Searchable abstracts of presentations at key conferences in endocrinology

ea0021oc3.8 | Young Endocrinologists prize session | SFEBES2009

Identification and functional impact of novel mutations in the gene encoding 11β-hydroxysteroid dehydrogenase type 1 in patients with hyperandrogenism

Lawson Alexander , Walker Elizabeth , Lavery Gareth , Bujalska Iwona , Hughes Beverly , Arlt Wiebke , Ride Jonathan , Stewart Paul

In peripheral target tissues, levels of active glucocorticoid hormones are controlled by 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) which catalyses the reduction of cortisone to cortisol within the endoplasmic reticulum. For functional 11-ketoreductase activity, 11β-HSD1 requires the NADPH-generating enzyme hexose-6-phosphate dehydrogenase (H6PDH). Loss of 11-ketoreductase activity results in increased cortisol clearance and activation of the HPA axis wi...

ea0015p150 | Diabetes, metabolism and cardiovascular | SFEBES2008

Activation of the unfolded protein response pathway in the skeletal muscle of hexose-6-phosphate dehydrogenase knockout mice induces a severe myopathy

Lavery Gareth , Bujalska Iwona , Turan Nil , Falciani Francesco , Walker Elizabeth , Stewart Paul

Hexose-6-phosphate dehydrogenase (H6PD) is a sarcoplasmic reticulum (SR) resident enzyme that metabolizes glucose-6-phosphate and generates NADPH that drives the activation of glucocorticoids by 11β-hydroxysteorid dehydrogenase type 1. H6PD KO mice exhibit improved skeletal muscle insulin sensitivity increased glucose uptake and glycogen storage. However, H6PD KO mice also develop a myopathy with switching from Type II to Type I fibers. Affected muscles have apparently no...

ea0013oc3 | Steroid synthesis and action | SFEBES2007

Transcriptional regulation of 11beta-hydroxysteroid dehydrogenase type 1 under the synergistic control of glucocorticoids and cytokines

Kaur Kirrenjit , Lavery Gareth , Walker Elizabeth , Stewart Paul , Hewison Martin , Cooper Mark , Rabbitt Elizabeth

It is well established that the use of therapeutic glucocorticoids to treat inflammatory disease has detrimental effects on bone and we have proposed that these clinical effects are determined by intracellular glucocorticoid generation (inactive cortisone/prednisone to cortisol/prednisolone) by 11beta-hydroxysteroid dehydrogenase type 1 (11b-HSD1). We have recently shown that glucocorticoids and cytokines are able to act cooperatively to upregulate the action of 11b-HSD1, a fi...

ea0013oc21 | Novartis Basic Endocrinology Award | SFEBES2007

Muscle cell differentiation is regulated by glucocorticoids, a process which is potentiated through the induction of 11 beta-hydroxysteroid dehydrogenase type 1 (11β-HSD1)

Sherlock Mark , Lavery Gareth , Horsburgh Jenny , Slabbert Ana , Toogood Andy , Stewart Paul

In vivo the 11β-HSD1 enzyme converts inactive cortisone to the active glucocorticoid cortisol. 11β-HSD1 is implicated in the metabolic syndrome through its expression in liver and adipose tissue by increasing local cortisol concentrations. However, little is known regarding the expression and function of 11β-HSD1 in muscle.Murine C2C12 muscle cells (myocytes) were differentiated from myoblasts to myotubules for 8 days, with and without the...

ea0013p178 | Diabetes, metabolism and cardiovascular | SFEBES2007

Abnormalities in lipogenesis and lipolysis in Mice Lacking Hexose-6-Phosphate Dehydrogenase (H6PDH)

Hewitt Kylie , Bujalska Iwona , Lavery Gareth , Hauton David , Walker Elizabeth , Stewart Paul

In humans, glucocorticoids (GC) are implicated in the pathogenesis of obesity and insulin resistance. In adipose tissue, GCs are regulated at the prereceptor level by oxo-reductase activity of 11beta-hydroxysteroid dehydrogenases type 1 (11β-HSD1). The hexose-6-phosphate dehydrogenase null mouse (H6PDH/KO) has shown that H6PDH is required for generating NADPH within the endoplasmic reticulum which determines the direction of 11β-HSD1 enzyme. We have shown that mRNA f...

