Effect of T0901317 on Hepatic Proinflammatory Gene Expression in ApoE−/− Mice Fed a High-fat/high-cholesterol Diet

Dai, Xiaoyan; Ou, Xiang; Hao, Xinrui; Cao, Dongli; Tang, Yaling; Hu, Yan‐Wei; Li, Xiaoxu; Tang, Chao-Ke

doi:10.1007/s10753-007-9026-2

Cited by 19 publications

(12 citation statements)

References 40 publications

(39 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In contrast, the T0901317-induced increase in cholesterol in apoE 2/2 was in HDL and accompanied by a marked increase in apoA1, but not ApoB levels (20). Interestingly, the apolipoprotein composition and size of the T0901317-induced particle in E3L is comparable to that induced by T0901317 in C57/Bl6 mice which was designated "enlarged HDL" (22).…”

Section: Discussionmentioning

confidence: 90%

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

Verschuren

Weij

Zadelaar

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

The aim of this study was to define the antiatherosclerotic role of liver-X-receptors (LXRs) under lesion progressive and lesion regressive conditions, to establish a temporal line of events, and to gain insights into the mechanisms underlying the anti-atherogenic potency of LXRs. We used apoE*3Leiden (E3L) mice to comprehensively and time-dependently dissect how T0901317, an LXR-agonist, inhibits initiation and progression of atherosclerotic lesions and regresses existing lipid-and macrophage-rich lesions. T0901317 suppresses lesion evolution and promotes lesion regression regarding lesion number, area, and severity. Quantitative plasma and vessel wall analyses corroborated by immunohistochemical evaluation of the aortic lesions revealed that under progressive (high-cholesterol diet) as well as regressive (cholesterol-free diet) conditions T0901317: i) significantly increases plasma triglyceride and total cholesterol levels; ii) does not affect the systemic inflammation marker, Serum amyloid A (SAA); iii) suppresses endothelial monocyte adhesion; and iv) induces the expression of the cholesterol efflux-related genes apolipoprotein E (apoE), ATP binding cassette (ABC) transporters ABCA1 and ABCG1. Furthermore, under progressive conditions, T0901317 suppresses the vascular inflammatory status (NF-kB) and the vascular expression of adhesion molecules [E-selectin, intercellular adhesion molecule (ICAM)-1, and CD44], lowers lesional macrophage accumulation, and blocks lesion evolution at the transition from lesional stage II to III. Under regressive conditions, T0901317 induces lesional macrophage disappearance and increases the expression of the chemokine receptor CCR7, a factor functionally required for regression. The LXR-agonist T0901317 retards vascular lesion development and promotes lesion regression at several levels.The findings support that vascular LXR is a potential antiatherosclerotic target.-Verschuren, L., J. de Vries-van der Weij, S. Zadelaar, R. Kleemann, and T. Kooistra. LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms. J. Lipid Res. 2009. 50: 301-311.

show abstract

Section: Discussionmentioning

confidence: 90%

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

Verschuren

Weij

Zadelaar

et al. 2009

Journal of Lipid Research

View full text Add to dashboard Cite

show abstract

“…Plasma HDL cholesterol levels are negatively related to cardiovascular disease events [34] . Although LXR activation increases the plasma levels of HDL, it promotes the TG synthesis and leads to hyperlipidemia, which is an independent risk factor of atherosclerosis.…”

Section: Discussionmentioning

confidence: 99%

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

Dai

Zhang

et al. 2008

SCI CHINA SER C

Self Cite

View full text Add to dashboard Cite

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.

show abstract

“…Liver X receptors and (LXR and LXR ) are ligand-activated transcription factors involved in the control of lipid metabolism and inflammation. Recently, studies from our laboratory reported that synthetic LXR agonists could inhibit the progression of atherosclerosis in apoE / mice fed a highfat/high-cholesterol diet [13][14][15] . The endogenous activators of these receptors are oxysterols and intermediates in the cholesterol biosynthetic pathway.…”

Section: Introductionmentioning

confidence: 99%

TGF-β1 Up-Regulates Expression of ABCA1, ABCG1 and SR-BI through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

Wang

et al. 2010

J Atheroscler Thromb

View full text Add to dashboard Cite

Effect of T0901317 on Hepatic Proinflammatory Gene Expression in ApoE−/− Mice Fed a High-fat/high-cholesterol Diet

Abstract: The synthetic LXR agonist T0901317 has paradoxical roles in hepatic gene expression of proinflammatory cytokines in apoE-/- mice.

Cited by 19 publications

References 40 publications

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

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

TGF-β1 Up-Regulates Expression of ABCA1, ABCG1 and SR-BI through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

Contact Info

Product

Resources

About

Effect of T0901317 on Hepatic Proinflammatory Gene Expression in ApoE−/− Mice Fed a High-fat/high-cholesterol Diet

Abstract: The synthetic LXR agonist T0901317 has paradoxical roles in hepatic gene expression of proinflammatory cytokines in apoE-/- mice.

Cited by 19 publications

References 40 publications

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

LXR agonist suppresses atherosclerotic lesion growth and promotes lesion regression in apoE*3Leiden mice: time course and mechanisms

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

TGF-&beta;1 Up-Regulates Expression of ABCA1, ABCG1 and SR-BI through Liver X Receptor &alpha; Signaling Pathway in THP-1 Macrophage-Derived Foam Cells

Contact Info

Product

Resources

About

TGF-β1 Up-Regulates Expression of ABCA1, ABCG1 and SR-BI through Liver X Receptor α Signaling Pathway in THP-1 Macrophage-Derived Foam Cells