Fibroblast growth factor-19, a novel factor that inhibits hepatic fatty acid synthesis.
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 alterations in the activity of the insulin signal transduction pathway or changes in the activity of ERK, p38 MAPK, and AMP-activated protein kinase (AMPK). In contrast, FGF-19 increased the activity of STAT3, an inhibitor of SREBP-1c expression and decreased the expression of peroxisome proliferator-activated receptor-gamma coactivator-1beta (PGC-1beta), 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 a SREBP-1c-independent mechanism. Inhibition of SREBP-1c activity by changes in STAT3 and PGC-1beta 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 that would explain the beneficial effect of FGF-19 on metabolic syndrome.
Bhatnagar
Sushant
S
Department of Biochemistry, West Virginia University, Morgantown, West Virginia 26506, USA.
Damron
Holly A
HA
Hillgartner
F Bradley
FB
D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D002790:Cholesterol 7-alpha-Hydroxylase / Q000378:metabolism; D019281:Dimerization; D005227:Fatty Acids / Q000378:metabolism*; D005346:Fibroblast Growth Factors / Q000378:metabolism / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D008954:Models, Biological; D051381:Rats; D017207:Rats, Sprague-Dawley; D051780:Sterol Regulatory Element Binding Protein 1 / Q000378:metabolism*
C117476:FGF19 protein, human; C540658:FGF19 protein, rat; D005227:Fatty Acids; D007328:Insulin; D051780:Sterol Regulatory Element Binding Protein 1; D005346:Fibroblast Growth Factors; C532838:CYP7A1 protein, rat; D002790:Cholesterol 7-alpha-Hydroxylase