Improved lipid profile through liver-specific knockdown of liver X receptor alpha in KKAy diabetic mice
| Autor: | Corinna Schoelch, Joerg F. Rippmann, Heidi Pavliska, Juergen Prestle, Helmuth van Es, André van Marle, Thomas Nolte |
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| Rok vydání: | 2008 |
| Předmět: |
medicine.medical_specialty
Receptors Cytoplasmic and Nuclear QD415-436 Biology Biochemistry Models Biological Adenoviridae Cell Line Diabetes Mellitus Experimental Small hairpin RNA Mice Endocrinology In vivo Internal medicine Gene expression medicine short hairpin RNA Animals RNA Messenger Liver X receptor triglycerides Liver X Receptors Hypertriglyceridemia Gene knockdown Lipoprotein lipase Cell Biology Orphan Nuclear Receptors Lipids adenoviral gene transfer DNA-Binding Proteins Lipoprotein Lipase nuclear hormone receptor Nuclear receptor Liver gene expression RNA lipids (amino acids peptides and proteins) Stearoyl-CoA desaturase-1 Sterol Regulatory Element Binding Protein 1 Stearoyl-CoA Desaturase |
| Zdroj: | Journal of Lipid Research, Vol 50, Iss 1, Pp 22-31 (2009) |
| ISSN: | 0022-2275 |
| Popis: | Nuclear hormone receptors liver X receptor (LXRalpha and LXRbeta) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRalpha in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectively knock down LXRalpha gene expression. Out of five different short hairpin RNAs (shRNAs) that were tested in vitro, one construct was selected for detailed analysis of LXRalpha knockdown in vivo. Reduction of LXRalpha transcript levels to 48 +/- 13% compared with control virus transduction resulted in a significant downregulation of the LXRalpha-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. Interestingly, ABCA1 and phoshoenolpyruvate carboxykinase 1 expression was not affected, whereas lipoprotein lipase (LPL) expression was found to be increased. In addition, 8 days after virus transduction, both plasma and liver triglycerides (TGs) were reduced by about 50%. Changes in TG levels were not due to reduced food intake in virus-treated animals, because pair-fed mice showed unchanged TG levels. Taken together, liver-specific knockdown of LXRalpha in vivo by shRNA reduced expression of lipogenic master genes, like SREBP1c, and improved the lipid profile of hypertriglyceridemic KKAy mice. |
| Databáze: | OpenAIRE |
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