Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver
Uric Acid Stimulates Fructokinase and Accelerates Fructose Metabolism in the Development of Fatty Liver
复制标题
DOI：
10.1371/journal.pone.0047948
复制
发表时间：
2012-10-24
期刊：
影响因子：
3.7
通讯作者：
Johnson, Richard J.
中科院分区：
文献类型：
--
作者：
Lanaspa, Miguel A.;Sanchez-Lozada, Laura G.;Johnson, Richard J.
过量的膳食果糖摄入可能在目前脂肪肝、肥胖和糖尿病的流行中起重要作用，因为其摄入与这些综合征的发展平行，并且因为其可以诱导代谢综合征的特征。然而，果糖诱导脂肪肝、高血糖症和胰岛素抵抗的作用在个体之间差异很大。果糖代谢的第一步是由果糖激酶（KHK）介导的，它将果糖磷酸化为果糖-1-磷酸;细胞内尿酸也是该反应期间发生的瞬时ATP消耗的结果。在这里，我们表明，在人类肝细胞中，尿酸上调KHK的表达，从而导致果糖的脂肪生成作用的放大。尿酸生成的抑制显着阻断果糖诱导的甘油三酯积累在肝细胞在体外和体内。尿酸刺激KHK表达的机制涉及转录因子ChREBP的激活，这反过来又通过结合其启动子内的特定序列而导致KHK的转录激活。由于对果糖敏感的受试者通常会出现与高尿酸血症相关的表型，因此尿酸可能是脂肪肝发生期间肝细胞对果糖代谢敏感的潜在因素。
Excessive dietary fructose intake may have an important role in the current epidemics of fatty liver, obesity and diabetes as its intake parallels the development of these syndromes and because it can induce features of metabolic syndrome. The effects of fructose to induce fatty liver, hypertriglyceridemia and insulin resistance, however, vary dramatically among individuals. The first step in fructose metabolism is mediated by fructokinase (KHK), which phosphorylates fructose to fructose-1-phosphate; intracellular uric acid is also generated as a consequence of the transient ATP depletion that occurs during this reaction. Here we show in human hepatocytes that uric acid up-regulates KHK expression thus leading to the amplification of the lipogenic effects of fructose. Inhibition of uric acid production markedly blocked fructose-induced triglyceride accumulation in hepatocytes in vitro and in vivo. The mechanism whereby uric acid stimulates KHK expression involves the activation of the transcription factor ChREBP, which, in turn, results in the transcriptional activation of KHK by binding to a specific sequence within its promoter. Since subjects sensitive to fructose often develop phenotypes associated with hyperuricemia, uric acid may be an underlying factor in sensitizing hepatocytes to fructose metabolism during the development of fatty liver.