Abstract
Vitamin E is a lipophilic anti-oxidant that can prevent the oxidative damage of atherogenic lipoproteins. However, human trials with vitamin E have been disappointing, perhaps related to ineffective levels of vitamin E in atherogenic apoB-containing lipoproteins. Phospholipid transfer protein (PLTP) promotes vitamin E removal from atherogenic lipoproteins in vitro, and PLTP deficiency has recently been recognized as an anti-atherogenic state. To determine whether PLTP regulates lipoprotein vitamin E content in vivo, we measured alpha-tocopherol content and oxidation parameters of lipoproteins from PLTP-deficient mice in wild type, apoE-deficient, low density lipoprotein (LDL) receptor-deficient, or apoB/cholesteryl ester transfer protein transgenic backgrounds. In all four backgrounds, the vitamin E content of very low density lipoprotein (VLDL) and/or LDL was significantly increased in PLTP-deficient mice, compared with controls with normal plasma PLTP activity. Moreover, PLTP deficiency produced a dramatic delay in generation of conjugated dienes in oxidized apoB-containing lipoproteins as well as markedly lower titers of plasma IgG autoantibodies to oxidized LDL. The addition of purified PLTP to deficient plasma lowered the vitamin E content of VLDL plus LDL and normalized the generation of conjugated dienes. The data show that PLTP regulates the bioavailability of vitamin E in atherogenic lipoproteins and suggest a novel strategy for achieving more effective concentrations of anti-oxidants in lipoproteins, independent of dietary supplementation.
Highlights
Effects of phospholipid transfer protein (PLTP) Deficiency on Plasma Levels and Distribution of Vitamin E in Hyperlipidemic Mice—To determine if accumulation of vitamin E in BLps might contribute to the athero-protective effect of PLTP deficiency [18], we further investigated the effects of the PLTP deficiency trait on plasma ␣-tocopherol levels and lipoprotein distribution in hyperlipidemic plasmas of LDLR0, apoE0, and apoB/CETPTg backgrounds
We have previously shown that PLTP deficiency provides protection against atherosclerosis in apoE0 and apoBTg/ CETPTg mice, due in part to decreased hepatic production of apoB and decreased plasma levels of atherogenic lipoproteins [18]
The present study demonstrates a novel in vivo role of PLTP in determining the concentration of vitamin E in BLps and suggests that increased vitamin E in BLps represents an additional mechanism by which PLTP deficiency protects against atherosclerosis in mice
Summary
PLTP knock-out (PLTP0) mice were recently shown to be resistant to atherosclerosis, in part related to decreased secretion and levels of apoB containing lipoproteins [18]. An anti-atherogenic effect of PLTP deficiency was seen in LDL receptor knock-out mice, even though plasma levels of apoB lipoproteins were identical to controls. This indicates an additional anti-atherogenic mechanism of PLTP deficiency. E in apoB-containing lipoproteins in PLTP-deficient mice, and a decreased susceptibility to oxidation Such findings would provide a plausible novel anti-atherogenic mechanism related to PLTP deficiency, beyond the effects of lowering BLp levels [18]
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