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

Abstract

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. 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 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. 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 virustreated 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. Supplementary key words nuclear hormone receptor • hypertriglyceridemia • short hairpin RNA • adenoviral gene transfer • triglycerides • gene expression Disorders in lipid metabolism still represent a major unmet medical need. Lipid disorders are main risk factors for cardiovascular diseases like atherosclerosis, which is the leading cause of death in industrialized countries. Statins, drugs that inhibit HMG-CoA reductase, are effective in lowering LDL cholesterol levels, but they have only moderate effects on plasma triglyceride (TG) and HDLcholesterol levels.The nuclear hormone receptors liver X receptors LXRa and LXRb are important cellular cholesterol sensors. Activated by oxygenated sterols, 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 (as reviewed in Refs.

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