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.

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    • "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. "
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