Increasing evidence points to the fact that plasma HDL cholesterol levels do not always accurately predict HDL function including reverse cholesterol transport and modulation of inflammation. These functions appear to have evolved as part of our innate immune system. HDL is anti inflammatory in healthy individuals in the absence of systemic oxidative stress and inflammation. In those with chronic illnesses such as renal failure however, HDL may become dysfunctional and actually promote inflammation. HDL may be thought of as a shuttle whose size can be estimated by HDL cholesterol levels. The content of the shuttle however, is what determines the anti inflammatory potential of HDL and can change from one, supporting reverse cholesterol transport to one that is less efficient in carrying out this function. Chronic kidney disease (CKD), and inflammatory disorder, is associated with development of accelerated atherosclerosis and premature death from coronary artery disease (CAD). Patients with CKD present with dyslipidemia, oxidative stress and systemic inflammation. Among the abnormalities in lipid metabolism in these patients is reduced levels and protective capacity of HDL. Recent studies have shown that HDL from patients with end stage renal disease is not capable of preventing LDL oxidation and that it induces monocyte migration in artery wall model systems. Treatment of plasma from these patients, with an HDL mimetic peptide improved the anti inflammatory properties of patient's HDL and made LDL more resistant to oxidative modification. Animal models of kidney disease also had proinflammatory HDL and treatment with the peptide mimetic improved markers of inflammation and anti inflammatory capacity of HDL. Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies.
IntroductionUpon feeding the LDL receptor deficient mice a high fat diet the circulating apoB containing lipoproteins in the animals rise, lipid oxidation increase and an inflammatory state is induced. Oxidation products of cell membrane arachidonic acid and linoleic acid including HETEs and HODES that are thus produced are known to induce inflammatory molecules in various organs and result in pathological complications.ObjectiveWe sought to study the effect of a high fat diet on the concentration of oxidized fatty acids and the potential protective effect of the anti inflammatory peptide 4F.MethodsGroups of female LDL R−/− mice (n=20 per group) were provided with a high fat‐high cholesterol diet for 6 weeks and were given drinking water or water containing anti inflammatory peptide 4F furnishing 900 ug per animal on a daily basis. At the end of the 56 weeks, using LC‐ESI‐MS/MS brains were analyzed for oxidized fatty acid content.ResultsThe concentration of 5‐HETE, 12‐HETE, 15‐HETE, 9‐HODE and 13‐HODE, PGD2, PGE2, TXB2 were significantly higher in the group that did not receive the peptide as compared to the mice that did receive the peptide 4F (p from 0.039 to 0.002).ConclusionThe oxidative cascade resulted from the hyperlipemia and the inflammatory pressure was inhibited by the anti inflammatory peptide 4F resulting in reduction of the level of proinflammatory oxidized fatty acids and reducing their concentration in brain. If the peptide would have a similar effect in humans, it might have major implications in reducing neuronal inflammation and improvement in CNS function.
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