Department of Chemistry and Lewis-Sigler Institute for Integrative Genomics, Princeton University, Princeton, NJ, USA.
Department of Biological Chemistry, University of California, Irvine, Irvine, CA, USA.
Nat Metab. 2020 Jul;2(7):586-593. doi: 10.1038/s42255-020-0222-9. Epub 2020 Jun 22.
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.
在上个世纪，人均果糖消耗量增加了 100 倍。流行病学研究表明，过量摄入果糖，尤其是饮用含糖饮料，与高脂血症、非酒精性脂肪肝、肥胖和糖尿病有关。果糖代谢始于其被酶酮己糖激酶（KHK）磷酸化，KHK 有两种不同剪接的形式。活性更高的同工酶 KHK-C 在肝脏中表达最强，但在小肠中也大量表达，在小肠中它驱动饮食中的果糖吸收，并在果糖到达肝脏之前将其转化为其他代谢物。目前尚不清楚肠道果糖代谢是预防还是促成果糖诱导的脂肪生成和肝病理。在这里，我们表明肠道果糖分解代谢减轻了果糖诱导的肝脂肪生成。在小鼠中，肠道特异性 KHK-C 缺失增加了饮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效应和肝脂肪变性敏感。相比之下，肠道特异性 KHK-C 过表达促进了肠道果糖清除并减少了果糖诱导的脂肪生成。因此，肠道果糖清除能力控制了可以安全摄入果糖的速度。与这一观点一致的是，我们表明，当以相同的量摄入果糖时，与食用或单次灌胃相比，果糖的致脂性更强，因为单次灌胃会导致果糖在短时间内快速进入血液，而多次、小剂量摄入则可以将果糖缓慢地输送到肝脏，从而减轻其对脂质代谢的影响。总之，这些数据表明，当饮食中果糖的摄入速度超过肠道的清除能力时，果糖会诱导脂肪生成。在现代方便食品随处可得的背景下，由此产生的果糖溢出会导致代谢综合征。更慢的果糖摄入，与肠道能力相匹配，可以减轻这些后果。
