The Effect of T0901317 on ATP-binding Cassette Transporter A1 and Niemann-Pick Type C1 in ApoE−/− Mice

Abstract

Although a range of studies indicated Liver X receptor (LXR) activation inhibited the development of atherosclerosis in animal models, the mechanism of this effect for LXR agonists has not been fully understood. A recent study has suggested LXR activators increased the amount of free cholesterol in the plasma membrane of human macrophages by inducing Niemann-Pick type C1 (NPC1) gene expression. Therefore, we hypothesize that LXRs may also promote NPC1 expression in vivo. Here we investigated the effect of a synthetic LXR agonist T0901317 on ATP-binding cassette transporter A1 (ABCA1) and NPC1 in apolipoprotein E knockout (apoE-/-) mice. Male apoE-/- mice were randomized into four groups: baseline group (n = 10), vehicle group (n = 14), prevention group (n = 14), and treatment group (n = 14). En face analysis and Oil red O staining were used to examine the aortic atherosclerotic lesions. Macrophage content of aortic root atherosclerotic lesions and cholesterol efflux form peritoneal macrophages were measured. Gene and protein expression was analyzed by real-time quantitative polymerase chain reaction and Western blotting, respectively. T0901317 treatment reduced aortic atherosclerotic lesion area by 64.2% in prevention group (P < 0.001) and 58.3% in treatment group (P < 0.001) and resulted in a reduction in macrophage content. Plasma triglyceride, total cholesterol, high-density lipoprotein cholesterol, and apoA-I concentrations were markedly increased in T0901317-treated groups. T0901317 also promoted ABCA1 and NPC1 gene and protein levels in the aorta, liver, and small intestine of apoE-/- mice and significantly increased cholesterol efflux from peritoneal macrophages. T0901317 upregulates ABCA1 and NPC1. This study gives us a new insight into the mechanism for antiatherogenic effect of LXR synthetic agonists.

Epigallocatechin-3-gallate prevents TNF-α-induced NF-κB activation thereby upregulating ABCA1 via the Nrf2/Keap1 pathway in macrophage foam cells

“…Targeting LXR activation is believed to enhance the expression of ABCA1 and remove cholesterol from the body (10)(11)(12). However, downregulation of ABCA1 has been observed following exposure to inflammatory stimuli including IL-1β, TNF-α, IFN-γ and LPS, in which the nuclear factor-κB (NF-κB) dependent pathway was reported to be involved (13)(14)(15)(16).…”

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

“…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.…”

Ibrolipim increases ABCA1/G1 expression by the LXRα signaling pathway in THP-1 macrophage-derived foam cells

“…Previous studies from our laboratory and others have also shown that increasing LPL activity in skeletal muscle results in decreased fat accumulation, and long-term administration of ibrolipim protects against the development of experimental atherosclerosis in animals [6][7][8] . However, the detailed mechanism for cholesterol transport proteins induced by ibrolipim is unclear.Recently, our laboratory revealed that the liver X receptors (LXR) synthetic agonist T0901317 promoted ABCA1 gene and protein levels in the aorta, liver, and small intestine of apoE-/-mice and significantly increased cholesterol efflux from peritoneal macrophages [9] . We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] .…”

“…Recently, our laboratory revealed that the liver X receptors (LXR) synthetic agonist T0901317 promoted ABCA1 gene and protein levels in the aorta, liver, and small intestine of apoE-/-mice and significantly increased cholesterol efflux from peritoneal macrophages [9] . We also showed that IFN-γ may first downregulate the expression of LXRα through the 1344 www.nature.com/aps Chen SG et al Acta Pharmacologica Sinica npg JAK/STAT1 signaling pathway and then decrease expression of ABCA1 and cholesterol efflux in THP-1 macrophagederived foam cells [10] .…”