Liver X Receptor Agonist Up-regulates Niemann-Pick Type C1 And Niemann-Pick Type C2 Expression In ApoE-/- Mice

NPC1 is a 47 kb gene with 25 exons found on chromosome 18q11, NPC1 protein is a multitransmembrane protein that localizes to late endosomes. NPC2, maps to chromosome 14q24.3, NPC2 protein is a intralysosomal protein that has been characterized biochemically as a cholesterol binding protein. NPC1 and NPC2 control cholesterol trafficking to the plasma membrane. The liver X receptors (LXR and LXR ) are ligand-dependent transcription factors belonging to the nuclear hormone receptor superfamily, they can regulate the expression of genes controlling lipid metabolism. Recent research shows that LXR agonist can up-regulate the expression of NPC1 and NPC2 of cultural macrophages in vitro, resulting in enriched cholesterol content in the outer layer of macrophages, thus becoming more available for efflux. At present, there are no reports whether LXR agonist can influence the expression of NPC1 and NPC2 in the organism.Objective To study the effect of T0901317, a kind of LXR agonists, on Niemann-Pick Type C1(NPC1) and Niemann-Pick Type C2(NPC2) expression in apoE-/- mice,and discuss the roles of NPC1 and NPC2 in the process of atherosclerotic lesion.Methods 52 male apoE-/- mice were randomly divided into four groups: a. base group (n=10); b. control group (n=14); c. LXR agonist treatment group (n=14); d. LXR agonist prevention group (n=14). All mice were fed a high-fat/high-cholesterol diet; the base group was treated with vehicle for 8 weeks; the control group was treated with vehicle for 14 weeks; the LXR agonist treatment group was treated with vehicle in the former 8 weeks and treated with T0901317 in the latter 6 weeks; the LXR agonist prevention group was treated with LXR agonist for 14 weeks. NPC1 and NPC2 level of several tissues were determined by Real-time RT-qPCR, Western blot and immunohistochemistry respectively; plasma total cholesterol(TC),triglyceride(TG),high density lipoprotein-cholesterol(HDL-C),low density lipoprotein-cholesterol,apolipoprotein A-â… ( ApoAâ… )and apolipoprotein B were determined by commercially enzymatic methods; atherosclerotic lesion in the aorta were detected by oil red O staining method and Sudanâ…£staining method; lipid cumulation in the liver was detected by oil red O staining method.Results TC,TG,HDL-C and ApoAâ… were markedly increased in LXR agonist treatment and prevention groups compared with control group(p<0.05); atherosclerotic plaques and lipid stripes in aorta of LXR agonist treatment and prevention groups were markedly less than control group(p<0.05); NPC1 and NPC2 expression of LXR agonist treatment and prevention groups in liver, aorta and small intestine were up-regulated when compared with control group(p<0.05).Conclusion LXR agonist can reduce atherosclerotic plaques and up-regulate the expression of NPC1 and NPC2 of liver,aorta and small intestine in apoE-/- mice fed with high-fat/high-cholesterol diet.