NASHVILLE—Multiple sclerosis (MS) traditionally has been considered a chronic inflammatory autoimmune disease, but inflammation decreases as the disease progresses. Many other biologic processes are dysregulated in MS, such as myelin signal transport, mitochondrial function, and iron metabolism. Lipid metabolism affects all of these processes, including inflammation, and thus could be a valuable therapeutic target, according to research presented at the 2018 CMSC Annual Meeting.
John D. Nieland, PhD
“MS is not an inflammatory disease,” said John D. Nieland, PhD, Associate Professor of Health Science and Technology at Aalborg University in Denmark. “The inflammatory response is important, but it is not the only component. If you do not focus on the other components, you will never be able to treat the disease.”
The Role of Lipids in the CNS
Healthy brains have a high amount of glucose metabolism, but glucose metabolism is reduced in MS and other neurologic disorders such as Parkinson’s disease and Alzheimer’s disease. “If glucose metabolism is downregulated, something else has to be taking over,” said Dr. Nieland. He and his colleagues hypothesize that lipid metabolism replaces glucose metabolism in MS. They further hypothesize that MS fundamentally is a dysfunction of lipid metabolism.
Lipids have an essential role in the CNS. Proper signal transduction requires lipids to be bound to the myelin sheath. The proteins that compose myelin sheaths are highly immunogenic, and lipids shield them from exposure to the immune system. The half-life of lipids attached to the myelin sheath is three days, so these lipids must be replaced constantly. In addition, lipids are essential for the function of glutamate, cannabinoid, and insulin receptors.
An increase in lipid metabolism decreases glucose metabolism and induces the production of prostaglandin E2, which is a key molecule in the inflammatory response. In the early stages of MS, inflammation attacks the myelin sheath and other brain proteins. Increased lipid metabolism decreases lipid concentrations in the CNS, including around myelin. When lipids are removed from the myelin sheath, they expose the immunogenic proteins that compose it, thus provoking an immune response. Dysregulated lipid metabolism also contributes to oxidative stress, mitochondrial dysfunction, demyelination, and neuronal loss.
Chemical Inhibition of Lipid Metabolism
Dr. Nieland and colleagues hypothesized that blocking lipid metabolism would reverse the inflammatory response and other harmful processes that occur in MS. Previous research by Shriver and colleagues indicated that inhibition of carnitine palmitoyltransferase 1 (CPT1), a molecule essential to lipid metabolism, in encephalitogenic T cells increases apoptosis and reduces the production of inflammatory cytokines. Two of the molecule’s three isoforms, CPT1A and CPT1C, are upregulated in MS. Stress prompts an increase in CPT1 expression, which spurs a shift to lipid metabolism. “If you block CPT1, you jam lipid metabolism,” Dr. Nieland said. “There is no way around it.” Dr. Nieland’s group thus chose CPT1 as its target.
The investigators first conducted studies using etomoxir, which inhibits CPT1 and blocks long-chain fatty acids from entering the mitochondria for beta oxidation. Through these effects, etomoxir causes cells to shift to glucose metabolism.
The researchers immunized 42 mice with myelin oligodendrocyte glycoprotein (MOG35–55) to induce experimental autoimmune encephalopathy (EAE). When the animals first exhibited symptoms at Day 10, they were randomized to receive subcutaneous etomoxir or placebo daily. Disease score decreased significantly in the treated animals, compared with the control animals. On Day 24, more than 50% of the treated mice exhibited normal behavior, compared with approximately 20% of control mice.
In another study, the investigators immunized 47 rats with myelin basic protein to induce EAE. The animals began having symptoms at Day 7, and the investigators randomized them to daily treatment with subcutaneous etomoxir or placebo. At Day 11, disease score was significantly lower among treated animals, compared with control animals. Body weight was significantly higher among rats that received etomoxir, compared with controls, at that time point. Also, 25% of treated animals exhibited normal behavior, but no controls did.
In a third study, the investigators compared etomoxir, interferon beta, and placebo in a rat model of EAE. Each treatment group included 10 rats, and etomoxir had superior effects on disease score and body weight, compared with interferon beta and placebo. When the investigators examined the rats’ serum, they found that levels of antibodies against brain antigens common in EAE were lower in rats treated with etomoxir, compared with those treated with interferon beta or placebo.