Date of Graduation
Previous studies have shown that administration of fibroblast growth factor-19 (FGF-19) reverses diabetes, hepatic steatosis, hyperlipidemia, and adipose accretion in animal models of obesity. To investigate the mechanism for this effect, we determined whether FGF-19 modulated hepatic fatty acid synthesis, a key process controlling glucose tolerance and triacylglycerol accumulation in liver, blood, and adipose tissue. Incubating primary hepatocyte cultures with recombinant FGF-19 suppressed the ability of insulin to stimulate fatty acid synthesis. This effect was associated with a reduction in the expression of lipogenic enzymes. FGF-19 also suppressed the insulin-induced expression of sterol regulatory element-binding protein-1c (SREBP-1c), a key transcriptional activator of lipogenic genes. FGF-19 inhibition of lipogenic enzyme expression was not mediated by changes in glucose metabolism, alterations in the activity of the insulin signal transduction pathway or changes in the activity of extracellular signal-regulated kinase, p38 mitogen-activated protein kinase and AMP-activated protein kinase. In contrast, FGF-19 increased the activity of signal transducer and activator of transcription 3 (STAT3), an inhibitor of SREBP-1c expression and decreased the expression of peroxisome proliferator-activated receptor-g coactivator-1 Î² (PGC-1 Î²), an activator of SREBP-1c activity. FGF-19 also increased the expression of small heterodimer partner (SHP), a transcriptional repressor that inhibits lipogenic enzyme expression via an SREBP-1c-independent mechanism. Inhibition of SREBP-1c activity by changes in STAT3 and PGC-1Î² activity and inhibition of gene transcription by an elevation in SHP expression can explain the inhibition of lipogenesis caused by FGF-19. In summary, the inhibitory effect of FGF-19 on insulin activation of hepatic fatty acid synthesis constitutes a mechanism explaining the beneficial effect of FGF-19 on metabolic syndrome.
Bhatnagar, Sushant, "Fibroblast growth factor -19: A novel factor that inhibits hepatic fatty acid synthesis." (2008). Graduate Theses, Dissertations, and Problem Reports. 8482.