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.

项目总结/摘要 在我们的社会中，含果糖的糖的饮食摄入量急剧增加， 人口吃25%的饮食或更多。虽然现在建议尝试减少糖的摄入量， 在今天的培养中，很难避免暴露于HFCS和蔗糖。一群人 来自广泛使用添加糖的是患有遗传性果糖不耐症（HFI）的个体， 常染色体隐性遗传，受试者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 引起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 分子转化为磷酸二氢丙酮和甘油三酸酯。HFI由醛缩酶B突变引起 导致果糖-1-磷酸的积累，显著的ATP消耗和尿酸的产生， 果糖的摄入量比正常人要高得多。我们的初步数据， 醛缩酶B缺陷小鼠表明，当暴露于饮食中的果糖或内源性产生的果糖时， 缺乏与果糖激酶过度活化、生长迟缓、严重低血糖 当果糖激酶被抑制时，肝/肠损伤和死亡被完全阻断。有趣的是， 在醛缩酶B缺陷小鼠中观察到的有害作用在小鼠高尿酸血症时加剧 提示尿酸在HFI发病机制中的重要有害作用。这些观察使我们 我们的总体假设，即阻断果糖代谢为果糖-1磷酸可以防止 醛缩酶B缺乏受试者的HFI。具体来说，我们提出：1）果糖激酶基因敲除小鼠， 醛缩酶B缺乏不会在暴露于果糖后发生HFI，2）内源性醛缩酶B的阻断， 通过抑制醛糖还原酶和多元醇途径产生的果糖与人类临床相关 醛缩酶B缺乏的患者; 3）降低尿酸的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在临床上是 相关，因为它们将为未来的治疗提供见解（靶向果糖激酶、醛糖还原酶、AMP 脱氨酶和/或黄嘌呤氧化酶），其中唯一的治疗（避免果糖） 在我们的社会中几乎是不可能的。

项目成果

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

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