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

针对果糖激酶、内源性果糖产生和嘌呤降解来预防和治疗遗传性果糖不耐受

• 批准号: 10543664
• 负责人: Miguel Angel Lanaspa Garcia
• 金额: $ 12.18万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2022-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10543664
• 关键词: Targeting; fructokinase; endogenous; fructose; production

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.

项目摘要/摘要 在我们的社会中，含糖的饮食摄入含糖的摄入量大大增加了 人口吃25％的饮食或更多。虽然现在建议尝试减少糖摄入量的尝试，但 在当今文化中，很难避免暴露于HFC和蔗糖。一组受苦 从添加糖的广泛使用中，是遗传性果糖不耐受（HFI）的个体 常染色体隐性，受试者在摄入果糖后会产生严重的反应，腹部 儿童的疼痛，呕吐，腹泻，有症状性低血糖，高尿酸血症甚至死亡。果糖 代谢是由两种酶引发的，果糖酶磷酸化果糖至果糖1磷酸盐 引起ATP耗竭和尿酸的产生，以及藻酶B，进一步分裂果糖1磷酸盐 分子进入二羟苯丙酮磷酸盐和甘油醛。 HFI是由藻酶B中的突变引起的 导致果糖1磷酸的积累，在 果糖摄入比正常个体中观察到的要大得多。我们的初步数据 醛固酶B缺乏小鼠表明，在饮食或内源性产生的果糖暴露时， 缺乏症与果糖酶的过度活化，生长迟钝，严重低血糖症有关 抑制果糖酶时，肝脏/肠损伤和死亡将完全阻塞。感兴趣的 当小鼠高尿液血症时，在醛固酶B缺乏小鼠中观察到的有害作用会加剧 提出尿酸在HFI发病机理中的重要有害作用。这些观察带领我们 关于我们的总体假设，即果糖代谢对果糖-1 phoshate的封锁可以预防 HFI在患有醛酶B缺乏症的受试者中。具体来说，我们建议1）与 暴露于果糖时，醛酶B缺乏不会发展HFI，2）内源性的阻塞 通过抑制醛糖还原酶和多元醇途径的果糖产生与人们有关 与醛酶B缺乏症和3）降低尿酸产生和积累ISAN重要治疗 预防和治疗HFI的方法。该应用中提出的研究在临床上是 相关性，因为它们将提供对未来疗法的见解（靶向果糖酶，醛糖还原，AMP 脱氨酶和/或黄嘌呤氧化酶）用于这种疾病，其中唯一的治疗（避免果糖） 在我们的社会中几乎变得不可能。

项目成果

Increased Serum Uric Acid over five years is a Risk Factor for Developing Fatty Liver.

• DOI: 10.1038/s41598-018-30267-2
• 发表时间: 2018-08-06
• 期刊: Scientific reports
• 影响因子: 4.6
• 作者: Jensen T;Niwa K;Hisatome I;Kanbay M;Andres-Hernando A;Roncal-Jimenez CA;Sato Y;Garcia G;Ohno M;Lanaspa MA;Johnson RJ;Kuwabara M
• 通讯作者: Kuwabara M

Different Risk for Hypertension, Diabetes, Dyslipidemia, and Hyperuricemia According to Level of Body Mass Index in Japanese and American Subjects.

• DOI: 10.3390/nu10081011
• 发表时间: 2018-08-03
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Kuwabara M;Kuwabara R;Niwa K;Hisatome I;Smits G;Roncal-Jimenez CA;MacLean PS;Yracheta JM;Ohno M;Lanaspa MA;Johnson RJ;Jalal DI
• 通讯作者: Jalal DI

Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance.

• DOI: 10.3390/nu15204376
• 发表时间: 2023-10-16
• 期刊: Nutrients
• 影响因子: 5.9
• 作者: Andres-Hernando A;Orlicky DJ;Kuwabara M;Cicerchi C;Pedler M;Petrash MJ;Johnson RJ;Tolan DR;Lanaspa MA
• 通讯作者: Lanaspa MA

Uric acid and hypertension.

• DOI: 10.1038/s41440-020-0481-6
• 发表时间: 2020-08
• 期刊: Hypertension research : official journal of the Japanese Society of Hypertension
• 作者: Lanaspa MA;Andres-Hernando A;Kuwabara M
• 通讯作者: Kuwabara M