Altered Lipid Metabolism in Brain Injury and Disorders

Overview

Journal Subcell Biochem

Publisher Springer

Specialty Biochemistry

Date 2008 Aug 30

PMID 18751914

Citations 155

Authors

Rao Muralikrishna Adibhatla

J F Hatcher

Affiliations

Soon will be listed here.

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.

Citing Articles

Cholesterol metabolism and its implications in psychotic disorders: a comparative study of individuals at ultra high risk and control groups.

Moreno M, Singulani M, van de Bilt M, Loch A, Gattaz W, Talib L Eur Arch Psychiatry Clin Neurosci. 2025; .

PMID: 39945822 DOI: 10.1007/s00406-025-01966-5.

Lipidomics of Huntington's Disease: A Comprehensive Review of Current Status and Future Directions.

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PMID: 39852353 PMC: 11766911. DOI: 10.3390/metabo15010010.

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PMID: 39483499 PMC: 11493208. DOI: 10.3390/neurosci5020016.

Advancements in the mechanisms of Naotai formula in treating stroke: A multi-target strategy.

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Spatial regulation of NMN supplementation on brain lipid metabolism upon subacute and sub-chronic PM exposure in C57BL/6 mice.

Jiang Y, Li F, Ye L, Zhang R, Chen S, Peng H Part Fibre Toxicol. 2024; 21(1):35.

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References

Aagaard L, Rossi J . RNAi therapeutics: principles, prospects and challenges. Adv Drug Deliv Rev. 2007; 59(2-3):75-86. PMC: 1978219. DOI: 10.1016/j.addr.2007.03.005. View

Bonifacio M, Palma P, Almeida L, Soares-da-Silva P . Catechol-O-methyltransferase and its inhibitors in Parkinson's disease. CNS Drug Rev. 2007; 13(3):352-79. PMC: 6494163. DOI: 10.1111/j.1527-3458.2007.00020.x. View

Agar J, Durham H . Relevance of oxidative injury in the pathogenesis of motor neuron diseases. Amyotroph Lateral Scler Other Motor Neuron Disord. 2004; 4(4):232-42. DOI: 10.1080/14660820310011278. View

Adibhatla R, Hatcher J, Larsen E, Chen X, Sun D, Tsao F . CDP-choline significantly restores phosphatidylcholine levels by differentially affecting phospholipase A2 and CTP: phosphocholine cytidylyltransferase after stroke. J Biol Chem. 2005; 281(10):6718-25. DOI: 10.1074/jbc.M512112200. View

Samadi P, Gregoire L, Rouillard C, Bedard P, Di Paolo T, Levesque D . Docosahexaenoic acid reduces levodopa-induced dyskinesias in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine monkeys. Ann Neurol. 2006; 59(2):282-8. DOI: 10.1002/ana.20738. View

Herrup K, Neve R, Ackerman S, Copani A . Divide and die: cell cycle events as triggers of nerve cell death. J Neurosci. 2004; 24(42):9232-9. PMC: 6730083. DOI: 10.1523/JNEUROSCI.3347-04.2004. View

Papandreou D, Pavlou E, Kalimeri E, Mavromichalis I . The ketogenic diet in children with epilepsy. Br J Nutr. 2006; 95(1):5-13. DOI: 10.1079/bjn20051591. View

Marusic S, Leach M, Pelker J, Azoitei M, Uozumi N, Cui J . Cytosolic phospholipase A2 alpha-deficient mice are resistant to experimental autoimmune encephalomyelitis. J Exp Med. 2005; 202(6):841-51. PMC: 2212947. DOI: 10.1084/jem.20050665. View

Zalewski A, Nelson J, Hegg L, Macphee C . Lp-PLA2: a new kid on the block. Clin Chem. 2006; 52(9):1645-50. DOI: 10.1373/clinchem.2006.070672. View

10.

Schuchman E . The pathogenesis and treatment of acid sphingomyelinase-deficient Niemann-Pick disease. J Inherit Metab Dis. 2007; 30(5):654-63. DOI: 10.1007/s10545-007-0632-9. View

11.

Whitfield J . Can statins put the brakes on Alzheimer's disease?. Expert Opin Investig Drugs. 2006; 15(12):1479-85. DOI: 10.1517/13543784.15.12.1479. View

12.

Sayeed I, Guo Q, Hoffman S, Stein D . Allopregnanolone, a progesterone metabolite, is more effective than progesterone in reducing cortical infarct volume after transient middle cerebral artery occlusion. Ann Emerg Med. 2006; 47(4):381-9. DOI: 10.1016/j.annemergmed.2005.12.011. View

13.

Temel R, Tang W, Ma Y, Rudel L, Willingham M, Ioannou Y . Hepatic Niemann-Pick C1-like 1 regulates biliary cholesterol concentration and is a target of ezetimibe. J Clin Invest. 2007; 117(7):1968-78. PMC: 1888567. DOI: 10.1172/JCI30060. View

14.

Mattson M, Cutler R, Jo D . Alzheimer peptides perturb lipid-regulating enzymes. Nat Cell Biol. 2005; 7(11):1045-7. DOI: 10.1038/ncb1105-1045. View

15.

Serhan C . Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annu Rev Immunol. 2006; 25:101-37. DOI: 10.1146/annurev.immunol.25.022106.141647. View

16.

Gao S, Zhang R, Greenberg M, Sun M, Chen X, Levison B . Phospholipid hydroxyalkenals, a subset of recently discovered endogenous CD36 ligands, spontaneously generate novel furan-containing phospholipids lacking CD36 binding activity in vivo. J Biol Chem. 2006; 281(42):31298-308. DOI: 10.1074/jbc.M604039200. View

17.

Ariza M, Pueyo R, Matarin M, Junque C, Mataro M, Clemente I . Influence of APOE polymorphism on cognitive and behavioural outcome in moderate and severe traumatic brain injury. J Neurol Neurosurg Psychiatry. 2006; 77(10):1191-3. PMC: 2077553. DOI: 10.1136/jnnp.2005.085167. View

18.

Mehta S, Manhas N, Raghubir R . Molecular targets in cerebral ischemia for developing novel therapeutics. Brain Res Rev. 2007; 54(1):34-66. DOI: 10.1016/j.brainresrev.2006.11.003. View

19.

Mandavilli A . The amyloid code. Nat Med. 2006; 12(7):747-51. DOI: 10.1038/nm0706-747. View

20.

Stack E, Smith K, Ryu H, Cormier K, Chen M, Hagerty S . Combination therapy using minocycline and coenzyme Q10 in R6/2 transgenic Huntington's disease mice. Biochim Biophys Acta. 2005; 1762(3):373-80. DOI: 10.1016/j.bbadis.2005.11.002. View