Lipids and Lipid Mediators Associated with the Risk and Pathology of Ischemic Stroke

Abstract

Stroke is a severe neurological disorder in humans that results from an interruption of the blood supply to the brain. Worldwide, stoke affects over 100 million people each year and is the second largest contributor to disability. Dyslipidemia is a modifiable risk factor for stroke that is associated with an increased risk of the disease. Traditional and non-traditional lipid measures are proposed as biomarkers for the better detection of subclinical disease. In the central nervous system, lipids and lipid mediators are essential to sustain the normal brain tissue structure and function. Pathways leading to post-stroke brain deterioration include the metabolism of polyunsaturated fatty acids. A variety of lipid mediators are generated from fatty acids and these molecules may have either neuroprotective or neurodegenerative effects on the post-stroke brain tissue; therefore, they largely contribute to the outcome and recovery from stroke. In this review, we provide an overview of serum lipids associated with the risk of ischemic stroke. We also discuss the role of lipid mediators, with particular emphasis on eicosanoids, in the pathology of ischemic stroke. Finally, we summarize the latest research on potential targets in lipid metabolic pathways for ischemic stroke treatment and on the development of new stroke risk biomarkers for use in clinical practice.

Keywords: cholesterol; eicosanoids; ischemia; ischemic stroke; lipoproteins; polyunsaturated fatty acids.

Figure 1

Lipid profile components and the risk of ischemic stroke. The reference values of the specified parameters may vary slightly according to different diagnostic recommendations. The arrow down indicates a low number of particles; the arrow up indicates a high number of particles. NA—not analyzed.

Figure 2

Eicosanoid biosynthesis pathways. Enzymes involved in biosynthetic pathways are denoted as: cPLA₂, cytosolic phospholipase A₂; COX-1, cyclooxygenase 1; COX-2, cyclooxygenase 2; PGIS, prostaglandin-I synthase; TBXAS-1, thromboxane-A synthase; PGES-1, prostaglandin E synthase; 12/15-LOX, 12/15-lipoxygenase; 5-LOX, 5-lipoxygenase; CYP4A, cytochrome P450 4A subfamily; CYP4F, cytochrome P450 4F subfamily; CYP2C, cytochrome P450 2C subfamily; CYP2J, cytochrome P450 2J subfamily; sEH, soluble epoxide hydrolase. Lipid molecules generated in biosynthesis are denoted as: AA, arachidonic acid; PGH₂, prostaglandin H₂; PGI₂, prostaglandin I₂, prostacyclin; TXA₂, thromboxane A₂; PGE₂, prostaglandin E₂; LTs, leukotrienes; 5-HETE, 5-hydroxyeicosatetraenoic acid; LXs, lipoxins; 12-HETE, 12-hydroxyeicosatetraenoic acid; 15-HETE, 15-hydroxyeicosatetraenoic acid; 20-HETE, 20-hydroxyeicosatetraenoic acid; 5,6-EET, 5,6-epoxyeicosatrienoic acid; 8,9-EET, 8,9-epoxyeicosatrienoic acid; 11,12-EET, 11,12-epoxyeicosatrienoic acid; 14,15-EET, 14,15-epoxyeicosatrienoic acid; DHETs, dihydroxyeicosatrienoic acids. Thumb symbol denotes beneficial or detrimental effects on the post-stroke brain of eicosanoids discussed in this review.

Figure 3

Possible mechanisms of involvement of serum lipids and eicosanoids in the pathophysiology of ischemic stroke. Arrows indicate stimulation, while bar-headed lines indicate inhibition. Green color stands for beneficial, while red for detrimental effects. Abbreviations used: 15-HETE, 15-hydroxyeicosatetraenoic acid; 20-HETE, 20-hydroxyeicosatetraenoic acid; EETs, epoxyeicosatrienoic acids; HDL, high-density lipoprotein; LDL, low-density lipoprotein; Lp(a), lipoprotein(a); PGE₂, prostaglandin E₂; PGI₂, prostaglandin I₂, prostacyclin; PUFAs, polyunsaturated fatty acids; TXA₂, thromboxane A₂.