Targeting fructokinase, endogenous fructose production and purine degradation for the prevention and treatment of hereditary fructose intolerance

项目摘要/摘要 在我们的社会中，含有果糖的饮食摄入量急剧增加，有六分之一的人 人口饮食的25%或更多。虽然现在建议尝试减少糖的摄入量， 在今天的培养中，很难避免接触到HFCS和蔗糖。一群受苦的人 由于广泛使用添加糖，患有遗传性果糖不耐受(HFI)的人 常染色体隐性遗传，其受试者在摄入果糖后出现严重反应，并伴有腹部 儿童出现疼痛、呕吐、腹泻、症状性低血糖、高尿酸血症，甚至死亡。果糖 新陈代谢由两种酶启动，一种是将果糖磷酸化为果糖-1磷酸的果糖激酶 导致ATP耗竭和尿酸生成，以及进一步分解果糖-1磷酸的醛缩酶b 分子转化为二氢丙酮磷酸和甘油醛。肾综合征出血热是由醛缩酶B突变引起的 导致1-磷酸果糖的积累，显著的ATP耗竭和尿酸的生成 果糖摄入量远大于正常人的摄入量。我们的初步数据在 醛缩酶b缺陷小鼠提示，当暴露于饮食中或内源性产生的果糖时，其 缺乏与果糖激酶过度激活、生长迟缓、严重低血糖、 当果糖激酶被抑制时，肝脏/肠道损伤和死亡完全被阻断。值得关注的是， 当小鼠出现高尿酸血症时，在醛缩酶b缺乏的小鼠中观察到的有害影响会加剧。 提示尿酸在HFI的发病机制中起着重要的有害作用。这些观察使我们 根据我们的总体假设，阻止果糖代谢对1-磷酸果糖具有保护作用 醛缩酶b缺乏症受试者的hfi。具体地说，我们提出1)果糖激酶基因敲除小鼠 醛缩酶b缺乏症在接触果糖后不会发生肾功能不全，2)内源性 通过抑制醛糖还原酶和多元醇途径来生产果糖对人类有临床意义 患有醛缩酶b缺乏症和3)减少尿酸的产生和积累是一种重要的治疗方法。 肾综合征出血热的防治探讨。本申请中提出的研究是临床研究。 相关，因为它们将为未来的治疗提供见解(靶向果糖激酶、醛糖还原、AMP 脱氨酶和/或黄嘌呤氧化酶)对本病的唯一治疗方法(避免使用果糖) 在我们的社会里几乎是不可能的。

Project Summary/Abstract Dietary intake of sugars containing fructose has dramatically increased in our society with one-sixth of the population eating 25% of their diet or more. While attempts to reduce sugar intake are now recommended, it isvery difficult to avoid exposure to HFCS and sucrose in today's culture. One group that suffers from the widespread use of added sugars are individuals with Hereditary Fructose Intolerance (HFI), an autosomal recessive whose subjects develop severe reactions following fructose ingestion,with abdominal pain, vomiting, diarrhea, symptomatic hypoglycemia, hyperuricemia, and even death in children. Fructose metabolism is initiated by two enzymes, fructokinase that phosphorylates fructose to fructose-1 phosphate causing ATP depletion and uric acid generation, and aldolase b that further splits the fructose-1 phosphate molecule into dihydroacetone phosphate and glyceraldehyd. HFI is caused by the mutation in aldolase B leading to accumulation of fructose-1phosphate, marked ATP depletion and uric acid generation following fructose ingestion that is much greater than that observed in normal individuals. Our preliminary data in aldolase b deficient mice suggest that upon exposure to fructose in diet or endogenously produced, its deficiency is associated with fructokinase hyperactivation, growth retardation, severe hypoglycemia, liver/intestinal injury and death which are completely blocked when fructokinase is inhibited. Of interest, the deleterious effects observed in aldolase b deficient mice are exacerbated when mice are hyperuricemic suggesting an important deleterious role of uric acid in the pathogenesis of HFI. These observation led us to our overall hypothesis that the blockade of fructose metabolism to fructose-1 phoshate protects against HFI in subjects with aldolase b deficiency. Specifically, we propose that 1) fructokinase knockout mice with aldolase b deficiency will not develop HFI upon exposure to fructose, 2) the blockade of endogenous fructose production by inhibition of aldose reductase and the polyol pathway is clinically relevant for people with aldolase b deficiency and 3) lowering uric acid production and accumulation isan important therapeutic approach in the prevention and treatment of HFI. The studies proposed in this application are clinically relevant as they will provide insights into future therapies (targeting fructokinase, aldose reducatse, AMP deaminase and/or xanthine oxidase) for this disease in which the only treatment (avoidance of fructose) has become almost impossible in our society.