Abstract
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.
Highlights
Nuclear hormone receptors liver X receptor (LXRa and LXRb) ligands are attractive approaches for the treatment of dyslipidemia and atherosclerosis
For the interference with the LXRa gene expression, a set of five different LXRa-short hairpin RNA (shRNA), one green fluorescent protein reporter, and one shRNA control adenovirus vectors were constructed. These vectors (LXRa_v1, LXRa_v2, LXRa_v3, LXRa_v4, and LXRa_v5), and shRNA sequence reference were first tested in an in vitro cell culture system for their efficiency to knock down LXRa mRNA, as well as for the downstream effects putatively related to reduced expression of this nuclear hormone receptor
The mouse cell line FL83B, which is of hepatic origin, is able to respond to the treatment of LXR-specific agonists, like T0901317
Summary
Nuclear hormone receptors liver X receptor (LXRa and LXRb) 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. Reduction of LXRa transcript levels to 48 6 13% compared with control virus transduction resulted in a significant downregulation of the LXRa-regulated lipogenic genes sterol-regulatory element binding protein-1c (SREBP1c) and stearoyl CoA desaturase 1 in vivo. 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. They form obligate heterodimers with retinoid X receptor and regulate expression of genes involved in cholesterol and lipid metabolism, as well as glucose homeostasis and inflammation
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