Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis
Fibroblast Growth Factor-19, a Novel Factor That Inhibits Hepatic Fatty Acid Synthesis
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DOI：
10.1074/jbc.m808818200
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发表时间：
2009-04-10
影响因子：
4.8
通讯作者：
Hillgartner, F. Bradley
中科院分区：
文献类型：
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作者：
Bhatnagar, Sushant;Damron, Holly A.;Hillgartner, F. Bradley
先前的研究表明，在肥胖动物模型中，给药成纤维细胞生长因子-19 （FGF-19）可以逆转糖尿病、肝脂肪变性、高脂血症和脂肪增加。为了研究这种作用的机制，我们确定了FGF-19是否调节肝脏脂肪酸合成，这是控制肝脏、血液和脂肪组织中葡萄糖耐量和甘油三酯积累的关键过程。用重组FGF-19培养原代肝细胞可抑制胰岛素刺激脂肪酸合成的能力。这种作用与脂肪生成酶表达的减少有关。FGF-19还抑制胰岛素诱导的固醇调节元件结合蛋白1c （SREBP-1c）的表达，SREBP-1c是脂肪生成基因的关键转录激活因子。FGF-19对脂肪生成酶表达的抑制不是由胰岛素信号转导通路活性的改变或ERK、p38 MAPK和amp活化蛋白激酶（AMPK）活性的改变介导的。相反，FGF-19增加了SREBP-1c表达抑制剂STAT3的活性，降低了SREBP-1c活性激活剂过氧化物酶体增殖物激活受体- γ辅助激活因子-1 β (PGC-1 β)的表达。FGF-19还增加了小异源二聚体伴侣（SHP）的表达，SHP是一种转录抑制因子，通过不依赖srebp -1c的机制抑制脂肪生成酶的表达。STAT3和PGC-1 β活性变化对SREBP-1c活性的抑制以及SHP表达升高对基因转录的抑制可以解释FGF-19对脂肪生成的抑制。综上所述，FGF-19对胰岛素激活肝脂肪酸合成的抑制作用可以解释FGF-19对代谢综合征的有益作用。
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-1 beta (PGC-1 beta), 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-1 beta 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.