A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake

Nishizawa, Takashi; Kitayama, Ken; Wakabayashi, Kenji; Yamada, Makiko; Uchiyama, Minoru; Abe, Kōji; Ubukata, Naoko; Inaba, Tomohiro; Oda, Tomiichiro; Amemiya, Yoshiya

doi:10.1016/j.atherosclerosis.2006.10.025

Cited by 10 publications

(7 citation statements)

References 25 publications

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“…However, this idea was discarded in the face of compelling evidence that SR-BI deficiency increased atherosclerosis in several different mouse models, sometimes in a dramatic fashion, while SR-BI overexpression had the opposite effects 7–9, 16, 29–32. Besides genetic models of SR-BI overexpression or deficiency, pharmacological SR-BI inhibitors such as BLTs, HDL376 and R-138329 have been characterized 14, 15, 27, 33, 34. The effects of the latter compound on atherosclerosis have been investigated in apoE −/− mice and moderate pro-atherogenic effects were observed but only at high concentration 35.…”

Section: Discussionmentioning

confidence: 99%

Increased HDL Cholesterol and ApoA-I in Humans and Mice Treated With a Novel SR-BI Inhibitor

Masson

Koseki

Ishibashi

et al. 2009

ATVB

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Objectives-Increasing HDL levels is a potential strategy for the treatment of atherosclerosis. Methods and Results-ITX5061, a molecule initially characterized as a p38 MAPK inhibitor, increased HDL-C levels by 20% in a human population of hypertriglyceridemic subjects with low HDL levels. ITX5061 also moderately increased apoA-I but did not affect VLDL/LDL cholesterol or plasma triglyceride concentrations. ITX5061 increased HDL-C in WT and human apoA-I transgenic mice, and kinetic experiments showed that ITX5061 decreased the fractional catabolic rate of HDL-CE and reduced its hepatic uptake. In transfected cells, ITX5061 inhibited SR-BI-dependent uptake of HDL-CE. Moreover, ITX5061 failed to increase HDL-C levels in SR-BI Ϫ/Ϫ mice. To assess effects on atherosclerosis, ITX5061 was given to atherogenic diet-fed Ldlr ϩ/Ϫ mice with or without CETP expression for 18 weeks. In both the control and CETP-expressing groups, ITX5061-treated mice displayed reductions of early atherosclerotic lesions in the aortic arch Ϫ40%, PϽ0.05), and a nonsignificant trend to reduced lesion area in the proximal aorta. Conclusions-Our data indicate that ITX5061 increases HDL-C levels by inhibition of SR-BI activity. This suggests that pharmacological inhibition of SR-BI has the potential to raise HDL-C and apoA-I levels without adverse effects on VLDL/LDL cholesterol levels in humans. Key Words: scavenger receptor B-I Ⅲ high-density lipoproteins Ⅲ inhibitors Ⅲ p38 MAPK Ⅲ atherosclerosis P lasma high-density lipoprotein (HDL) levels are inversely correlated with atherosclerotic cardiovascular disease, and raising HDL levels by lifestyle changes or pharmacological interventions is an emerging strategy that might help to reduce the residual burden of disease in patients treated with low-density lipoprotein (LDL)-lowering approaches. 1,2 Whereas increasing synthesis or infusion of apolipoprotein A-I (apoA-I) or HDL reduces atherosclerosis in animals and humans, it is not clear that all approaches to raising HDL will reduce atherosclerosis.The scavenger receptor B-I (SR-BI) is a major factor regulating HDL catabolism. SR-BI binds HDL and mediates the selective uptake of HDL-cholesteryl ester (CE) in the liver and steroidogenic tissues. 3 Although the role of SR-BI in HDL metabolism in mice and rats has been clearly shown, much less information is available on the function of SR-BI in humans. Primary human hepatocytes do demonstrate selective uptake of HDL-CE, 4 but the quantitative importance of this pathway has not been shown. In humans, cholesteryl ester transfer protein (CETP), a factor lacking in mice and rats, plays a major role in HDL-CE catabolism. In the present study, we demonstrate that ITX5061, a molecule initially characterized as a p38 mitogen-activated protein kinase (MAPK) inhibitor, caused an increase in HDL cholesterol (HDL-C) and apoA-I levels in humans. Studies in mice and cultured cells indicated that ITX5061 is an inhibitor of the SR-BI activity. Interestingly, ITX5061 did not cause increases in very-low-density lipopr...

