Fibrates upregulate TRB3 in lymphocytes independent of PPARα by augmenting CCAAT/enhancer-binding proteinβ (C/EBPβ) expression

Fibrates, which function by binding and activating peroxisome proliferator-activated receptor α (PPARα), have been used successfully to treat hyperlipidemia and atherosclerosis. Increasing evidence suggests that in addition to their lipid lowering activities these medications also function as immunosuppressive agents. Tribbles is a Drosophila protein that slows cell cycle progression, and its mammalian homolog, TRB3 interferes with insulin-induced activation of AKT. In these studies we demonstrate that fibrates upregulate TRB3 expression in mitogen-activated lymphocytes. Interestingly, in lymphocytes fibrates augment TRB3 expression in both PPARα wildtype and knockout mice, suggesting that upregulation of this protein occurs in a PPARα-independent manner. Fibrates activate a proximal TRB3 promoter construct and mutation or partial deletion of a potential PPAR response element does not alter the ability of fibrates to drive TRB3 expression. Subsequent studies reveal that fibrates upregulate C/EBPβ and CHOP in lymphocytes and mutation of potential C/EBPβ and CHOP consensus sequences abrogates the ability of fibrates to upregulate TRB3 promoter activity. Accordingly, fibrates enhance the recruitment of C/EBPβ and CHOP to the proximal TRB3 promoter. Finally, TRB3 expression in lymphocytes induces G2 cell cycle delay and cellular depletion. These studies outline a novel PPARα-independent mechanism of action of fibrates and document for the first time the expression of TRB3 in activated lymphocytes.