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The Importance of Lipids in MS (CMSC 2016)
A presentation at the 2016 Annual Meeting of the Consortium of Multiple Sclerosis Centers (CMSC), held June 1-4 in National Harbor, MD, demonstrated the important of lipids for the brain in MS. Lipids are important for the myelin sheath, and minimize signaling speed through nerve cells, and reduce the energy requirements for transmitting signals. Lipids contribute to protein transport, and are important components of neurotransmitters. Additionally, lipids are important activators and chemotactic molecules for the immune system, explained John Nieland, PhD, Aalborg University, Aalborg, DK.
Lipids bind to immunogenic sites in a protein, prevent post-translational modification, and prevent immunogenic proteins of the myelin sheath from being detected by B and T cells. Although lipids bound to the myelin sheath have a half-life of only 3 days.
Under conditions of stress (pathological, physiological, and psychological), a state of local hypoxia can occur and shift metabolism from normal glucose metabolism to lipid metabolism. When lipid levels are reduced, this prevents lipidation of the myelin sheath, and leads to downstream effects that leave the myelin sheath vulnerable to inflammatory attack. By focusing treatment on the inflammatory attack, this may only be treating a symptom of the disease.
Angelique Corthals, PhD, Stony Brook Medicine, Stony Brook, NY, explained that the immune system may only be part of the pathological progression of MS. White matter in patients with MS has structural abnormalities in lipids, and serum lipids show these alterations as well. These structural abnormalities cannot be detected with standard clinical laboratory tests.
The endogenous pathway for lipid metabolism plays an important role in CNS myelination. Peroxisome proliferator activated receptors (PPARS) are at the center of the regulation between lipid metabolism and immune system homeostasis. PPARS regulate key enzymes involved in lipid metabolism and the acute-phase response of the immune system. Dr. Corthals proposed that MS pathogenesis may originate in a dysregulation of lipid homeostasis through faulty PPAR genes and environmental triggers, such as diet and pathogens, that accentuate a dysregulatory loop.
A diet high in fat and carbohydrates compounded with environmental factors, and genetic factors linked to PPAR regulatory functions in lipid homeostasis and the immune system may represent increased risk for certain populations to develop MS. A symptom-by-symptom approach will not be successful in treating MS under these circumstances. However, rebalancing homeostasis in both lipid metabolism and the immune system, may be effective. Dr. Corthals concluded that to fully understand the influence of PPARS on MS and potential therapeutic options will take much more work to understand.
Ann Skottrup Morkholt, PhD, Aalborg University, Aalborg, DK, discussed a therapeutic target of lipid metabolism that is under investigation in preclinical models. CPT-1 is an important component in beta-oxidation, inhibition of CPT-1 can block lipid metabolism and can influence the development of MS. Blocking of CPT-1 completely blocks mitochondrial lipid metabolism.
Etomoxir (MIQ-001) blocks CPT-1, which leads to inhibition of lipid metabolism and the inflammatory response. In a preclinical model of MS (intradermal injection of myelin oligodendrocyte glycoprotein (MOG35-55), etomoxir reduced the severity of MS symptoms and restored neural functioning in more than 50% of mice. In a comparison study with interferon-β, etomoxir was significantly better for reducing disease score compared with interferon-β and placebo on days 1 and 5 after disease induction. Given the success in preclinical models, the researchers plan to conduct clinical trials in MS patients with secondary progressive MS and acute optic neuritis.