The small intestine shields the liver from fructose-induced steatosis.
The small intestine shields the liver from fructose-induced steatosis.
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小肠保护肝脏免受果糖引起的脂肪变性。
DOI：
10.1038/s42255-020-0222-9
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发表时间：
2020-07
影响因子：
20.8
通讯作者：
Rabinowitz JD
中科院分区：
文献类型：
--
作者：
Jang C;Wada S;Yang S;Gosis B;Zeng X;Zhang Z;Shen Y;Lee G;Arany Z;Rabinowitz JD
人均果糖消费量比上个世纪增加了 100 倍。流行病学研究表明，过量果糖摄入，尤其是甜饮料摄入，与高脂血症、非酒精性脂肪肝、肥胖和糖尿病有关。果糖代谢始于酮己糖激酶 (KHK) 的磷酸化，该酶以两种选择性剪接形式存在。活性更强的同工酶 KHK-C 在肝脏中表达最强烈，但在小肠中也有大量表达，在小肠中，它驱动膳食果糖吸收并在果糖到达肝脏之前转化为其他代谢物。目前尚不清楚肠道果糖代谢是否会阻止或促进果糖诱导的脂肪生成和肝脏病理。在这里，我们发现肠道果糖分解代谢减轻了果糖诱导的肝脏脂肪生成。在小鼠中，肠道特异性 KHK-C 缺失增加了膳食果糖向肝脏和肠道微生物群的转运，并使小鼠对果糖的高脂血症作用和肝脂肪变性敏感。相反，肠道特异性 KHK-C 过度表达可促进肠道果糖清除并减少果糖诱导的脂肪生成。因此，肠道果糖清除能力控制着果糖被安全摄入的速率。与此相一致的是，我们发现相同量的果糖在饮用时比在食用时或单次灌胃时（而不是在 45 分钟内分多次服用）时具有更强的脂肪生成作用。总的来说，这些数据表明，当膳食摄入率超过肠道清除能力时，果糖会诱导脂肪生成。在现成食品供应充足的现代背景下，由此产生的果糖溢出会导致代谢综合征。根据肠道容量减慢果糖摄入量可以减轻这些后果。
Per capita fructose consumption has increased 100-fold over the last century. Epidemiological studies suggest that excessive fructose consumption, and especially consumption of sweet drinks, is associated with hyperlipidaemia, non-alcoholic fatty liver disease, obesity and diabetes. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver. It is unclear whether intestinal fructose metabolism prevents or contributes to fructose-induced lipogenesis and liver pathology. Here we show that intestinal fructose catabolism mitigates fructose-induced hepatic lipogenesis. In mice, intestine-specific KHK-C deletion increases dietary fructose transit to the liver and gut microbiota and sensitizes mice to fructose’s hyperlipidaemic effects and hepatic steatosis. In contrast, intestine-specific KHK-C overexpression promotes intestinal fructose clearance and decreases fructose-induced lipogenesis. Thus, intestinal fructose clearance capacity controls the rate at which fructose can be safely ingested. Consistent with this, we show that the same amount of fructose is more strongly lipogenic when drunk than eaten, or when administered as a single gavage, as opposed to multiple doses spread over 45 min. Collectively, these data demonstrate that fructose induces lipogenesis when its dietary intake rate exceeds the intestinal clearance capacity. In the modern context of ready food availability, the resulting fructose spillover drives metabolic syndrome. Slower fructose intake, tailored to intestinal capacity, can mitigate these consequences.
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影响因子：
29
作者：
Jang C;Hui S;Lu W;Cowan AJ;Morscher RJ;Lee G;Liu W;Tesz GJ;Birnbaum MJ;Rabinowitz JD
通讯作者：
Rabinowitz JD
影响因子：
4.7
作者：
通讯作者：
--
影响因子：
4.3
作者：
Chao CY;Battat R;Al Khoury A;Restellini S;Sebastiani G;Bessissow T
通讯作者：
Bessissow T
影响因子：
15.9
作者：
Lanaspa, Miguel A.;Andres-Hernando, Ana;Tolan, Dean R.
通讯作者：
Tolan, Dean R.
影响因子：
3.6
作者：
DURAN, M;BEEMER, FA;WADMAN, SK
通讯作者：
WADMAN, SK