Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11β-hydroxysteroid dehydrogenase type 1 null mice.

Excess tissue glucocorticoid action may underlie the dyslipidemia, insulin resistance, and impaired glucose tolerance of the metabolic syndrome. 11 beta -Hydroxy-steroid dehydrogenase type 1 (11 beta -HSD-1) catalyzes conversion of circulating inert 11-dehydrocorticosterone into active corticosterone, thus amplifying local intracellular glucocorticoid action, particularly in liver. The importance of 11 beta -HSD-1 in glucose homeostasis is suggested by the resistance of 11 beta -HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses. The present study further investigates the metabolic consequences of 11 beta -HSD-1 deficiency, focusing on the lipid and lipoprotein profile. Ad lib fed 11 beta -HSD-1(-/-) mice have markedly lower plasma triglyceride levels. This appears to be driven by increased hepatic expression of enzymes of fat catabolism (carnitine palmitoyltransferase-I, acyl-CoA oxidase, and uncoupling protein-2) and their coordinating transcription factor, peroxisome proliferator-activated receptor-a (PPAR alpha). 11 beta -HSD-1(-/-) mice also have increased HDL cholesterol, with elevated liver mRNA and serum levels of apolipoprotein Al. Conversely, liver A alpha -fibrinogen mRNA levels are decreased. Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-a mRNA is lost in 11 beta -HSD-1(-/-) mice, consistent with attenuated glucocorticoid induction. Despite this, crucial oxidative responses to fasting are maintained; carnitine palmitoyltransferase-I induction and glucose levels are similar to wild type. Refeeding shows exaggerated induction of genes encoding lipogenic enzymes and a more marked suppression of genes for fat catabolism in 11 beta -HSD-1(-/-) mice, implying increased liver insulin sensitivity. Concordant with this, 24-h refed 11 beta -HSD-1(-/-) mice have higher triglyceride but lower glucose levels. Further, 11 beta -HSD-1(-/-) mice have improved glucose tolerance. These data suggest that 11 beta -HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype.