D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice.
ABSTRACT To test the hypothesis that intestine is a major site of action for D-4F, LDLR(-/-) mice were fed a Western diet (WD) and administered the peptide subcutaneously (SQ) or orally. Plasma and liver D-4F levels were 298-fold and 96-fold higher, respectively, after SQ administration, whereas peptide levels in small intestine only varied by 1.66 ± 0.33-fold. Levels of metabolites of arachidonic and linoleic acids known to bind with high affinity to D-4F were significantly reduced in intestine, liver and hepatic bile to a similar degree whether administered SQ or orally. However, levels of 20-HETE, which is known to bind the peptide with low affinity, were unchanged. D-4F treatment reduced plasma serum amyloid A (SAA) and triglyceride levels (P < 0.03) and increased HDL-cholesterol levels (P < 0.04) similarly after SQ or oral administration. Plasma levels of metabolites of arachidonic and linoleic acids significantly correlated with SAA levels (P < 0.0001). Feeding 15-HETE in chow (without WD) significantly increased plasma SAA and triglyceride levels and decreased HDL-cholesterol and paraoxonase activity (P < 0.05), all of which were significantly ameliorated by SQ D-4F (P < 0.05). We conclude that D-4F administration reduces levels of free metabolites of arachidonic and linoleic acids in the small intestine and this is associated with decreased inflammation in LDL receptor deficient mice.
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ABSTRACT: Oxidized phospholipids are found in the vasculature of animal models of atherosclerosis, in human atherosclerotic lesions, and in other inflammatory diseases. Oxidized phospholipids cause vascular and nonvascular cells to initiate an inflammatory reaction. Metabolites of arachidonic acid, such as 12-hydroxyeicosatetraenoic acid, can mimic some of the inflammatory properties of oxidized phospholipids. In vitro and in vivo normal high-density lipoprotein (HDL), normal apolipoprotein A-I, and apolipoprotein A-I mimetic peptides, each likely acting in a different manner, prevent the inflammatory reaction characteristic of atherosclerosis, and this is associated with decreased levels of oxidized lipids in tissues and cells. HDL from animal models of atherosclerosis or from humans with atherosclerosis or from humans or animals with other chronic inflammatory diseases does not prevent the inflammatory reaction characteristic of atherosclerosis and may even enhance the inflammatory reaction. In mice and perhaps humans, ≈30% of the steady-state plasma HDL-cholesterol pool is derived from the small intestine. The metabolism of phospholipids by gut bacteria has been recently implicated in atherosclerosis in both mice and humans. Studies with apolipoprotein A-I mimetic peptides suggest that the small intestine is a major tissue regulating systemic inflammation in mouse models of atherosclerosis and may be important for determining the functionality of HDL.Arteriosclerosis Thrombosis and Vascular Biology 11/2012; 32(11):2553-60. DOI:10.1161/ATVBAHA.112.300282 · 5.53 Impact Factor
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ABSTRACT: Transgenic tomato plants were constructed with an empty vector (EV) or a vector expressing an apoA-I mimetic peptide, 6F. EV or 6F tomatoes were harvested, lyophilized, ground into powder, added to Western Diet (WD) at 2.2% by weight, and fed to LDLR-/- mice at 45 mg/kg/day 6F. After 13 weeks, percent aorta with lesions was 4.1+/-4, 3.3+/-2.4, and 1.9+/-1.4 for WD, WD+EV, and WD+6F, respectively (WD+6F vs. WD, p=0.0134; WD+6F vs. WD+EV, p=0.0386; WD+EV vs. WD, not significant). While body weight did not differ, plasma serum amyloid A (SAA), total cholesterol, triglycerides, and lysophosphatidic acid (LPA) levels were less in WD+6F mice; p<0.0295. HDL-cholesterol and paroxonase-1 activity (PON) were higher in WD+6F mice (p=0.0055, p=0.0254, respectively), but not in WD+EV mice. Plasma SAA, total cholesterol, triglycerides, LPA and 15-HETE levels positively correlated with lesions (p<0.0001); HDL-cholesterol and PON were inversely correlated (p<0.0001). After feeding WD+6F, i) intact 6F was detected in small intestine (but not in plasma); ii) small intestine LPA was decreased compared to WD+EV (p<0.0469); iii) small intestine LPA 18:2 positively correlated with percent aorta with lesions (p<0.0178). These data suggest that 6F acts in the small intestine and provide a novel approach to oral apoA-I mimetic therapy.The Journal of Lipid Research 02/2013; DOI:10.1194/jlr.M033555 · 4.73 Impact Factor
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ABSTRACT: Background- Exposure to ambient particulate matter (PM) is a risk factor for cardiovascular diseases. The redox-active ultrafine particles promote vascular oxidative stress and inflammatory responses. We hypothesized that UFP modulated lipid metabolism and anti-oxidant capacity of high density lipoprotein (HDL) with an implication in atherosclerotic lesion size. Methods and Results- Fat-fed LDL Receptor-null (LDLR-/-) mice were exposed to filtered air (FA) or UFP for 10 weeks with or without administering an apolipoprotein A-I mimetic peptide, D-4F. LDLR-null mice exposed to UFP developed reduced plasma HDL level (p < 0.01), paraoxonase (PON) activity (p < 0.01), and HDL anti-oxidant capacity (p < 0.05), but increased LDL oxidation, free oxidized fatty acids, triglycerides, serum Amyloid A (SAA) (p < 0.05) and TNF-α (p<0.05), accompanied by a 62% increase in atherosclerotic lesion ratio of the en face aortic staining and a 220% increase in cross-sectional lesion area of aortic sinus (p < 0.001). D-4F administration significantly attenuated these changes. Conclusions- UFP exposure promoted pro-atherogenic lipid metabolism and reduced HDL anti-oxidant capacity in fat-fed LDLR-null mice, associated with a greater atherosclerotic lesion size compared to FA exposed animals. D-4F attenuated UFP-mediated pro-atherogenic effects, suggesting the role of lipid oxidation underlying UFP-mediated atherosclerosis.The Journal of Lipid Research 04/2013; DOI:10.1194/jlr.M035014 · 4.73 Impact Factor