Liver X receptor agonist T0901317 reduces atherosclerotic lesions in apoE-/- mice by up-regulating NPC1 expression

• Published in: Science China. Life sciences Vol. 51; no. 5; pp. 418 - 429
• Main Authors: Ou, Xiang, Dai, XiaoYan, Long, ZhiFeng, Tang, YaLing, Cao, DongLi, Hao, XinRui, Hu, YanWei, Li, XiaoXu, Tang, ChaoKe
• Format: Journal Article
• Language: English
• Published: Beijing Science China Press 01.05.2008; Springer Nature B.V
• Subjects: Agonists; Animals; Aorta; Aorta - metabolism; Apolipoprotein E; Apolipoproteins E - blood; Apolipoproteins E - genetics; Apolipoproteins E - physiology; Arteriosclerosis; Atherosclerosis; Atherosclerosis - genetics; Atherosclerosis - metabolism; Atherosclerosis - pathology; Atherosclerosis - prevention & control; Base Sequence; Biomedical and Life Sciences; C1 protein; Cell Line; Cholesterol; DNA Primers; DNA-Binding Proteins - agonists; Gene expression; High cholesterol diet; High density lipoprotein; High fat diet; Hydrocarbons, Fluorinated; Immunohistochemistry; Intestinal Mucosa - metabolism; Intracellular Signaling Peptides and Proteins; Life Sciences; Liver - metabolism; Liver X Receptors; Macrophages; Male; Mice; Mice, Knockout; Niemann-Pick C1 Protein; Niemann-Pick disease; Npc1 protein; Orphan Nuclear Receptors; Proteins; Proteins - genetics; Receptors, Cytoplasmic and Nuclear - agonists; RNA-mediated interference; siRNA; Small intestine; Sulfonamides - pharmacology; Up-Regulation - drug effects; Western blotting; atherosclerosis; plaque; liver X receptor agonist; Niemann-Pick C1 protein
• ISSN: 1006-9305; 1674-7305; 1862-2798; 1869-1889
• DOI: 10.1007/s11427-008-0054-4

In this study, we studied the effect of liver X receptor (LXR) agonist T0901317 on Niemann-Pick C1 protein (NPC1) expression in apoE -/- mice. Male apoE -/- mice were randomized into 4 groups, baseline group ( n =10), control group ( n =14), treatment group ( n =14) and prevention group ( n =14). All of the mice were fed with a high-fat/high-cholesterol (HFHC) diet containing 15% fat and 0.25% cholesterol. The baseline group treated with vehicle was sacrificed after 8 weeks of the diet. The control group and the prevention group were treated with either vehicle or T0901317 daily by oral gavage for 14 weeks. The treatment group was treated with vehicle for 8 weeks, and then was treated with the agonist T0901317 for additional 6 weeks. Gene and protein expression was analyzed by real-time quantitative PCR, immunohistochemistry and Western blotting, respectively. Plasma lipid concentrations were measured by commercially enzymatic methods. We used RNA interference technology to silence NPC1 gene expression in THP-1 macrophage-derived foam cells and then detected the effect of LXR agonist T0901317 on cholesterol efflux. Plasma triglyceride (TG), total cholesterol (TC), high density lipoprotein cholesterol (HDL-C) and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 treatment reduced the aortic atherosclerotic lesion area by 64.2% in the prevention group and 58.3% in the treatment group. LXR agonist treatment increased NPC1 mRNA expression and protein levels in the small intestine, liver and aorta of apoE -/- mice. Compared with the normal cells, cholesterol efflux of siRNA THP-1 macrophage-derived foam cells was significantly decreased, whereas cholesterol efflux of LXR agonist T0901317-treated THP-1 macrophage-derived foam cells was significantly increased. Our results suggest that LXR agonist T0901317 inhibits atherosclerosis development in apoE -/- mice, which is related to up-regulating NPC1 expression.