1. Introduction

Polyunsaturated fatty acids (PUFAs) are divided into omega-3 (n-3) fractions (with the main synthesis pathway from α-linolenic acid) and omega-6 (n-6), which is synthesized from linoleic acid (LA) [1]. Linoleic acid can be metabolized to n-6 via desaturase, resulting via the biosynthesis of gamma-linolenic acid (GLA), dihomo-gamma-linolenic acid (DGLA), and finally arachidonic acid (AA)[2]. The largest amount of AA, however, is found in phospholipid membranes, competing with n-3 acids for metabolism and with their products for receptors [2,3].The role of omega-6 and the proportions of omega-3/omega-6 are a controversial subject. Higher level of LA and  AA in circulation are dangerous.

2. Physiologic Mechanisms

The proposed damage mechanism is based on increased inflammation, driven by the conversion of AA into proinflammatory and prothrombotic eicosanoids, such as prostaglandin E2, thromboxane A2 and leukotriene B4. In this cascade, AA is transformed by cyclooxygenase (COX) enzymes [4]. Eicosanoids, mainly epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), are produced throughout cytochrome P450 (CYP) enzyme activity [5]. However, as a result of AA metabolism mediated by lipooxygenase (LOX) enzymes, including 5-, 8-, 12-, and 15-LOX, from which, in turn, HPETE acids are adequately produced, followed by HETE and oxo-ETE, shown in Figure 1 [6]. A strong chemoattractant for basophils, eosinophils, monocytes and neutrophils is 5-oxoETE, 12 HETE. Moreover, 15 HETE stimulates mitogenesis of endothelial cells, increases the activity of granulocytes and lymphocytes.

Two isoforms of the COX enzyme (COX-1 and COX-2) are distinguished. COX-1 participates in basic physiological functions, such as platelet aggregation control, while COX-2 mainly takes part in inflammation and pathophysiological processes [7]. LA acid metabolism (by LOX enzymes) leads to the formation of hydroxyoctadecadienoic acids (HODEs), i.e., 9- and 13-HODE and subsequently oxo-HODE [2]. Both 13-HODE and 9-HODE should be regarded as atherosclerosis biomarkers. Eicosanoids are also formed from the n-6 pathway, which, together with other oxidized fatty acids metabolites, are called oxylipins. The oxylipin presence is correlated with the occurrence of inflammation and the main pathways for their synthesis, comparable with AA, are the COX, LOX, and CYP pathways [8]. Some CYP polymorphisms are associated with many diseases, including cancer and cardiovascular diseases. The CYP4A10 and CYPA12 isoforms are enzymes associated with hepatic and renal biosynthesis of atherosclerotic 20-HETE. In contrast, CYP2J2 is responsible for the formation of EET in extrahepatic tissues, including the heart, kidneys, lungs, and intestines in humans [9].

Figure 1. Synthesis of proinflammatory mediators from linoleic acid (LA) and arachidonic acid (AA). LOX- lipoxygenase, HETE- hydroperoxyeicosatetraenoic acid, HPETE- Hydroperoxyeicosatetraenoic acid, HODE- hydroxyoctadecadiene acids, COX- cyclooxygenase, CYP- cytochrome P450, HETEs- hydroxyeicosatetraenoic acids, EETs- epoxyeicosatrienoic acids, PG- prostaglandins, TX- thromboxane.

This entry is adapted from the peer-reviewed paper 10.3390/ijms21249628