This suggests a defect in the gene HSD11B1 encoding 11beta-hydroxysteroid dehydrogenase type 1 (11beta-HSD1), a primary regulator of tissue-specific glucocorticoid bioavailability. We identified intronic mutations in HSD11B1 that resulted in reduced gene transcription in three individuals with CRD. In vivo, 11beta-HSD1 catalyzes the reduction of cortisone to cortisol whereas purified enzyme acts as a dehydrogenase converting cortisol to cortisone. Oxo-reductase activity can be regained using a NADPH-regeneration system and the cytosolic enzyme glucose-6-phosphate dehydrogenase. But the catalytic domain of 11beta-HSD1 faces into the lumen of the endoplasmic reticulum (ER; ref. 6). We hypothesized that endolumenal hexose-6-phosphate dehydrogenase (H6PDH) regenerates NADPH in the ER, thereby influencing directionality of 11beta-HSD1 activity. Mutations in exon 5 of H6PD in individuals with CRD attenuated or abolished H6PDH activity. These individuals have mutations in both HSD11B1 and H6PD in a triallelic digenic model of inheritance, resulting in low 11beta-HSD1 expression and ER NADPH generation with loss of 11beta-HSD1 oxo-reductase activity. CRD defines a new ER-specific redox potential and establishes H6PDH as a potential factor in the pathogenesis of PCOS.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗

PubMed2002

Prereceptor regulation of glucocorticoid action by 11beta-hydroxysteroid dehydrogenase: a novel determinant of cell proliferation.

Isozymes of 11beta-hydroxysteroid dehydrogenase (11beta-HSD) act at a prereceptor level to regulate the tissue-specific availability of active glucocorticoids. To examine the effect of this on cell proliferation and differentiation, we have developed transfectant variants of a rat osteosarcoma cell line that express cDNA for 11beta-HSD1 (ROS 17/2.8beta1) or 11beta-HSD2 (ROS 17/2.8beta2). ROS 17/2.8beta1 showed net conversion of cortisone to cortisol whereas ROS 17/2.8beta2 showed only inactivation of cortisol to cortisone. There was no significant difference in glucocorticoid receptor (GR) expression between the different clones. However, in proliferation and differentiation studies, ROS 17/2.8beta2 cells were completely resistant to cortisol. In contrast, ROS 17/2.8beta1 were sensitive to both cortisone and cortisol. Expression of 11beta-HSD1 decreased cell proliferation whereas 11beta-HSD2 increased proliferation. These responses appear to be due to metabolism of endogenous serum glucocorticoids; proliferation of ROS 17/2.8beta1 decreased further with exogenous cortisone or cortisol whereas ROS 17/2.8beta2 were resistant to both compounds. The pro-proliferative effects of 11beta-HSD2 were abrogated by 18beta-glycyrrhetinic acid, an 11beta-HSD inhibitor, and in cells transfected with cDNA encoding inactive 11beta-HSD2. Data indicate that differential regulation of 11beta-HSD1 and 2 (rather than GR expression) is a key determinant of cell proliferation. Dysregulated expression of 11beta-HSD2 may be a novel feature of tumorigenesis.

11-beta-Hydroxysteroid Dehydrogenase Type 1↗

PubMed2002

Association studies between the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2), type 1 diabetes mellitus and diabetic nephropathy.

OBJECTIVE: Mutations in the HSD11B2 gene (encoding human 11beta-hydroxysteroid dehydrogenase type 2) explain the syndrome of apparent mineralocorticoid excess where cortisol acts as a mineralocorticoid. A microsatellite marker within the HSD11B2 gene associates with salt sensitivity and hypertension--phenotypes characterising diabetic nephropathy. Here, we evaluate the HSD11B2 gene as a susceptibility locus for diabetic nephropathy. DESIGN: 150 patients with type 1 diabetes and nephropathy (DN), 145 patients with type 1 diabetes with a long duration of non-nephropathy (LDNN) and 151 normal controls were studied. METHODS: We determined allele frequencies for the (CA)n repeat marker within intron I of the HSD11B2 gene. Duration of type 1 diabetes, diabetic status and renal function were recorded. RESULTS: 11 alleles (138-158) for the marker were observed. Allele 152 was significantly increased in controls compared with LDNN (70.5% vs 57.6%, P(c)<0.05 where P(c) is the P value corrected for multiple comparisons) but no difference was observed between DN and LDNN subjects. Allele 154 was significantly increased in the LDNN compared with the DN subjects (15.9% vs 7.0%, P(c)<0.01) but no difference was observed between DN and controls. A greater proportion of subjects carried at least 1 allele <152 in DN compared with control subjects (47.3% vs 28.5%, P(c)<0.01), but no difference was observed in LDNN compared with control and DN subjects. CONCLUSIONS: Weak associations are reported between the HSD11B2 gene, type 1 diabetes mellitus and nephropathy. The increased frequency of HSD11B2 short alleles in the diabetic groups may reflect reduced renal 11beta-hydroxysteroid dehydrogenase type 2 (11beta-HSD2) activity and may, in part, explain the enhanced salt sensitivity observed in patients with type 1 diabetes.

11-beta-Hydroxysteroid Dehydrogenase Type 2↗