title: Gemfibrozil, a lipid-lowering drug, increases myelin genes in human oligodendrocytes via peroxisome proliferator-activated receptor-β.
abstract: An increase in CNS remyelination and a decrease in CNS inflammation are important steps to halt the progression of multiple sclerosis. Earlier studies have shown that gemfibrozil, a lipid-lowering drug, has anti-inflammatory properties. The current study identified another novel property of gemfibrozil in stimulating the expression of myelin-specific genes (myelin basic protein, myelin oligodendrocyte glycoprotein, 2',3'-cyclic-nucleotide 3'-phosphodiesterase, and proteolipid protein (PLP)) in primary human oligodendrocytes, mixed glial cells, and spinal cord organotypic cultures. Although gemfibrozil is a known activator of peroxisome proliferator-activated receptor-α (PPAR-α), we were unable to detect PPAR-α 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-α(-/-) mice. On the other hand, gemfibrozil markedly increased the expression of PPAR-β but not PPAR-γ. Consistently, antisense knockdown of PPAR-β, but not PPAR-γ, abrogated the stimulatory effect of gemfibrozil on myelin genes in human oligodendrocytes. Gemfibrozil also did not up-regulate myelin genes in oligodendroglia isolated from PPAR-β(-/-) mice. Chromatin immunoprecipitation analysis showed that gemfibrozil induced the recruitment of PPAR-β to the promoter of PLP and myelin oligodendrocyte glycoprotein genes in human oligodendrocytes. Furthermore, gemfibrozil treatment also led to the recruitment of PPAR-β to the PLP promoter in vivo in the spinal cord of experimental autoimmune encephalomyelitis mice and suppression of experimental autoimmune encephalomyelitis symptoms in PLP-T cell receptor transgenic mice. These results suggest that gemfibrozil stimulates the expression of myelin genes via PPAR-β and that gemfibrozil, a prescribed drug for humans, may find further therapeutic use in demyelinating diseases.
authors.affiliation: Department of Neurological Sciences, Rush University Medical Center, Chicago, Illinois 60612, USA.
authors.forename: Malabendu
authors.initials: M
authors.lastname: Jana
authors.forename: Susanta
authors.initials: S
authors.lastname: Mondal
authors.forename: Frank J
authors.initials: FJ
authors.lastname: Gonzalez
authors.forename: Kalipada
authors.initials: K
authors.lastname: Pahan
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D003711:Demyelinating Diseases / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D015248:Gemfibrozil / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D000960:Hypolipidemic Agents / Q000494:pharmacology*; D051379:Mice; D018345:Mice, Knockout; D009186:Myelin Sheath / Q000235:genetics / Q000378:metabolism*; D009419:Nerve Tissue Proteins / Q000096:biosynthesis*; D009836:Oligodendroglia / Q000166:cytology / Q000378:metabolism*; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D048068:PPAR-beta / Q000235:genetics / Q000378:metabolism*; D020218:Response Elements / Q000502:physiology
chemical_list: D000960:Hypolipidemic Agents; D009419:Nerve Tissue Proteins; D047495:PPAR gamma; D048068:PPAR-beta; D015248:Gemfibrozil