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Controlling blood lipids is a major public health challenge of our time. The pleiotropic hormone-like polypeptide fibroblast growth factor 21 (FGF21) was recently recognized as a potent modulator of lipid and glucose metabolism and a promising treatment strategy for obesity related metabolic disorders, including dyslipidemia. A cost effective and practical alternative to the administration of recombinant FGF21 is to stimulate endogenous FGF21 production through diet. Our research identified (R)-a-lipoic acid (LA), a naturally occurring enzyme cofactor and dietary molecule found in green leafy vegetable and red meat, as an inducer of FGF21 expression. LA stimulated FGF21 production, demonstrated by a 3-fold increase in circulating FGF21, in the obese animal by upregulating hepatic Fgf21 expression. Concomitantly, feeding LA to dyslipidemic obese rats corrected high blood triacylglycerol levels and lowered abdominal adiposity by stimulating liver gene expression of peroxisome proliferator-activated receptor a (PPARa) target genes involved in lipid disposal and conjointly decreasing de novo lipid synthesis as a two-sided complementary mechanism to mitigate lipid burden. Since the metabolic effects of LA mimic those of FGF21, we posit that FGF21 mediates the beneficial phenotype evoked by LA and sought to determine how LA and its reduced form, (R)-a-dihydrolipoic acid (DHLA), induce the Fgf21 promoter. To that end, we employed HepG2 hepatocellular carcinoma cells under fed and starved states and in the presence of LA and DHLA. Serum withdrawal markedly induced FGF21 mRNA abundance from 24 to 48 hours after serum removal. Both LA and DHLA induced FGF21 mRNA levels at 36 hours after serum removal when compared to vehicle control. To further determine the regulatory mechanism of FGF21 transcription, we have begun to develop the FAIRE (Formaldehyde-Assisted Isolation of Regulatory Elements) assay coupled to qPCR to isolate and identify active regulatory promoter regions. We designed and validated a collection of primers specific for human FGF21 promoter that will allow the functional mapping of a 4,573-bp 5’ UTR region.
Advisor: Regis Moreau