Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice
Ketohexokinase C blockade ameliorates fructose-induced metabolic dysfunction in fructose-sensitive mice
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DOI：
10.1172/jci94427
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发表时间：
2018-06-01
影响因子：
15.9
通讯作者：
Tolan, Dean R.
中科院分区：
文献类型：
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作者：
Lanaspa, Miguel A.;Andres-Hernando, Ana;Tolan, Dean R.
越来越多的证据表明，在西方饮食中过量摄入果糖是导致目前代谢综合征和肥胖症流行的一个因素。遗传性果糖不耐受（HFI）是一种与果糖代谢受损相关的困难且可能致命的孤儿疾病。在HFI中，醛缩酶B的缺乏导致细胞内磷酸化果糖的积累，导致磷酸盐螯合和消耗，增加的三磷酸腺苷（ATP）周转，以及导致临床表现如脂肪肝、高尿酸血症、范可尼综合征和严重低血糖症的多种病症。不幸的是，目前没有治疗HFI的方法，避免糖和果糖在我们的社会中已经成为一个挑战。在这份报告中，通过使用转基因小鼠和药理学抑制剂，我们证明，酮己糖激酶（Khk），醛缩酶B的上游酶的情况下或抑制，足以防止低血糖症和肝脏和肠道损伤与HFI。在此，我们首次提供了证据，以我们的知识，一个潜在的治疗方法HFI。从机制上讲，我们的研究表明，它是抑制的Khk C亚型，而不是A亚型，保护动物免受HFI。
Increasing evidence suggests a role for excessive intake of fructose in the Western diet as a contributor to the current epidemics of metabolic syndrome and obesity. Hereditary fructose intolerance (HFI) is a difficult and potentially lethal orphan disease associated with impaired fructose metabolism. In HFI, the deficiency of aldolase B results in the accumulation of intracellular phosphorylated fructose, leading to phosphate sequestration and depletion, increased adenosine triphosphate (ATP) turnover, and a plethora of conditions that lead to clinical manifestations such as fatty liver, hyperuricemia, Fanconi syndrome, and severe hypoglycemia. Unfortunately, there is currently no treatment for HFI, and avoiding sugar and fructose has become challenging in our society. In this report, through use of genetically modified mice and pharmacological inhibitors, we demonstrate that the absence or inhibition of ketohexokinase (Khk), an enzyme upstream of aldolase B, is sufficient to prevent hypoglycemia and liver and intestinal injury associated with HFI. Herein we provide evidence for the first time to our knowledge of a potential therapeutic approach for HFI. Mechanistically, our studies suggest that it is the inhibition of the Khk C isoform, not the A isoform, that protects animals from HFI.