Arachidonic acid metabolism in health and disease

Abstract

Arachidonic acid (AA), an n-6 essential fatty acid, is a major component of mammalian cells and can be released by phospholipase A2. Accumulating evidence indicates that AA plays essential biochemical roles, as it is the direct precursor of bioactive lipid metabolites of eicosanoids such as prostaglandins, leukotrienes, and epoxyeicosatrienoic acid obtained from three distinct enzymatic metabolic pathways: the cyclooxygenase pathway, lipoxygenase pathway, and cytochrome P450 pathway. AA metabolism is involved not only in cell differentiation, tissue development, and organ function but also in the progression of diseases, such as hepatic fibrosis, neurodegeneration, obesity, diabetes, and cancers. These eicosanoids are generally considered proinflammatory molecules, as they can trigger oxidative stress and stimulate the immune response. Therefore, interventions in AA metabolic pathways are effective ways to manage inflammatory-related diseases in the clinic. Currently, inhibitors targeting enzymes related to AA metabolic pathways are an important area of drug discovery. Moreover, many advances have also been made in clinical studies of AA metabolic inhibitors in combination with chemotherapy and immunotherapy. Herein, we review the discovery of AA and focus on AA metabolism in relation to health and diseases. Furthermore, inhibitors targeting AA metabolism are summarized, and potential clinical applications are discussed.

Keywords: arachidonic acid; bioactive lipid metabolites; organ homeostasis; targeted therapy.

FIGURE 1

Metabolites and enzymes involved in AA metabolism. AA is released from phospholipids by cPLA2, and it can be reincorporated into phospholipids (Land's cycle) or can be enzymatically changed into active metabolites mainly through three metabolic pathways involving COX, CYP‐450, or LOX. cPLA2, cytosolic phospholipase. COX, cyclooxygenase. The enzymes involved in AA metabolism are mainly found in the cytoplasm, endoplasmic reticulum, mitochondria and nuclear membrane of the cell. CYP‐450, cytochrome P450; LOX, lipoxygenase; 15‐HPDG, 15‐hydroxyprostaglandin dehydrogenase; HETE, hydroxyeicosatetraenoic acid; HPETE, hydroperoxyeicosatetraenoic acid; LTA‐4 hydrolase, leukotriene A(4) hydrolase; LCT‐4 synthase, leukotriene C(4) synthase; 5‐oxo‐ETE, 5‐oxoeicosatetraenoic acid; PGE‐2, prostaglandin E‐2; PGF‐2, prostaglandin F‐2; PGD‐2, prostaglandin D‐2; PGI‐2, prostaglandin I‐2; TXA‐2, thromboxane A‐2; TXB‐2, thromboxane B‐2; EETs, epoxyeicosatrienoic acids; DHETs, dihydroxyeicosatrienoic acids; 5‐HEDH, 5‐hydroxyeicosanoid dehydrogenase; GPX‐1, glutathione peroxidase 1.

FIGURE 2

Regulation of bone marrow stem cells (BMSCs) differentiation by AA metabolites. AA metabolites, such as PGI‐2 and PGE‐2, facilitate adipocyte differentiation by promoting the expression of PPARγ and suppress osteoblast differentiation by inhibiting the expression of TGF‐β and RUNX2. In the inflammatory state, COX‐2 and PGE‐2 are induced by IL‐6 and LPS in osteoblasts, resulting in the downregulation of OPG and the upregulation of RANKL, which ultimately promote osteoclast differentiation through the RANK–cFOS–TRAP pathway. PGI‐2, prostaglandin I‐2; IL‐6, interleukin‐6; LPS, lipopolysaccharide; RANK, receptor activator of nuclear factor kappa‐B; RANKL, ligand to receptor activator of NFkB ligand; c‐FOS, cellular oncogene fos; TRAP, tartrate‐resistant acid phosphatase; PGE‐2, prostaglandin E2; PPARγ, peroxisome proliferator‐activated receptor; OPG, osteoprotegerin.

FIGURE 3

Roles of AA metabolites in the control of synaptic transmission. Potassium influx and sodium efflux via the TASK pathway, postsynaptic IP3 receptor‐mediated Ca²⁺ release from internal stores, and AA metabolites could reduce N‐methyl‐D‐aspartic receptor‐induced calcium and neurotransmitter (like d‐serine) influx via CB1‐mediated closing of voltage‐sensitive calcium channels in the brain. CB, cannabinoid receptor. NMDAR, N‐methyl‐d‐aspartic acid receptor; TASK, TWIK‐related acid‐sensitive K; IP₃ receptor, inositol 1,4,5‐trisphosphate receptors.

FIGURE 4

Roles of AA metabolites in the cardiovascular system. On the one hand, vascular endothelial injury reduces the release of endothelial protective molecules (PGI2 and NO), triggering the aggregation of platelets, red blood cells, and fibrin deposits and leading to thrombosis. On the other hand, platelet aggregation is induced through the interaction between collagens and platelets via self‐activation by TXA‐2 caused by COX‐1. Furthermore, relaxation and contraction of myocardial cells are regulated by cAMP and Ca²⁺ signaling triggered by PGI‐2 and TXA‐2. ADP, adenosine diphosphate; PAR1/4, protease‐activated receptor 1/4; VWF, von Willebrand factor; PGIS, prostacyclin synthetase; PGI‐2, prostaglandin I‐2; TXA₂, thromboxane; COX‐1, cyclooxygenase 1; TXA‐2, thromboxane synthase‐2; cAMP, cyclic adenosine monophosphate.

FIGURE 5

Roles of AA metabolites in the regulation of the tumor microenvironment. AA metabolites act as messengers among tumor cells, fibroblasts, macrophages, and endothelial cells. For example, PGE2 and LTB4, which are derived from the COX‐2 and 5‐LOX AA metabolic pathways, promote the expression of cytokines through BLT 1/2, CysLT R1/R2, or EP 1−4 receptors and lead to the recruitment of macrophages through ERK‐P38 MAPK/NF‐κB signaling, as well as the release of CCL17, which binds to CCR4 and leads to fibrosis via upregulation of collagens, α‐SMA, and FGF. AA metabolites, such as PGE‐2, LTB‐4, and LTC4, can also trigger angiogenesis by regulating the expression of VEGF in endothelial cells. FGF, fibroblast growth factor; VEGF‐A, vascular endothelial growth factor‐A; TNF‐α, tumor necrosis factor‐α; IL‐6, interleukin‐6; BLT 1/2, leukotriene B4 receptor 1/2; CysLT R1/R2, cysteinyl‐leukotriene receptor; EP 1−4, prostaglandin EP receptor 1−4; CCL17, CC chemokine ligand 17; CCR4, CC chemokine receptor 4; P‐Smad 2/3, phosphorylated Smad 2/3; α‐SMA, α‐smooth muscle actin.

FIGURE 6

Target inhibitors used to intervene the activation of AA metabolic pathways. AA metabolites play essential roles in regulating inflammation, apoptosis, fibrosis, endothelial dysfunction, and so on. Specific inhibitors, including those used in the clinic and preclinical studies, targeting three AA metabolic pathways are presented here.