Dietary polyunsaturated fat intake is associated with low-density lipoprotein size, but not with susceptibility to oxidation in subjects with impaired glucose metabolism and type II diabetes: the Hoorn study

OBJECTIVE: A high monounsaturated fatty acid (MUFA) and polyunsaturated fatty acid (PUFA) intake is associated with lower plasma low-density lipoprotein (LDL)-cholesterol. However, PUFA may increase the susceptibility of LDL to undergo oxidative modifications. The aim of this study was to analyze the association of habitual dietary fat intake with LDL size and oxidizability. DESIGN: Cross-sectional. SETTING: Cohort study. SUBJECTS: Seven hundred and fifty-eight subjects with normal, impaired glucose metabolism and type II diabetes. INTERVENTIONS: Mean LDL size was measured by high-performance gel-filtration chromatography. In vitro oxidizability of LDL was determined by measuring lag time, reflecting the resistance of LDL to copper-induced oxidation. Information about dietary fat intake was obtained by a validated food frequency questionnaire. RESULTS: PUFA intake (energy percent) was significantly and negatively associated with LDL size in subjects with type II diabetes (standardized beta (95% confidence interval) -0.17 (-0.28;-0.06)) and impaired glucose metabolism - although not statistically significant - (-0.09 (-0.24;0.05)), but not in subjects with normal glucose metabolism (0.01 (-0.10;0.12)) (P-value for interaction=0.02). No significant associations were observed for total, saturated fat and MUFA intake with LDL size. Intake of fat was associated with lag time; however, the small magnitude of the associations suggested that the composition of dietary fat is not a major factor affecting lag time. The same association with lag time was observed in all three glucose metabolism categories. CONCLUSIONS: In individuals with abnormal glucose metabolism, higher PUFA intake is associated with smaller LDL particle size, but does not alter the susceptibility of LDL to in vitro oxidation. SPONSORSHIP: Dutch Diabetes Research Foundation, and the Nederlandse Organisatie voor Wetenschappelijk Onderzoek (NWO)

Apolipoprotein A-I Attenuates Palmitate-Mediated NF-κB Activation by Reducing Toll-Like Receptor-4 Recruitment into Lipid Rafts

While high-density lipoprotein (HDL) is known to protect against a wide range of inflammatory stimuli, its anti-inflammatory mechanisms are not well understood. Furthermore, HDL's protective effects against saturated dietary fats have not been previously described. In this study, we used endothelial cells to demonstrate that while palmitic acid activates NF-κB signaling, apolipoprotein A–I, (apoA-I), the major protein component of HDL, attenuates palmitate-induced NF-κB activation. Further, vascular NF-κB signaling (IL-6, MCP-1, TNF-α) and macrophage markers (CD68, CD11c) induced by 24 weeks of a diabetogenic diet containing cholesterol (DDC) is reduced in human apoA-I overexpressing transgenic C57BL/6 mice compared to age-matched WT controls. Moreover, WT mice on DDC compared to a chow diet display increased gene expression of lipid raft markers such as Caveolin-1 and Flotillin-1, and inflammatory Toll-like receptors (TLRs) (TLR2, TLR4) in the vasculature. However apoA-I transgenic mice on DDC show markedly reduced expression of these genes. Finally, we show that in endothelial cells TLR4 is recruited into lipid rafts in response to palmitate, and that apoA-I prevents palmitate-induced TLR4 trafficking into lipid rafts, thereby blocking NF-κB activation. Thus, apoA-I overexpression might be a useful therapeutic tool against vascular inflammation