Per capita fructose consumption has increased 100-fold over the last century¹. 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^2,3,4,5,6,7. Fructose metabolism begins with its phosphorylation by the enzyme ketohexokinase (KHK), which exists in two alternatively spliced forms⁸. The more active isozyme, KHK-C, is expressed most strongly in the liver, but also substantially in the small intestine^9,10 where it drives dietary fructose absorption and conversion into other metabolites before fructose reaches the liver^11,12,13. 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.

上个世纪，人均果糖消费量增长了100倍¹。流行病学研究表明，果糖的过量摄入，尤其是甜饮料的摄入，与高脂血症，非酒精性脂肪肝，肥胖和糖尿病^{2,3,4,5,6,7有关}。果糖的代谢开始于其酶ketohexokinase（KHK）的磷酸化作用，该酶以两种交替剪接的形式存在⁸。更具活性的同工酶KHK-C在肝脏中表达最强，但在小肠^9,10中也有大量表达，在果糖到达肝脏之前，它会促使饮食中果糖吸收并转化为其他代谢产物^11,12,13。尚不清楚肠道果糖代谢是否阻止或促进果糖诱导的脂肪生成和肝脏病理。在这里，我们显示肠道果糖分解代谢减轻了果糖诱导的肝脂肪形成。在小鼠中，肠道特异性KHK-C缺失会增加饮食中果糖向肝脏和肠道菌群的转移，并使小鼠对果糖的高血脂作用和肝脂肪变性敏感。相反，肠道特异性KHK-C的过表达促进肠道果糖清除，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可安全摄入果糖的速度。与此相符的是，我们证明了当喝酒比单独吃或当单独管饲时，相同量的果糖更容易产生脂肪。而不是在45分钟内分多次服用。总体而言，这些数据表明，当果糖的饮食摄入率超过肠道清除能力时，果糖就会诱导脂肪形成。在现成的食物可供使用的现代背景下，所产生的果糖溢出会导致代谢综合症。根据肠道容量的不同，减少果糖的摄入量可以减轻这些后果。