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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/E1045    most recent 00276.2007v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via ISI Web of Science (6) Citing Articles via Google Scholar Google Scholar Articles by Berthiaume, M. Articles by Deshaies, Y. Search for Related Content PubMed PubMed Citation Articles by Berthiaume, M. Articles by Deshaies, Y.

11-HSD1 inhibition improves triglyceridemia through reduced liver VLDL secretion and partitions lipids toward oxidative tissues

Faculty of Medicine, ¹Laval Hospital Research Center and ³Division of Kinesiology, Department of Social and Preventive Medicine, Laval University, Sainte-Foy, Quebec, Canada; ²Department of Kinesiology, University of Southern California, Los Angeles, California; ⁴Department of Medical Biochemistry and Biophysics, Umeå University, Umeå, Sweden; and ⁵Department of External Scientific Affairs, Merck Research Laboratories, Rahway, New Jersey

Submitted 12 May 2007 ; accepted in final form 26 July 2007

Tissue-specific alterations in 11-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 11-HSD1 inhibitor (compound A, 3 mg·kg^–1·day^–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 11-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.

11-hsd1 inhibitor; glucocorticoids; diet-induced obesity; triglycerides; lipid metabolism; lipid partitioning; lipid oxidation

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