Abstract
11β-hydroxysteroid dehydrogenase 1 (11β-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 11β-HSD1 in livers of C57BL/6J mice consuming a Western-type diet (WTD). 11β-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 11β-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 11β-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 11β-HSD1-treated mice. Our results indicate that inhibition of 11β-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.
Highlights
11-hydroxysteroid dehydrogenase 1 (11-HSD1) converts inactive 11-keto derivatives to active glucocorticoids within tissues and may play a role in the metabolic syndrome (MS)
The lower rates of de novo lipogenesis were associated with decreased levels of both the precursor and mature forms of SREBP1 protein (Fig. 3F) and reductions in FAS protein (Fig. 3G), despite no effects of 11-HSD1 antisense oligonucleotide (ASO) on mRNA levels of SREBP1C and FAS (Fig. 3H). -oxidation, measured ex vivo in primary hepatocytes isolated from each group of mice, was increased by 81% in the 11-HSD1 ASO-treated mice compared with control ASO mice and 55% compared with food-matched control (FMC) ASO controls (Fig. 3I)
These studies have clearly increased our knowledge in this area, several important issues regarding the role of 11-HSD1 in energy metabolism remain incompletely characterized
Summary
We studied male C57BL/6J wide-type mice purchased from The Jackson Laboratory (Bar Harbor, ME). 4 h-fasted mice were injected intravenously with a mixture of 200 mCi of [35S]methionine (1175 Ci/mmol, PerkinElmer Life Sciences) and 500 mg/kg Triton WR1339 (Sigma-Aldrich) in 0.9% sodium chloride. They were bled prior to injection and at 30, 60, 90, and 120 min. Snap-frozen in liquid nitrogen, and maintained at Ϫ80°C These tissues were analyzed for hepatic lipids determination, quantitative real-time PCR, and immunoblots. The rate of hepatic de novo lipogenesis was determined by measuring the amount of newly synthesized FA present in the liver 1 h after intraperitoneal injection of 3H2O 1 mCi into 4 h-fasted mice as previously described [28].
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