11beta-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues.
Tissue-specific alterations in 11beta-hydroxysteroid dehydrogenase (HSD) type 1 activity, which amplifies glucocorticoid action, are thought to contribute to some of the metabolic complications of obesity. The present study tested whether hypertriglyceridemia is one such complication by investigating the effects of an 11beta-HSD1 inhibitor (compound A, 3 mgxkg(-1)xday(-1), 21 days) on triglyceride (TG) metabolism in a rat model of diet-induced obesity. The dose of compound A used did not affect food intake or final body weight. Compound A improved fasting triglyceridemia (-42%) through a robust reduction (-41%) in hepatic TG secretion rate, without change in plasma TG clearance rate. Uptake of TG-derived fatty acids was, however, increased in oxidative tissues, including red gastrocnemius (+47%), heart (+39%), and brown adipose tissue (BAT, +46%) at the expense of the liver, with a concomitant increase in plasma membrane fatty acid-binding protein. Lipid oxidation products were increased in red gastrocnemius (+35%) and heart (+33%), as were levels of uncoupling protein 1 mRNA in BAT (+48%), and carnitine palmitoyltransferase 1 activity tended to be increased in some oxidative tissues. These findings demonstrate that pharmacological inhibition of 11beta-HSD1 at a dose that does not affect food intake improves triglyceridemia by reducing hepatic very low density lipoprotein-TG secretion, with a shift in the pattern of TG-derived fatty acid uptake toward oxidative tissues, in which lipid accumulation is prevented by increased lipid oxidation.
Faculty of Medicine, Laval Hospital Research Center, Laval Univ., 2725 Ch Sainte-Foy, QC, Canada G1V 4G5.
Magalie
M
Berthiaume
Mathieu
M
Laplante
William T
WT
Festuccia
Katherine
K
Cianflone
Lorraine P
LP
Turcotte
Denis R
DR
Joanisse
Gunilla
G
Olivecrona
Rolf
R
Thieringer
Yves
Y
Deshaies
D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000037:antagonists & inhibitors*; D002001:Adipose Tissue, Brown / Q000187:drug effects / Q000378:metabolism; D000818:Animals; D004791:Enzyme Inhibitors / Q000494:pharmacology; D006321:Heart / Q000187:drug effects; D015228:Hypertriglyceridemia / Q000097:blood / Q000378:metabolism*; D050356:Lipid Metabolism / Q000187:drug effects*; D008079:Lipoproteins, VLDL / Q000187:drug effects* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects* / Q000378:metabolism; D008297:Male; D018482:Muscle, Skeletal / Q000187:drug effects / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism; D010084:Oxidation-Reduction / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D014230:Triazoles / Q000494:pharmacology*; D014280:Triglycerides / Q000378:metabolism*
D004791:Enzyme Inhibitors; D008079:Lipoproteins, VLDL; D014230:Triazoles; D014280:Triglycerides; C524574:compound A (octyltriazole); C030106:very low density lipoprotein triglyceride; D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1