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

11 beta-hydroxysteroid dehydrogenase 1 (11 beta-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 beta-HSD1 in livers of C57BL/6J mice consuming a Western-type diet (WTD). 11 beta-HSD1 ASO-treated mice consumed less food, so we compared them to ad libitum-fed mice and to food-matched mice receiving control ASO. Knockdown of 11 beta-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 significantly reduced in mice treated with 11 beta-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 beta-HSD1-treated mice.jlr Our results indicate that inhibition of 11 beta-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.-Li, G., A. Hernandez-Ono, R. M. Crooke, M. J. Graham, and H. N. Ginsberg. Effects of antisense-mediated inhibition of 11 beta-hydroxysteroid dehydrogenase type 1 on hepatic lipid metabolism. J. Lipid Res. 2011. 52: 971-981.