Department of Medicine, Imperial College London, UK.
Breakspear Medical Group, Hemel Hempstead, Hertfordshire, UK.
Med Hypotheses. 2019 Mar;124:40-41. doi: 10.1016/j.mehy.2019.02.019. Epub 2019 Feb 4.
Modern diets have become increasingly rich in fructose, for example through the addition of high-fructose corn syrup to many foods and drinks. It has been suggested that this might lead to hepatotoxicity, including the development of non-alcoholic fatty liver disease. After entering hepatocytes via insulin-independent glucose transporter 2 transmembrane carrier proteins, fructose is phosphorylated to fructose-1-phosphate in a reaction catalysed by fructokinase (ketohexokinase). In turn, fructose-1-phosphate is hydrolysed by aldolase B to glyceraldehydes. Glyceraldehydes may enter gluconeogenesis via fructose-1,6-bisphosphate and fructose-6-phosphate; glyceraldehydes may also enter glycogenolysis via pyruvate. The last pathway involves conversion of pyruvate to acetyl-CoA. Alternatively, pyruvate may be converted, via the action of the hepatic lactate dehydrogenase isoenzyme LDH-5, into lactate. In liver damage, the LDH-5 isoenzyme becomes elevated, predominantly in serum/plasma. We therefore hypothesised that if dietary fructose is associated with hepatotoxicity, there should be a positive correlation between erythrocyte fructose-6-phosphate and plasma LDH-5. This hypothesis was tested by assaying venous blood samples taken from 39 patients at rest, three hours after eating. Quantitative Fourier transform infrared spectrometry following gel electrophoresis was used to assay erythrocyte fructose-6-phosphate levels. Similarly, plasma LDH-5 concentrations were spectrophotometrically analysed, using the pyruvate-lactate reaction, following electrophoretic separation of the LDH isoenzymes. A significant positive correlation was found between the two variables (r = 0.44, p = 0.0047). This result, which supports our hypothesis, is evidence in favour of the possibility that dietary fructose is associated with hepatotoxicity. In addition to being a marker of hepatic damage, LDH-5 may play a more direct epigenetic role in causing liver damage; acute hepatic injury is associated with nuclear translocation of LDH, causing the production of lactate from pyruvate in the nucleus; in turn, the lactate inhibits histone deacetylase and is associated with upregulation of genes associated with the damage response, leading to cell death.
现代饮食中果糖的含量越来越高，例如在许多食物和饮料中添加高果糖玉米糖浆。有人认为，这可能导致肝毒性，包括非酒精性脂肪肝疾病的发展。果糖通过胰岛素非依赖性葡萄糖转运蛋白 2 跨膜载体蛋白进入肝细胞后，在果糖激酶（己酮糖激酶）催化下磷酸化为果糖-1-磷酸。反过来，果糖-1-磷酸被醛缩酶 B 水解为甘油醛。甘油醛可以通过果糖-1,6-二磷酸和果糖-6-磷酸进入糖异生；甘油醛也可以通过丙酮酸进入糖原分解。最后一条途径涉及将丙酮酸转化为乙酰辅酶 A。或者，丙酮酸可以通过肝乳酸脱氢酶同工酶 LDH-5 的作用转化为乳酸。在肝损伤中，LDH-5 同工酶升高，主要在血清/血浆中升高。因此，我们假设如果饮食中的果糖与肝毒性有关，那么红细胞果糖-6-磷酸和血浆 LDH-5 之间应该存在正相关。通过检测 39 名患者在休息时和进食后 3 小时的静脉血样，对这一假设进行了检验。采用凝胶电泳后的定量傅里叶变换红外光谱法检测红细胞果糖-6-磷酸水平。同样，采用乳酸-丙酮酸反应，在电泳分离 LDH 同工酶后，分光光度法分析血浆 LDH-5 浓度。发现这两个变量之间存在显著的正相关（r=0.44，p=0.0047）。这一结果支持了我们的假设，为饮食中的果糖可能与肝毒性有关的可能性提供了证据。除了作为肝损伤的标志物外，LDH-5 可能在导致肝损伤方面发挥更直接的表观遗传作用；急性肝损伤与 LDH 的核转位有关，导致核内丙酮酸生成乳酸；反过来，乳酸抑制组蛋白去乙酰化酶，并与损伤反应相关基因的上调有关，导致细胞死亡。
