Antiatherogenic Effects of Dietary Plant Sterols Are Associated with Inhibition of Proinflammatory Cytokine Production in Apo E-KO Mice

Abstract

Dietary phytosterols significantly reduce atherosclerosis in apo E-deficient mice. Because atherosclerosis is a chronic inflammatory disease, we investigated whether the antiatherogenic effects of phytosterols are associated with reductions in proinflammatory cytokine production as well as the effect of this diet on global immunocompetence. Apolipoprotein (apo) E-deficient mice were fed a cholesterol-supplemented diet in the presence or absence of 2% dietary phytosterols for 14 wk and then immunized with ovalbumin. The relations between plasma lipid concentrations, atherosclerotic lesions, and cytokine production and proinflammatory stimuli or foreign antigens were characterized. Phytosterol-enriched diets were strongly associated with reduced plasma cholesterol concentrations and atherosclerosis in conjunction with higher anti-inflammatory [interleukin (IL)-10] and lower proinflammatory cytokine [IL-6, tumor necrosis factor (TNF)-alpha] production. In contrast, development of cytokine and chemokine responses to ovalbumin was as strong as or even improved in the phytosterol-treated mice relative to controls. The antiatherogenic effects of dietary phytosterols in apo E-knockout mice were associated with beneficial alterations in both lipoprotein metabolism and inflammatory pathways. Decreased capacity to mount proinflammatory cytokine and chemokine responses to inflammatory stimuli did not interfere with the global immunocompetence of such mice. Thus, the desirable suppression of proinflammatory cytokine production that was associated with inhibition of atherogenesis did not impair the capacity to mount responses to foreign antigens.

Do clinical and experimental investigations support an antiatherogenic role for dietary phytosterols/stanols?

“…While several investigations (30-32) have shown a reduction in atherosclerotic lesions with PS administration, other studies have obtained contradictory results (27,33). Apo E-KO animals fed a fat-rich diet to induce atherosclerosis showed a regression of atherosclerotic lesions following introduction of a normal-fat diet or a diet enriched with PS (32). The induction of atherosclerosis period raised the cholesterol level, while in the regression phase, there was decrease in plasma cholesterol in the groups studied.…”

“…In most, the effect of PS on atherosclerotic lesions was evaluated (27,(30)(31)(32)(33). In some, a reduction in atherosclerotic lesions was observed (30)(31)(32) probably because of the cholesterol-lowering efficiency of PS. In Apo E-KO mice fed a fat-rich diet to Greater ratios of cholesterol levels to levels of cholesterol precursors and absorption markers in the serum were associated with similarly high ratios in the stenotic aortic valves.…”

“…Because of the severe hypercholesterolemia and advanced arterial lesions, which are rare in humans, some investigators may have criticized use of the apo E-KO mouse model in studies on progression or regression of atherosclerosis. Although this model may not be ideal for investigating atherosclerosis (32), the recent demonstration that esters of PS or phytostanols protect apo E-KO mice against atherosclerosis is a major advance in this field (28).…”

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“…Furthermore, sterols (daucosterol, campesterol, stigmasterol, beta-sitosterol) have shown an anticancer effect via; Inhibition of pro-inflammatory cytokines 98 , PC-3 apoptosis and cell cycle arrest via ROS changes and prostaglandin release 99,100 , and Reverts impaired glutathione/oxidized glutathione ratio via estrogen/phosphatidylinositol 3-kinase pathway 101 .…”

Fitoesteróides reduzem endotelina-1 em indivíduos moderadamente hipercolesterolêmicos

“…Corroborando os nossos dados, não se observou em hipercolesterolêmicos diferença na PCR com FE (1,3 g/dia) administrado em cápsulas (Acuff et al, 2007). Já em camundongos apoE-KO, houve diminuição na produção de citocinas pró-inflamatórias (TNFα e IL-6) e aumento nas citocinas anti-aterogênicas (IL-10) e conseqüente redução de 60 % do tamanho da lesão aterosclerótica com o fitoesterol (Nashed et al, 2005 Jong et al, 2008, Nashed et al, 2005.…”