Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance.
Endogenous Fructose Production and Metabolism Drive Metabolic Dysregulation and Liver Disease in Mice with Hereditary Fructose Intolerance.
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DOI：
10.3390/nu15204376
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发表时间：
2023-10-16
期刊：
影响因子：
5.9
通讯作者：
Lanaspa MA
中科院分区：
文献类型：
--
作者：
Andres-Hernando A;Orlicky DJ;Kuwabara M;Cicerchi C;Pedler M;Petrash MJ;Johnson RJ;Tolan DR;Lanaspa MA
过量摄入糖，特别是果糖，与人类和动物模型代谢综合征的发生和进展密切相关。然而，果糖代谢的遗传障碍会产生截然不同的后果。虽然果糖激酶（参与果糖代谢的第一种酶）的缺乏是良性的并且有些可取，但第二种酶醛缩酶 B 的错义突变会导致一种非常严重且有时致命的病症，称为遗传性果糖不耐受 (HFI)。迄今为止，HFI 尚无治愈方法，治疗仅限于避免果糖和糖。因此，对于患有 HFI 的受试者来说，葡萄糖是他们饮食中碳水化合物的唯一来源。然而，临床症状仍然出现，表明仍然消耗少量果糖，或者体内正在内源性产生果糖。在这里，我们证明，由于食用高血糖食物，多元醇途径（一种从葡萄糖产生果糖的代谢途径）被激活，触发一种有害机制，葡萄糖、山梨醇和酒精在醛缩酶 B 敲除小鼠中诱发严重的肝病和生长迟缓。我们表明，从总体上和药理学上阻断该途径可显着改善代谢功能障碍和生长发育，并提高醛缩酶 B 敲除小鼠对内源性果糖产生的饮食触发因素的耐受性。
Excessive intake of sugar, and particularly fructose, is closely associated with the development and progression of metabolic syndrome in humans and animal models. However, genetic disorders in fructose metabolism have very different consequences. While the deficiency of fructokinase, the first enzyme involved in fructose metabolism, is benign and somewhat desirable, missense mutations in the second enzyme, aldolase B, causes a very dramatic and sometimes lethal condition known as hereditary fructose intolerance (HFI). To date, there is no cure for HFI, and treatment is limited to avoiding fructose and sugar. Because of this, for subjects with HFI, glucose is their sole source of carbohydrates in the diet. However, clinical symptoms still occur, suggesting that either low amounts of fructose are still being consumed or, alternatively, fructose is being produced endogenously in the body. Here, we demonstrate that as a consequence of consuming high glycemic foods, the polyol pathway, a metabolic route in which fructose is produced from glucose, is activated, triggering a deleterious mechanism whereby glucose, sorbitol and alcohol induce severe liver disease and growth retardation in aldolase B knockout mice. We show that generically and pharmacologically blocking this pathway significantly improves metabolic dysfunction and thriving and increases the tolerance of aldolase B knockout mice to dietary triggers of endogenous fructose production.
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影响因子：
20.8
作者：
Jang C;Wada S;Yang S;Gosis B;Zeng X;Zhang Z;Shen Y;Lee G;Arany Z;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
5.9
作者：
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通讯作者：
Spagnuolo, Maria Immacolata
影响因子：
6.6
作者：
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通讯作者：
VARNEY, JK
影响因子：
15.9
作者：
Lanaspa, Miguel A.;Andres-Hernando, Ana;Tolan, Dean R.
通讯作者：
Tolan, Dean R.
DOI：
10.1073/pnas.1713837115
发表时间：
2018-03-20
影响因子：
11.1
作者：
Lanaspa, Miguel A.;Kuwabara, Masanari;Johnson, Richard J.
通讯作者：
Johnson, Richard J.