An Immunomodulating Fatty Acid Analogue Targeting Mitochondria Exerts Anti-Atherosclerotic Effect beyond Plasma Cholesterol-Lowering Activity in apoE-/- Mice

Abstract

Tetradecylthioacetic acid (TTA) is a hypolipidemic antioxidant with immunomodulating properties involving activation of peroxisome proliferator-activated receptors (PPARs) and proliferation of mitochondria. This study aimed to penetrate the effect of TTA on the development of atherosclerotic lesions in apolipoprotein (apo)-E-/- mice fed a high-fat diet containing 0.3% TTA for 12 weeks. These mice displayed a significantly less atherosclerotic development vs control. Plasma cholesterol was increased by TTA administration and triacylglycerol (TAG) levels in plasma and liver were decreased by TTA supplementation, the latter, probably due to increased mitochondrial fatty acid oxidation and reduced lipogenesis. TTA administration also changed the fatty acid composition in the heart, and the amount of arachidonic acid (ARA) and eicosapentaenoic acid (EPA) was reduced and increased, respectively. The heart mRNA expression of inducible nitric oxidase (NOS)-2 was decreased in TTA-treated mice, whereas the mRNA level of catalase was increased. Finally, reduced plasma levels of inflammatory mediators as IL-1α, IL-6, IL-17, TNF-α and IFN-γ were detected in TTA-treated mice. These data show that TTA reduces atherosclerosis in apoE-/- mice and modulates risk factors related to atherosclerotic disorders. TTA probably acts at both systemic and vascular levels in a manner independent of changes in plasma cholesterol, and triggers TAG catabolism through improved mitochondrial function.

Effect of Dietary Components from Antarctic Krill on Atherosclerosis in apoE‐Deficient Mice

“…ApoE possesses relevant immunomodulatory properties, including the capacity to suppress lymphocyte proliferation, immunoglobulin synthesis, and neutrophil activation . As a consequence, apoE deletion is associated with increased T lymphocyte proliferation, cytokine synthesis and adhesion molecule expression, so that apoEKO mice have been used to evaluate the effect of dietary or pharmacological treatments on inflammation . Based on these data, we cannot exclude that in the present study the modulatory effects of n‐3 PUFAs on these parameters have been counterbalanced by the pro‐inflammatory milieu driven by apoE deficiency, resulting in a neutral effect of n‐3 PUFAs on inflammation.…”

Fenretinide treatment accelerates atherosclerosis development in apoE‐deficient mice in spite of beneficial metabolic effects

“…Hearts were removed, fixed in 10% formalin, and processed as previously described (Vik et al, ). Serial cryosections (7 micron thick) of the aortic sinus were cut and stained with haematoxylin and eosin (H&E; Parolini et al, ) to detect plaque area, calculated as the mean area of those sections showing the three cusps of the aortic valves.…”

Effects of Vegetable Proteins on Hypercholesterolemia and Gut Microbiota Modulation

“…Studies in lactating rats fed diet containing 20% of L. angustifolius protein markedly reduced both total cholesterol and triglyceride plasma levels [ 49 ]. A reduction of cholesterolemia and triglyceridemia were also found in apo-E deficient mice fed 10% L. angustifolius protein for 16 weeks [ 50 , 51 , 52 , 53 ].…”