Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor beta.

An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis (MS). Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identifies another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (MBP, MOG, CNPase, and PLP) in primary human oligodendrocytes, mixed glial cells and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-a (PPAR-a), we were unable to detect PPAR-a in either gemfibrozil-treated or untreated human oligodendrocytes and gemfibrozil increased the expression of myelin genes in oligodendrocytes isolated from both wild type and PPAR-a (-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-b, but not PPAR-g. Consistently, antisense knockdown of PPAR-b, but not PPAR-g, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not upregulate myelin genes in oligodendroglia isolated from PPAR-b (-/-) mice. Chromatin immunoprecipitation analysis shows that gemfibrozil induces the recruitment of PPAR-b to the promoter of PLP and MOG genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-b to the PLP promoter in vivo in the spinal cord of EAE mice and suppression of EAE symptoms in PLP-TCR transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-b and that gemfibrozil, a prescribed drug for humans, may further find its therapeutic use in demyelinating diseases.
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