NI02
Identifying the Role of Lipid Metabolism in an Experimental Autoimmune Encephalomyelitis Mice Model
Multiple Sclerosis (MS) is a disease characterized by demyelination and inflammation. Dysregulated fatty acid metabolism and mitochondrial function are mechanisms also hypothesized to be involved in the pathogenesis. Carnitine Palmitoyl Transferase 1 (CPT1) is a rate-limiting enzyme, which plays a pivotal role in mitochondrial fatty acid oxidation and blockage of CPT1 results is reversing metabolism from fatty acids to glucose. Moreover, mutations in CPT1a are frequently found among Hutterite and Inuit populations with residual CPT1a activities of 0 % and 22 %, respectively. The prevalence for developing MS in these populations is significantly reduced compared to the Canadian population. Therefore, we hypothesize that a CPT1a mutation protects against MS.
Objectives:
To clarify the role of CPT1a mutation and pharmacological inhibition of CPT1 by etomoxir in an autoimmune experimental encephalomyelitis (EAE) model of MS.
Methods:
CRISPR-Cas9 technology was used to develop two mice strains with a reduced activity of the metabolic enzyme CPT1 required for beta-oxidation. The first mice strain has a base pair mutation at position 1436 C to T (c.1436C>T) resulting in an amino acid mutation at position 479 Pro to Leu mimicking the mutation present among Inuits. The second strain has a 13 base pair deletion at position 1436-1448 causing a frame shift and therefore functional knock out of CPT1a, which is comparable to CPT1a activity in the Hutterite population. An MOG35-55-induced EAE model with wild type and CPT1a (c.1436C>T) mutated mice will be used to test the effect of the mutation and treatment with etomoxir. Afterwards, molecular biological tests as well as immunological tests will be performed.
Results:
We have generated two different mice strains with mutations in CPT1a similar to the mutations present in Hutterite and Inuit populations. Both mice strains have been bred to CPT1a homozygosity. Preliminary data concerning CPT1a heterozygous mice showed decreased immune response by lowering the pro-inflammatory cytokine level compared to wild type mice. Experiments are ongoing and results will be presented at the CMSC meeting 2018.
Conclusions:
This research indicates that CPT1, a key molecule involved in lipid metabolism, is involved in immune response as well as disease induction and progression. Inhibition of CPT1 opens up for novel strategies for treating MS by reversing the metabolism and decreasing inflammation.