Improved lipid and lipoprotein profile, hepatic insulin sensitivity, and glucose tolerance in 11beta-hydroxysteroid dehydrogenase type 1 null mice.
Excess tissue glucocorticoid action may underlie the dyslipidemia, insulin resistance, and impaired glucose tolerance of the metabolic syndrome. 11beta-Hydroxysteroid dehydrogenase type 1 (11beta-HSD-1) catalyzes conversion of circulating inert 11-dehydrocorticosterone into active corticosterone, thus amplifying local intracellular glucocorticoid action, particularly in liver. The importance of 11beta-HSD-1 in glucose homeostasis is suggested by the resistance of 11beta-HSD-1(-/-) mice to hyperglycemia upon stress or obesity, due to attenuated gluconeogenic responses. The present study further investigates the metabolic consequences of 11beta-HSD-1 deficiency, focusing on the lipid and lipoprotein profile. Ad lib fed 11beta-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-alpha (PPARalpha). 11beta-HSD-1(-/-) mice also have increased HDL cholesterol, with elevated liver mRNA and serum levels of apolipoprotein AI. Conversely, liver Aalpha-fibrinogen mRNA levels are decreased. Upon fasting, the normal elevation of peroxisome proliferator-activated receptor-alpha mRNA is lost in 11beta-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 11beta-HSD-1(-/-) mice, implying increased liver insulin sensitivity. Concordant with this, 24-h refed 11beta-HSD-1(-/-) mice have higher triglyceride but lower glucose levels. Further, 11beta-HSD-1(-/-) mice have improved glucose tolerance. These data suggest that 11beta-HSD-1 deficiency produces an improved lipid profile, hepatic insulin sensitization, and a potentially atheroprotective phenotype.
Morton
N M
NM
Molecular Endocrinology, Molecular Medicine Centre, University of Edinburgh, Western General Hospital, Crewe Rd. S., Edinburgh EH4 2XU, United Kingdom. nik.morton@ed.ac.uk
Holmes
M C
MC
Fiévet
C
C
Staels
B
B
Tailleux
A
A
Mullins
J J
JJ
Seckl
J R
JR
D042842:11-beta-Hydroxysteroid Dehydrogenases; D000818:Animals; D001483:Base Sequence; D017931:DNA Primers; D005340:Fibrinogen / Q000378:metabolism; D005951:Glucose Tolerance Test; D006913:Hydroxysteroid Dehydrogenases / Q000235:genetics / Q000378:metabolism*; D007333:Insulin Resistance; D008055:Lipids / Q000097:blood*; D008074:Lipoproteins / Q000097:blood*; D008099:Liver / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D014158:Transcription, Genetic
D017931:DNA Primers; D008055:Lipids; D008074:Lipoproteins; D005340:Fibrinogen; D006913:Hydroxysteroid Dehydrogenases; D042842:11-beta-Hydroxysteroid Dehydrogenases