Division of Renal Diseases and Hypertension, Department of Medicine, University of Colorado, Denver, CO 80045, USA.
J Biol Chem. 2012 Nov 23;287(48):40732-44. doi: 10.1074/jbc.M112.399899. Epub 2012 Oct 3.
Uric acid is an independent risk factor in fructose-induced fatty liver, but whether it is a marker or a cause remains unknown.
Hepatocytes exposed to uric acid developed mitochondrial dysfunction and increased de novo lipogenesis, and its blockade prevented fructose-induced lipogenesis.
Rather than a consequence, uric acid induces fatty liver
Hyperuricemic people are more prone to develop fructose-induced fatty liver. Metabolic syndrome represents a collection of abnormalities that includes fatty liver, and it currently affects one-third of the United States population and has become a major health concern worldwide. Fructose intake, primarily from added sugars in soft drinks, can induce fatty liver in animals and is epidemiologically associated with nonalcoholic fatty liver disease in humans. Fructose is considered lipogenic due to its ability to generate triglycerides as a direct consequence of the metabolism of the fructose molecule. Here, we show that fructose also stimulates triglyceride synthesis via a purine-degrading pathway that is triggered from the rapid phosphorylation of fructose by fructokinase. Generated AMP enters into the purine degradation pathway through the activation of AMP deaminase resulting in uric acid production and the generation of mitochondrial oxidants. Mitochondrial oxidative stress results in the inhibition of aconitase in the Krebs cycle, resulting in the accumulation of citrate and the stimulation of ATP citrate lyase and fatty-acid synthase leading to de novo lipogeneis. These studies provide new insights into the pathogenesis of hepatic fat accumulation under normal and diseased states.
尿酸是果糖诱导脂肪肝的独立危险因素，但它是标志物还是病因尚不清楚。
尿酸作用于肝细胞可导致线粒体功能障碍和从头合成脂增加，而尿酸阻断则可预防果糖诱导的脂生成。
尿酸可引起脂肪肝而非其后果。高尿酸血症患者更容易发生果糖诱导的脂肪肝。代谢综合征代表了一系列异常，包括脂肪肝，目前美国有三分之一的人口受其影响，它已成为全球主要的健康关注点。果糖摄入主要来自饮料中的添加糖，可在动物中引起脂肪肝，并且在流行病学上与人类非酒精性脂肪肝疾病相关。由于果糖代谢直接生成甘油三酯，因此被认为具有生脂作用。在这里，我们表明果糖还通过嘌呤降解途径刺激甘油三酯合成，该途径是由果糖激酶对果糖的快速磷酸化引发的。生成的 AMP 通过 AMP 脱氨酶的激活进入嘌呤降解途径，导致尿酸生成和线粒体氧化剂的产生。线粒体氧化应激导致三羧酸循环中的顺乌头酸酶抑制，导致柠檬酸积累，并刺激 ATP 柠檬酸裂解酶和脂肪酸合酶导致从头合成脂。这些研究为正常和疾病状态下肝脂肪堆积的发病机制提供了新的见解。
