title: 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.
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA. Electronic address: mnavab@mednet.ucla.edu.
authors.forename: Mohamad
authors.initials: M
authors.lastname: Navab
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Srinivasa T
authors.initials: ST
authors.lastname: Reddy
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, AL.
authors.forename: G M
authors.initials: GM
authors.lastname: Anantharamaiah
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Greg
authors.initials: G
authors.lastname: Hough
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Georgette M
authors.initials: GM
authors.lastname: Buga
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Jan
authors.initials: J
authors.lastname: Danciger
authors.affiliation: Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA.
authors.forename: Alan M
authors.initials: AM
authors.lastname: Fogelman
mesh_terms: D000818:Animals; D016632:Apolipoprotein A-I / Q000627:therapeutic use*; D016718:Arachidonic Acid / Q000097:blood* / Q000378:metabolism*; D001646:Bile / Q000187:drug effects / Q000378:metabolism; D005260:Female; D007249:Inflammation / Q000188:drug therapy* / Q000378:metabolism*; D007421:Intestine, Small / Q000187:drug effects / Q000378:metabolism*; D008041:Linoleic Acids / Q000097:blood* / Q000378:metabolism*; D008099:Liver / Q000187:drug effects / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D011973:Receptors, LDL / Q000235:genetics / Q000378:metabolism*
chemical_list: D016632:Apolipoprotein A-I; C465468:D-4F peptide; D008041:Linoleic Acids; D011973:Receptors, LDL; D016718:Arachidonic Acid