Altered lipid metabolism in brain injury and disorders

Abstract

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A2 IIA and lipoprotein-PLA2 are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A2 attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.

Keywords: Atherosclerosis; Cholesterol; Inflammation; Neurodegenerative diseases; Stroke.

Figure 1

Lipid systems affected in CNS disorders (shaded) and injuries (clear). Neurosteroid synthesis in the brain is affected in various brain disorders and injuries and treatment with neurosteroids (pregnenolone, dehydroepiandrosterone and allopregnanolone) showed positive trend in these brain pathologies (Figure 3).

Figure 2

Atherosclerosis, a major risk factor for ischemic stroke. Under inflammatory conditions (OxLDL, homocysteine, cigarette smoke, shear stress and infectious agents such as Chlamydia pneumoniae) endothelia cells of the artery express adhesion molecules that allow monocytes (1) to adhere to endothelia (2). Chemoattractants such as monocyte chemoattractant protein-1 (MCP-1) draw the monocytes through the endothelium into the arterial intima. Once resident in the intima, monocytes differentiate into macrophages (3) in response to locally produced agents such as monocyte colony stimulating factor. LDL (4) under oxidative stress gets oxidized to OxLDL. The macrophages increase expression of scavenging receptors such as CD36, SR-A and SR-B. These scavenger receptors then internalize specifically oxidized LDL (OxLDL, specifically OxPC) particles such that cholesteryl esters accumulate in cytoplasmic droplets, resulting in lipid-loaded macrophages (foam cells, 5). Foam cells produce ROS, which further propagate LDL oxidation, and secrete cytokines and matrix metalloproteinases (MMPs). The MMPs contribute to degradation of the fibrous cap surrounding the plaque, resulting in its rupture and formation of a blood clot (6). If the blood clot dislodges from the plaque, arterial blood flow can carry it to the brain, where it lodges in a cerebral artery (embolism) and causes an ischemic stroke (7).

Figure 3

Synthesis of neurosteroids in the brain and their effects on various brain disorders and injuries. Niemann-Pick C protein transports cholesterol from endosome/lysosome system to mitochondria where the neurosteroid synthesis occurs. DHEA and allopregnanolone may provide beneficial effects based on the following studies: NPC (Griffin, et al., 2004), AD, Schizophrenia, bipolar disorders, epilepsy (Marx, et al., 2006a; Marx, et al., 2006b), PD (Wojtal, et al., 2006), stroke (Sayeed, et al., 2006), TBI (Djebaili, et al., 2005) and SCI (Lapchak, et al., 2000). Studies showed both DHEA and allopregnanolone stimulated neurogenesis in stroke. (Marx, et al., 2006b) and increased neuroprogenitor cells in AD models (Wang, et al., 2007a).