Lipid mediators are critical in resolving inflammation: a review of the emerging roles of eicosanoids in diabetes mellitus

Abstract

The biosynthesis pathway of eicosanoids derived from arachidonic acid, such as prostaglandins and leukotrienes, relates to the pathophysiology of diabetes mellitus (DM). A better understanding of how lipid mediators modulate the inflammatory process may help recognize key factors underlying the progression of diabetes complications. Our review presents recent knowledge about eicosanoid synthesis and signaling in DM-related complications, and discusses eicosanoid-related target therapeutics.

Figure 1

Eicosanoid synthesis pathways. After cell stimulation, arachidonic acid (AA) can be metabolized by three enzymes: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 (CYP 450). COX catalyzes AA in (prostaglandin) PGG₂ and PGH₂, and these are converted into PGD₂, PGE₂, PGF_2α, PG₁₂, TXA₁, and TXA₂. The LOX pathway catalyzes AA into hydroxyeicosatetraenoic acids (HETEs) and diverse hydroperoxyeicosatetraenoic acids (HPETEs). This pathway involves four enzymes: 5-LOX, 8-LOX, 12-LOX, and 15-LOX. 5-LOX interacts with a 5-LOX-activating protein (FLAP), enhancing the interaction of 5-LOX to AA. LTA₄ hydrolases convert LTA₄ into LTB₄, and LTC₄ synthase can convert LTA₄ to LTC₄, whereupon it is then metabolized to LTD₄ and LTE₄. 5-LOX synthetizes LXA₄ and LXB₄ using 15-HETE. The pathway of CYP-450 leads to the conversion of HETEs, including 16-, 17-, 18-, 19-, and 20-HETE and epoxyeicosatrienoic acids (EETs): 5,6-, 8,9-, 11,12-, and 14,15-EET.

Figure 2

Eicosanoid compounds affect different organs in diabetes complications. Diabetic nephropathy, one of the most common complications in diabetes, shows low PGE₂ levels and altered glomerular hemodynamics. This dilates arteries and increases microvascular permeability. In normal conditions PGE₂ downregulates TNF-α production and upregulates IL-10 production through EP2 and EP4 receptor signaling. However, a proinflammatory environment leads to cell permeabilization, low concentrations of PGE₂, and mesangial cell proliferation. Diabetic retinopathy is another common complication in diabetes. In diabetes, the environment in the retina has a particular lipid profile, with higher COX-2 and abnormal production of PG. LTA₄ and LTB₄ are enhanced in addition to IL-8. Diabetic peripheral neuropathy is correlated with high COX-2 and PGE₂. In a diabetic's cardiovascular system, PGE₂ has an important role in microvascular permeability, and 12-HETE and 20-HETE lower the activity of endothelial progenitor cell (EPC) function.