Improved lipid profile through liver-specific knockdown of liver X receptor alpha in KKAy diabetic mice

Nuclear hormone receptors liver X receptor (LXR alpha and LXR beta) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis. To further elucidate the function of LXRa in liver lipid metabolism in a disease-relevant animal model, the KKAy mouse, we used adenoviral vectors to selectively knock down LXRa gene expression. Out of five different short hairpin RNAs (shRNAs) that were tested in vitro, one construct was selected for detailed analysis of LXRa knockdown in vivo. Reduction of LXRa transcript levels to 48 +/- 13% compared with control virus transduction resulted in a significant downregulation of the LXR alpha-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. Interestingly, ABCA1 and phoshoenol-pyruvate 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 LXRa in vivo by shRNA reduced expression of lipogenic master genes, like SREBP1c, and improved the lipid profile of hypertriglyceridemic KKAy mice.-Rippmann, J. F., C. Schoelch, T. Nolte, H. Pavliska, A. van Marle, H. van Es, and J. Prestle. Improved lipid profile through liver-specific knockdown of liver X receptor a in KKA y diabetic mice. J. Lipid Res. 2009. 50: 22-31.