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: 4.73). 12/2011; 53(3):437-45. DOI: 10.1194/jlr.M023523
Source: PubMed

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.

  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: High density lipoprotein (HDL) cholesterol levels are inversely related to cardiovascular disease risk and associated with a reduced risk of type 2 diabetes. Apolipoprotein A-I (apoA-I; major HDL protein) mimetics have been reported to reduce atherosclerosis and decrease adiposity. This study investigated the effect of L4F mimetic peptide and apoA-I overexpression on weight gain, insulin resistance, and atherosclerosis in an LDL receptor deficient (Ldlr-/-) model fed a high fat high sucrose with cholesterol (HFHSC) diet.
    PLoS ONE 10/2014; 9(10):e109252. · 3.53 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Restenosis is an integral pathological process central to the recurrent vessel narrowing after interventional procedures. Although the mechanisms for restenosis are diverse in different pathological conditions, endothelial dysfunction, inflammation, vascular smooth muscle cell (SMC) proliferation, and myofibroblasts transition have been thought to play crucial role in the development of restenosis. Indeed, there is an inverse relationship between high-density lipoprotein (HDL) levels and risk for coronary heart disease (CHD). However, relatively studies on the direct assessment of HDL effect on restenosis are limited. In addition to involvement in the cholesterol reverse transport, many vascular protective effects of HDL, including protection of endothelium, antiinflammation, antithrombus actions, inhibition of SMC proliferation, and regulation by adventitial effects may contribute to the inhibition of restenosis, though the exact relationships between HDL and restenosis remain to be elucidated. This review summarizes the vascular protective effects of HDL, emphasizing the potential role of HDL in intimal hyperplasia and vascular remodeling, which may provide novel prophylactic and therapeutic strategies for antirestenosis. Clin Trans Sci 2014; Volume #: 1–12
    Clinical and Translational Science 07/2014; · 2.33 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Background and Objective: Exposure to ambient ultrafine particulate matter (UFP) is a well-recognized risk factor for cardiovascular and respiratory diseases. However, little is known about the effects of air pollution on gastrointestinal disorders. We sought to assess whether exposure to ambient ultrafine particles (UFP: diameter < 180 nm) increased free fatty acids and lipid metabolites in the mouse small intestine. Methods and Results: LDLR-null mice were exposed to filtered air (FA) or UFP collected at an urban Los Angeles site heavily impacted by vehicular emissions for 10 weeks in the presence or absence of D-4F, an apolipoprotein A-I mimetic peptide with anti-oxidant and anti-inflammation properties on a high-fat or normal chow diet. Compared to FA, exposure to UFP significantly increased intestinal hydroxyeicosatetraenoic acids (HETEs), including 15-HETE, 12-HETE, 5-HETE, as well as hydroxyoctadecadienoic acids (HODEs), including 13-HODE and 9-HODE. Arachidonic acid and prostaglandin D2 (PGD2) as well as some of the lysophosphatidic acids (LPA) in the small intestine were also increased in response to UFP exposure. Administration of D-4F significantly reduced UFP-mediated increase in HETES, HODEs, AA, PGD2 and LPA. While exposure to UFP further led to shortened villus length accompanied by prominent macrophage and neutrophil infiltration into the intestinal villi, administration of D-4F mitigated macrophage infiltration. Conclusions: Exposure to UFP promotes lipid metabolism, villus shortening and inflammatory responses in mouse small intestine, whereas administration of D-4F attenuated these effects. Our findings provide a basis to further assess the mechanisms underlying UFP-mediated lipid metabolism in the digestive system with clinical relevance to gut homeostasis and diseases.
    Environmental Health Perspectives 08/2014; · 7.03 Impact Factor