Abstract
The main pharmacological treatment that shows PPARα as a target of action is based on fibrates, drugs currently recommended for the management of hypertriglyceridemia by the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS). In the group of bioactive substances capable to affect TG metabolism through a PPARα-mediated pathway, a growing interest is focused on the supplementation with omega-3 fatty acids. Omega-3 and omega-6 fatty acids represent two categories of polyunsaturated fatty acids (PUFAs), whose consumption through diet is considered essential, due to the mammalian lack of ability to introduce double bonds into FAs. Fish is the main source of long-chain omega-3 FAs, mainly eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), while some plant-based foods (such as flaxseed oil, soy and canola oil, chia seeds, pumpkin seeds and walnuts) contain omega-3 in the form of precursor alpha-linolenic acid (ALA). PPARα is well-recognized to be directly bound and activated by omega-3, leading to the induction of genes involved in FA oxidation. An in vitro study also showed that the 9-oxo-10(E),12(Z),15(Z)-octadecatrienoic acid (9-oxo-OTA), an active compound deriving from ALA occurring in tomato fruit extract, was able to activate PPARα and induce mRNA expression of PPARα target genes in murine hepatocytes. Overall, based on this mechanism of action, and through other mechanisms described below, omega-3 may allow to address liver lipid metabolism toward a state of oxidation, rather than synthesis or accumulation.
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Key Points
It is still a matter of debate whether ALA itself mediates effects on lipid metabolism and inflammation or if these beneficial effects are mediated by EPA and DHA. In the present review, the most relevant evidence about the triglycerides (TG) reducing effect of different food-derived bioactive compounds is presented. Omega-3, is demonstrated as a plasma TG-lowering effect after a chronic supplementation in humans, with action targets including (a) influence on FA beta-oxidation, (b) reduction of FFA flux to the liver, (c) inhibition of FA synthesis, (d) increased clearance of plasma TG, and (e) inhibition of TG intestinal absorption. The increase of FA beta-oxidation and the inhibition of FA synthesis represent two different and opposite targets of action which, in both cases, may lead to an increased rate of FA oxidation, rather than synthesis or accumulation. Since TG molecules are composed of FAs, it is reasonable to hypothesize that the effects of food-derived bioactive compounds on these two targets may lead to a final TG-lowering effect. Furthermore, two other putative metabolic targets are the reduction of FFA flux to the liver and the increased clearance of plasma TG. In both cases, the effect of bioactive compounds described above would be mediated by the reduced and increased activity of HSL and LPL, respectively. Plasma TG can origin from FAs provided from both endogenous and exogenous sources. The inhibition of intestinal absorption of TG represents the last target of action described in this review, and it refers, specifically, to the improved metabolism of TG from exogenous sources (dietary food).