Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis

Sushant Bhatnagar,Holly A Damron,F.Bradley Hillgartner

doi:10.1074/jbc.m808818200

Sushant Bhatnagar, Holly A Damron + Show 1 more

Open Access

https://doi.org/10.1074/jbc.m808818200

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Abstract

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.

Highlights

Motes glucose intolerance, as accumulation of fatty acid metabolites in the liver suppresses the ability of insulin activate glycogen synthesis and inhibit gluconeogenesis [3]
As hepatic fatty acid synthesis plays an important role in controlling triacylglycerol accumulation in adipose tissue, liver, and blood, we determined the effects of recombinant human Fibroblast growth factor-19 (FGF-19) on fatty acid synthesis in primary cultures of rat hepatocytes incubated in the absence and presence of insulin
The addition of FGF-19 (50 ng/ml) suppressed the insulin-induced increase in fatty acid synthesis by 23% but had no effect on fatty acid synthesis in the absence of insulin. These data suggest that alterations in hepatic fatty acid synthesis play a role in mediating the inhibitory effect of FGF-19 on triacylglycerol levels in intact animals and that FGF-19 inhibits hepatic fatty acid synthesis by suppressing the action of a key hormone that mediates the activation of lipogenesis in response to dietary carbohydrate

Summary

Introduction

Motes glucose intolerance, as accumulation of fatty acid metabolites in the liver suppresses the ability of insulin activate glycogen synthesis and inhibit gluconeogenesis [3]. To investigate the mechanism by which FGF-19 inhibits insulin-induced expression of lipogenic enzymes, time course experiments were performed to determine the effect of FGF-19 on the concentration of mSREBP-1.

Results

Conclusion