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.

项目概要/摘要 在我们的社会中，含果糖的膳食摄入量急剧增加，六分之一的人 人口的饮食占其饮食的 25% 或更多。虽然现在建议尝试减少糖的摄入量， 在当今的文化中，很难避免接触高果糖玉米糖浆和蔗糖。一组受苦受难的群体 广泛使用添加糖导致患有遗传性果糖不耐症 (HFI) 的个体，这是一种 常染色体隐性遗传，其受试者在摄入果糖后出现严重反应，伴有腹部 疼痛、呕吐、腹泻、症状性低血糖、高尿酸血症，甚至导致儿童死亡。果糖 代谢由两种酶启动，果糖激酶将果糖磷酸化为果糖-1 磷酸盐 导致 ATP 消耗和尿酸生成，醛缩酶 b 进一步分解果糖 1 磷酸盐 分子分解为磷酸二氢丙酮和甘油醛。 HFI 是由醛缩酶 B 突变引起的 导致 1 磷酸果糖积累、ATP 显着消耗和尿酸生成 果糖摄入量远高于正常人的摄入量。我们的初步数据在 醛缩酶 B 缺陷小鼠表明，在接触饮食中或内源产生的果糖后，其 缺乏与果糖激酶过度激活、生长迟缓、严重低血糖有关， 当果糖激酶被抑制时，肝脏/肠道损伤和死亡就被​​完全阻断。有趣的是， 当小鼠患有高尿酸血症时，在醛缩酶 B 缺陷小鼠中观察到的有害作用会加剧 表明尿酸在 HFI 的发病机制中具有重要的有害作用。这些观察引导我们 根据我们的总体假设，即阻断果糖代谢为果糖 1 磷酸盐可防止 醛缩酶 b 缺乏症受试者的 HFI。具体来说，我们建议 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 HFI，2) 内源性的阻断 通过抑制醛糖还原酶和多元醇途径产生果糖对于人类具有临床意义 醛缩酶 B 缺乏症和 3) 降低尿酸产生和积累是重要的治疗方法 预防和治疗 HFI 的方法。本申请中提出的研究是临床 相关，因为它们将提供对未来疗法的见解（针对果糖激酶、醛糖还原酶、AMP 脱氨酶和/或黄嘌呤氧化酶）对于这种疾病，唯一的治疗方法是（避免果糖） 在我们的社会中这几乎是不可能的。

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