Apolipoprotein A-I (apoA-I) mimetic peptides have been studied in animals and humans for their ability to improve biomarkers of infl ammation and in animal mod- els of atherosclerosis for their ability to decrease lesions

Journal of Lipid Research Volume 53, 2012 437 Copyright © 2012 by the American Society for Biochemistry and Molecular Biology, Inc. Apolipoprotein A-I (apoA-I) mimetic peptides have been studied in animals and humans for their ability to improve biomarkers of infl ammation and in animal models of atherosclerosis for their ability to decrease lesions ( 1 ). The mechanism of action of these peptides has been thought to be due to their remarkable ability to bind oxidized lipids compared with apoA-I ( 2 ). The classes of oxidized lipids bound with high affi nity by these mimetic peptides include oxidized phospholipids, oxidized metabolites of arachidonic and linoleic acids, and oxidized sterols ( 2 ). Oxidized metabolites of arachidonic and linoleic acids can be generated by enzymatic systems such as lipoxygenases or cyclooxygenases, or they can be generated by nonspecifi c oxidation. Except for 20-hydroxyeicosatetraenoic acid (HETE), all of the oxidized metabolites of arachidonic and linoleic acids that we studied bound to the peptide with much higher affi nity than was the case for the binding to apoA-I ( 2, 3 ). We recently reported that the dosage of the apoA-I mimetic peptide 4F administered to apoE / mice determined effi cacy, but plasma and hepatic levels of peptide did not ( 1 ). Because effi cacy was similar at the same dosages but plasma and hepatic levels were dramatically higher when the peptide was administered by subcutaneous injection (SQ) compared with oral administration, we suspected that there might be a compartment outside of the liver or plasma where peptide concentration would be 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 affi nity to D-4F were signifi cantly 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 affi nity, 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 signifi cantly correlated with SAA levels ( P < 0.0001). Feeding 15-HETE in chow (without WD) signifi cantly increased plasma SAA and triglyceride levels and decreased HDL-cholesterol and paraoxonase activity ( P < 0.05), all of which were signifi cantly 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 infl ammation in LDL receptor defi cient mice . —Navab, M., S. T. Reddy, G. M. Anantharamaiah, G. Hough, G. M. Buga, J. Danciger, and A. M. Fogelman. D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased infl ammation in low-density lipoprotein receptor-null mice. J. Lipid Res . 2012. 53:437–445.