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Section: Discussionmentioning

confidence: 99%

Increased HDL Cholesterol and ApoA-I in Humans and Mice Treated With a Novel SR-BI Inhibitor

Masson

Koseki

Ishibashi

et al. 2009

ATVB

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“…After submission of this work, Nishizawa and colleagues (80,81) reported the identification of N-[4-(4-tert-butoxycarbonylpiperazin-1-yl)phenyl]-(2-chloro-5-nitrophenyl)carboxamide (R-138329) as a small molecule that can increase plasma HDLcholesterol in hamsters and mice, decrease murine hepatic selective uptake of [ 3 H]CE from HDL in vivo, exacerbate atherosclerotic lesion formation in apolipoprotein E-deficient mice, and inhibit rodent SR-BI-mediated lipid uptake activity in cultured cells. …”

Section: Note Added In Proofmentioning

confidence: 99%

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

Nieland

Shaw

Jaipuri

et al. 2007

Journal of Lipid Research

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Treatment of atherosclerotic disease often focuses on reducing plasma LDL-cholesterol or increasing plasma HDL-cholesterol. We examined in vitro the effects on HDL receptor [scavenger receptor class B type I (SR-BI)] activity of three classes of clinical and experimental plasma HDL-cholesterol-elevating compounds: niacin, fibrates, and HDL376. Fenofibrate (FF) and HDL376 were potent (IC 50 ? 1 mM), direct inhibitors of SR-BI-mediated lipid transport in cells and in liposomes reconstituted with purified SR-BI. FF, a prodrug, was a more potent inhibitor of SR-BI than an activator of peroxisome proliferator-activated receptor a, a target of its active fenofibric acid (FFA) derivative. Nevertheless, FFA, four other fibrates (clofibrate, gemfibrozil, ciprofibrate, and bezafibrate), and niacin had little, if any, effect on SR-BI, suggesting that they do not directly target SR-BI in vivo. However, similarities of HDL376 treatment and SR-BI gene knockout on HDL metabolism in vivo (increased HDL-cholesterol and HDL particle sizes) and structure-activity relationship analysis suggest that SR-BI may be a target of HDL376 in vivo. HDL376 and other inhibitors may help elucidate SR-BI function in diverse mammalian models and determine the therapeutic potential of SR-BI-directed pharmaceuticals.-Nieland, T.

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“…Thus, the novel compound R-138329 transiently increased HDL-C (+41%) in normolipidemic hamsters at a dose of 100 mg/kg [484]. These effects are mediated by R-154716, a metabolite of R-138329, which inhibits the selective uptake of HDL cholesteryl ester by hepatoma cells through SR-BI [484]. In hamsters, R-138329 also increased HDL size, delayed the clearance of HDL cholesteryl ester in mice and reduced the accumulation of HDL cholesteryl ester in the liver, whereas the clearance of the HDL protein moiety remained unaffected.…”

Section: Sr-bi Inhibitorsmentioning

confidence: 88%

Enhancement of HDL Formation and Normalization of Intravascular HDL Remodeling

Kontush¹,

Chapman²

2011

High‐Density Lipoproteins

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A novel compound, R-138329, increases plasma HDL cholesterol via inhibition of scavenger receptor BI-mediated selective lipid uptake

Cited by 10 publications

References 25 publications

Increased HDL Cholesterol and ApoA-I in Humans and Mice Treated With a Novel SR-BI Inhibitor

Increased HDL Cholesterol and ApoA-I in Humans and Mice Treated With a Novel SR-BI Inhibitor

Influence of HDL-cholesterol-elevating drugs on the in vitro activity of the HDL receptor SR-BI

Enhancement of HDL Formation and Normalization of Intravascular HDL Remodeling

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