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

Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA.
The Journal of Lipid Research (Impact Factor: 4.42). 12/2011; 53(3):437-45. DOI: 10.1194/jlr.M023523
Source: PubMed


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.

2 Reads
  • Source
    • "Our findings are consistent with several observations that mimetic peptides have a major effect on the functionality of the lipoproteins they bind to [10], [11], [13] or even on exchange of constituencies between LDL and HDL [31]. An alternative explanation is that peptides reduce local production of metabolites of arachidonic and linoleic acids in the intestine as was suggested by Navab et al [32], [33], a possibility especially relevant for the experiments with intraperitoneal route of administration. A limitation of this study is that we did not evaluate the effect of the peptide on the number of monocytes in the plasma that could be influenced by the peptide [34] and to contribute to the observed effects. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Apolipoprotein A-I (apoA-I) mimetic peptides are considered a promising novel therapeutic approach to prevent and/or treat atherosclerosis. An apoA-I mimetic peptide ELK-2A2K2E was designed with a reductionist approach and has shown exceptional activity in supporting cholesterol efflux but modest anti-inflammatory and anti-oxidant properties in vitro. In this study we compared these in vitro properties with the capacity of this peptide to modify rates of reverse cholesterol transport and development of atherosclerosis in mouse models. The peptide enhanced the rate of reverse cholesterol transport in C57BL/6 mice and reduced atherosclerosis in Apoe(-/-) mice receiving a high fat diet. The peptide modestly reduced the size of the plaques in aortic arch, but was highly active in reducing vascular inflammation and oxidation. Administration of the peptide to Apoe(-/-) mice on a high fat diet reduced the levels of total, high density lipoprotein and non-high density lipoprotein cholesterol and triglycerides. It increased the proportion of smaller HDL particles in plasma at the expense of larger HDL particles, and increased the capacity of the plasma to support cholesterol efflux. Thus, ELK-2A2K2E peptide reduced atherosclerosis in Apoe(-/-) mice, however, the functional activity profile after chronic in vivo administration was different from that found in acute in vitro studies.
    PLoS ONE 07/2013; 8(7):e68802. DOI:10.1371/journal.pone.0068802 · 3.23 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    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 · 6.00 Impact Factor
  • [Show abstract] [Hide abstract]
    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; 54(4). DOI:10.1194/jlr.M033555 · 4.42 Impact Factor
Show more