Effects of antisense-mediated inhibition of 11 β -hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism

Abstract

11 β -hydroxysteroid dehydrogenase 1 (11 β -HSD1) converts inactive 11-keto derivatives to active glucocorticoids within tissues and may play a role in the metabolic syndrome (MS). We used an antisense oligonucleotide (ASO) to knock down 11 β -HSD1 in livers of C57BL/6J mice consuming a Western-type diet (WTD). 11 β -HSD1 ASO-treated mice consumed less food, so we compared them to ad libitumfed mice and to food-matched mice receiving control ASO. Knockdown of 11 β -HSD1 directly protected mice from WTD-induced steatosis and dyslipidemia by reducing synthesis and secretion of triglyceride (TG) and increasing hepatic fatty acid oxidation. These changes in hepatic and plasma lipids were not associated with reductions in genes involved in de novo lipogenesis. However, protein levels of both sterol regulatory element-binding protein (SREBP) 1 and fatty acid synthase were signifi cantly reduced in mice treated with 11 β -HSD1 ASO. There was no change in hepatic secretion of apolipoprotein (apo)B, indicating assembly and secretion of smaller apoB-containing lipoproteins by the liver in the 11 β -HSD1-treated mice. Our results indicate that inhibition of 11 β -HSD1 by ASO treatment of WTD-fed mice resulted in improved plasma and hepatic lipid levels, reduced lipogenesis by posttranslational regulation, and secretion of similar numbers of apoB-containing lipoproteins containing less TG per particle. Copyright © 2011 by the American Society for Biochemistry and Molecular Biology, Inc.