Searchable abstracts of presentations at key conferences in endocrinology
Endocrine Abstracts (2011) 25 P166

Diabetes, metabolism and cardiovascular

Lack of beneficial metabolic profile in liver-specific 11β-hydroxysteroid dehydrogenase type 1 (11β-HSD1) knockout mice

Gareth Lavery, Elizabeth Rabbitt, Agnieszka Zielinszka, Beverley Huges, Nina Semjonous, Khalid Saqib, Stuart Morgan, Laura Gathercole, Elizabeth Walker & Paul Stewart


University of Birmingham, Birmingham, UK.

In humans glucocorticoid (GC) excess can promote hepatic glucose and triglyceride production contributing to obesity, fatty liver and diabetes. 11β-HSD1 activates GCs (11-DHC to corticosterone in mice), thereby increasing tissue concentrations. The liver has the highest 11β-HSD1 activity, and its inhibition has emerged as a therapeutic option. To investigate this we generated 11β-HSD1 liver-specific knockouts (HSD1LKO) and examined GC metabolism and responses to high-fat diet (HFD).

We generated HSD1LKOs using an albumin-Cre transgenic mouse and showed abolished 11β-HSD1 activity only in the liver; 11β-HSD1 knockout (HSD1KO) mice were used as additional controls.

An oral cortisone challenge resulted in serum cortisol concentrations of 1830±184 nM (control), 691±70 nM (HSD1LKO) and 67±24 nM (HSD1KO) (control vs. HSD1LKO P<0.002, n=7–9), indicating significant extra-hepatic GC production in HSD1LKOs. Corticosterone/11-DHC urinary metabolite ratios were the same in HSD1LKO and controls (0.08) and elevated (0.5) in HSD1KOs, indicating that despite diminished hepatic GC production there is no impact on hepatic metabolism set-point in HSD1LKOs. HSD1LKO and controls had similar basal serum corticosterone concentrations and adrenals were only significantly larger in HSD1KOs. HSD1LKO and controls were alike for body, liver, epididymal fat pad and muscle weight. No differences were observed for fed and fasting glucose and insulin levels on regular and HFD. HFD induced glucose intolerance to similar levels in both HSD1LKO and controls subjected to glucose tolerance tests. Both HSD1LKO and controls developed fatty liver on HFD assessed by Oil Red O staining and hepatic triglyceride (TAG) assays, and no differences were observed between serum TAG, NEFA and cholesterol profiles.

Despite the loss of hepatic GC regeneration, HSD1LKOs had no protection from the metabolic consequences of a HFD as seen in HSD1KOs. This model produces a novel insight into the target for 11β-HSD1 inhibition in terms of improving metabolic homeostasis and suggests a primary role for extra-hepatic enzyme expression.

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