ea0094p64 | Metabolism, Obesity and Diabetes | SFEBES2023

Female AKR1D1 knockout mice are protected against diet induced obesity and insulin resistance but not hepatic steatosis

Bailey Maira , Potter Tom , Larner Dean , Morgan Stuart , Lavery Gareth , Tomlinson Jeremy , Gathercole Laura

Bile acids and steroid hormones are potent regulators of metabolic phenotype. 5β-reductase (AKR1D1) is highly expressed in the liver where it catalyses a fundamental step in bile acid synthesis and inactivates steroid hormones. We have previously shown that male, but not female, AKR1D1 knockout (KO) mice on a normal chow diet are leaner than wildtype littermates but are not protected against diet induced obesity. Here we investigate the impact of a high fat diet on female...

ea0077p44 | Metabolism, Obesity and Diabetes | SFEBES2021

11β-HSD1 determines the extent of muscle atrophy during an acute exacerbation of COPD

Michelle Webster Justine , Waaijenberg Kelsy , Worp Wouter van de , Lambrichts Sara , Lavery Gareth , Hardy Rowan S , Langen Ramon

Introduction: Muscle atrophy is a major clinical complication of acute exacerbations (AE) in chronic obstructive pulmonary disease (COPD). The enzyme 11 beta-hydroxysteroid dehydrogenase 1 (11β-HSD1) activates glucocorticoids (GCs) within muscle, is induced by inflammation, and has been shown to contribute towards GC-induced muscle wasting. In this study, we examined the role of 11β-HSD1 in this context using a murine model of COPD-AE in animals with transgenic globa...

ea0086oc4.6 | Adrenal and Cardiovascular | SFEBES2022

Glucocorticoid excess elevates metabolic rate via a 11β-HSD1 dependent mechanism in C57BL/6J mice

Heaselgrave Samuel , Heising Silke , Morgan Stuart , Kabli Ali , Sagmeister Michael , Hardy Rowan , Doig Craig , Morton Nicholas , Tsintzas Kostas , Lavery Gareth

Introduction: Glucocorticoids are vital metabolic regulators. However, glucocorticoid excess (GE) causes severe metabolic dysfunction, ultimately leading to Cushing’s Syndrome. This dysfunction is often dependent on the presence of the enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1). Whether GE also alters metabolic rate, and whether this is also dependent on 11β-HSD1, remains unclear.Methods: Male and female wild-type (WT) ...

ea0086p157 | Adrenal and Cardiovascular | SFEBES2022

Depleting NAD+ pools specifically in the endoplasmic reticulum lumen impairs 11β-hydroxysteroid dehydrogenase activity

Kabli Ali , Heising Silke , Heaselgrave Samuel , Elhassan Yasir , Hardy Rowan , Stromland Oyvind , Ziegler Mathias , Morgan Stuart , Hodson David , Lavery Gareth

Introduction: The endoplasmic reticulum (ER) lumen enzyme 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) obtains NADPH from hexose-6-phosphate dehydrogenase to reduce cortisone to the active glucocorticoid cortisol. Cells depleted in NAD+ (parent molecule of NADPH) have impaired 11β -HSD1 activity, which can be rapidly rescued with supplementation of the NAD+ precursor nicotinamide riboside. This suggests the existence of an ER-specific pathway to NAD(P)(H)....

ea0044p187 | Obesity and Metabolism | SFEBES2016

NAD+ supplementation normalises central carbon metabolism in skeletal muscle: a mechanistic insight into the energetic consequences of age-related NAD+ decline

Oldacre-Bartley Lucy , Fletcher Rachel , Hollinshead Kate , Elhassan Yasir , Doig Craig , Tennant Daniel , Ludwig Christian , Lavery Gareth

A decline in skeletal muscle nicotinamide adenine dinucleotide (NAD+) can decrease mitochondrial function and energy metabolism in age-related metabolic disease. Restoration of NAD+ using the precursor nicotinamide riboside (NR) may serve to support age and disease driven impairment of mitochondrial energy metabolism. Manipulating NAD+, and consequently cellular pyridine nucleotide NAD(P)(H) pools, may impact the flux of glucose through intermediary energy metabolism pathways....