A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism.
A critical role for ChREBP-mediated FGF21 secretion in hepatic fructose metabolism.
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DOI：
10.1016/j.molmet.2016.11.008
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发表时间：
2017-01
影响因子：
8.1
通讯作者：
Herman MA
中科院分区：
文献类型：
--
作者：
Fisher FM;Kim M;Doridot L;Cunniff JC;Parker TS;Levine DM;Hellerstein MK;Hudgins LC;Maratos-Flier E;Herman MA
果糖摄入量的增加是非酒精性脂肪性肝病（NAFLD）迅速流行的原因之一。最近的证据表明，在人类和啮齿动物中，代谢激素FGF 21受果糖消耗的调节，并可能在这种营养环境中发挥功能性作用。在这里，我们试图定义果糖摄入调节FGF 21的机制，并确定FGF 21是否有助于对果糖消耗的适应性代谢反应。我们使用ChREBP基因敲除小鼠检测了转录因子碳水化合物反应元件结合蛋白（ChREBP）在果糖介导的FGF 21调控中的作用。使用FGF 21敲除小鼠，我们研究了FGF 21在果糖消耗的背景下是否具有代谢功能。此外，我们测试了ChREBP-FGF 21相互作用是否可能在人类受试者中保守。在果糖灌胃后，ChREBP-β和Fgf 21的肝脏表达分别急剧增加2倍和3倍，并且这伴随着循环FGF 21的增加。在ChREBP敲除小鼠中，果糖灌胃后循环FGF 21的急性增加是不存在的。在喂食高果糖饮食的FGF 21敲除小鼠中，ChREBP-β及其糖酵解、果糖分解和脂肪生成基因靶点的诱导减弱，与喂食果糖的对照组相比，这伴随着新生脂肪生成a减少50%，VLDL分泌减少30%，肝脏脂肪减少25%。在人类受试者中，血清FGF 21与通过稳定同位素示踪剂测量的新生脂肪生成率相关（R = 0.55，P = 0.04），这与ChREBP-FGF 21相互作用的保守性一致。在高果糖饮食8周后，FGF 21敲除小鼠的肝脏表现出萎缩和纤维化，伴随着炎症和星状细胞活化的分子标志物;而在对照组中没有发生这种情况。总之，ChREBP和FGF 21构成了可能在人类中保守的信号传导轴，其介导对果糖摄入的必要适应性反应，其可能参与NAFLD和肝纤维化的发病机制。ChREBP是果糖诱导的循环FGF 21增加所必需的。果糖诱导的FGF 21反馈肝脏以增强ChREBP活性、脂肪生成、VLDL分泌和脂肪肝。循环FGF 21与人类受试者中的从头脂肪生成速率相关。在高果糖喂养的情况下，FGF 21保护肝脏免受炎症和纤维化。
Increased fructose consumption is a contributor to the burgeoning epidemic of non-alcoholic fatty liver disease (NAFLD). Recent evidence indicates that the metabolic hormone FGF21 is regulated by fructose consumption in humans and rodents and may play a functional role in this nutritional context. Here, we sought to define the mechanism by which fructose ingestion regulates FGF21 and determine whether FGF21 contributes to an adaptive metabolic response to fructose consumption. We tested the role of the transcription factor carbohydrate responsive-element binding protein (ChREBP) in fructose-mediated regulation of FGF21 using ChREBP knockout mice. Using FGF21 knockout mice, we investigated whether FGF21 has a metabolic function in the context of fructose consumption. Additionally, we tested whether a ChREBP-FGF21 interaction is likely conserved in human subjects. Hepatic expression of ChREBP-β and Fgf21 acutely increased 2-fold and 3-fold, respectively, following fructose gavage, and this was accompanied by increased circulating FGF21. The acute increase in circulating FGF21 following fructose gavage was absent in ChREBP knockout mice. Induction of ChREBP-β and its glycolytic, fructolytic, and lipogenic gene targets were attenuated in FGF21 knockout mice fed high-fructose diets, and this was accompanied by a 50% reduction in de novo lipogenesis a, 30% reduction VLDL secretion, and a 25% reduction in liver fat compared to fructose-fed controls. In human subjects, serum FGF21 correlates with de novo lipogenic rates measured by stable isotopic tracers (R = 0.55, P = 0.04) consistent with conservation of a ChREBP-FGF21 interaction. After 8 weeks of high-fructose diet, livers from FGF21 knockout mice demonstrate atrophy and fibrosis accompanied by molecular markers of inflammation and stellate cell activation; whereas, this did not occur in controls. In summary, ChREBP and FGF21 constitute a signaling axis likely conserved in humans that mediates an essential adaptive response to fructose ingestion that may participate in the pathogenesis of NAFLD and liver fibrosis. ChREBP is required for fructose-induced increases in circulating FGF21. Fructose-induced FGF21 feeds back on the liver to enhance ChREBP activity, lipogenesis, VLDL secretion, and fatty liver. Circulating FGF21 correlates with rates of de novo lipogenesis in human subjects. In the setting of high-fructose feeding, FGF21 protects the liver against inflammation and fibrosis.
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影响因子：
25.7
作者：
Ma J;Fox CS;Jacques PF;Speliotes EK;Hoffmann U;Smith CE;Saltzman E;McKeown NM
通讯作者：
McKeown NM
影响因子：
29.4
作者：
Lambert JE;Ramos-Roman MA;Browning JD;Parks EJ
通讯作者：
Parks EJ
DOI：
10.1073/pnas.0401516101
发表时间：
2004-05-11
影响因子：
11.1
作者：
Iizuka, K;Bruick, RK;Uyeda, K
通讯作者：
Uyeda, K
影响因子：
5.8
作者：
Hudgins, Lisa C.;Parker, Thomas S.;Hellerstein, Marc K.
通讯作者：
Hellerstein, Marc K.
循环的FGF21是肝脏的，并在进食和过度喂养过程中增强了葡萄糖的摄取。
影响因子：
7.7
作者：
Markan KR;Naber MC;Ameka MK;Anderegg MD;Mangelsdorf DJ;Kliewer SA;Mohammadi M;Potthoff MJ
通讯作者：
Potthoff MJ