R‐α‐lipoic acid potentiates fasting‐induced transcription and secretion of hepatic fibroblast growth factor 21 (FGF21)

Abstract

Recombinant FGF21 (rFGF21) is an experimental polypeptide therapy against type‐2 diabetes and lipid anomalies. However, the high costs of producing rFGF21 and the mode of delivery by injection are important limitations to its wide therapeutic use. The stimulation of endogenous FGF21 production through diet is being explored as an alternative approach. Our research showed that naturally occurring dietary organosulfur compound R‐α‐lipoic acid (LA) stimulated liver Fgf21 expression (+175%) and blood FGF21 levels (+330%) and replicated the adaptive metabolic response to fasting evoked by FGF21 in vivo. In the present study, we examined the mechanism(s) by which serum manipulation and LA induce FGF21 in HepG2 human hepatocellular carcinoma cells. Serum starvation markedly induced FGF21 mRNA levels (50 fold) and FGF21 secreted in the media (19 fold). LA induced FGF21 mRNA 7 fold above DMSO‐treated control cells and FGF21 secretion 3 fold. These effects were several‐fold greater than those of PPARα agonist, Wy14643, an inducer of FGF21. The use of transcription inhibitor, actinomycin D, revealed that de novo mRNA synthesis drives FGF21 secretion in response to serum starvation and LA, and FGF21 does not accumulate in HepG2 cells to a significant degree. Previously unrecognized loci of FGF21 distal promoter were nucleosome depleted and transcriptionally active revealing new putative transcription factors. We conclude that LA activates FGF21 distal promoter resulting in FGF21 secretion by liver cells. LA may prove to be a safe and affordable means to stimulate FGF21 production. Supported by UNL ARD Hatch, and Layman Seed Award.