Endocrine Abstracts

Nearly all the functions of the liver display zonation in distribution within each the lobule. Hepatic cortisol availability is controlled by enzymes that regenerate cortisol from inactive cortisone (11β-hydroxysteroid dehydrogenase type 1, 11β-HSD1). Dysregulation of hepatic 11β-HSD1 activity has been implicated in insulin resistance. Key processes such as gluconeogenesis are located in the periportal hepatocytes, although current dogma describes hepatic 11&#94...

11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inactive glucocorticoid to their active form (cortisone to cortisol in humans, 11-dehydrocorticosterone (11-DHC) to corticosterone in mice), and is dependent upon the presence of cofactor NADPH generated by the enzyme hexose-6-phosphate (H6PDH) for its activity. The 11β-HSD1/H6PDH system is implicated in the pathogenesis of the metabolic syndrome by generating tissue specific glucocorticoid excess. The ...

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...