Nature：果糖促进脂肪肝，菌群起了啥作用？
- ①肝脏中，酶ACLY能将果糖代谢产生的柠檬酸转化为乙酰辅酶A，为脂肪酸合成提供底物，但在小鼠肝脏中敲除该酶不能抑制果糖引起的肝脏脂肪生成；
- ②大剂量摄入时，肠道菌群将果糖转化为乙酸，在肝脏中被酶ACSS2转化为乙酰辅酶A，促进脂肪酸生成；
- ③逐渐摄入果糖可促进其在小肠的吸收，这种情况下肝细胞中的柠檬酸裂解以及肠道菌群产生的乙酸，都参与肝脏脂肪生成；
- ④果糖诱导ChREBP-β等肝脏脂肪生成相关基因的表达，不依赖于乙酰辅酶A代谢。
主编推荐语
饮食中添加的蔗糖和高果糖玉米糖浆等，是膳食果糖的一个主要来源，而大量摄入果糖会增加肝脏脂肪生成，可引起脂肪肝。此前研究认为，果糖代谢产生的柠檬酸，经ATP柠檬酸裂解酶（ACLY）转化为乙酰辅酶A，为脂肪生成提供原料。然而Nature发表的一项最新研究却揭示了一种新的机制，表明果糖诱导的肝脏脂肪生成包含两方面的因素：① 肝细胞中的果糖分解过程会诱导脂肪生成基因的表达；② 肠道菌群发酵果糖产生的乙酸，为脂肪生成提供底物乙酰辅酶A。这些发现为脂肪肝等代谢疾病中的饮食、菌群与宿主代谢之间的关系，提供了新视角。值得注意的是，酒精在体内可被转化为乙酸，而且菌群发酵膳食纤维也可产生乙酸，这些乙酸是否也参与果糖诱导的脂肪肝发生，或许值得进一步研究。
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Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
膳食果糖通过菌群衍生的乙酸促进肝脏脂肪生成
10.1038/s41586-020-2101-7
2020-03-18, Article
Abstract & Authors:展开
Abstract:收起
Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease2,3,4. Fructose intake triggers de novo lipogenesis in the liver4,5,6, in which carbon precursors of acetyl-CoA are converted into fatty acids. The ATP citrate lyase (ACLY) enzyme cleaves cytosolic citrate to generate acetyl-CoA, and is upregulated after consumption of carbohydrates7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases8. However, the route from dietary fructose to hepatic acetyl-CoA and lipids remains unknown. Here, using in vivo isotope tracing, we show that liver-specific deletion of Acly in mice is unable to suppress fructose-induced lipogenesis. Dietary fructose is converted to acetate by the gut microbiota9, and this supplies lipogenic acetyl-CoA independently of ACLY10. Depletion of the microbiota or silencing of hepatic ACSS2, which generates acetyl-CoA from acetate, potently suppresses the conversion of bolus fructose into hepatic acetyl-CoA and fatty acids. When fructose is consumed more gradually to facilitate its absorption in the small intestine, both citrate cleavage in hepatocytes and microorganism-derived acetate contribute to lipogenesis. By contrast, the lipogenic transcriptional program is activated in response to fructose in a manner that is independent of acetyl-CoA metabolism. These data reveal a two-pronged mechanism that regulates hepatic lipogenesis, in which fructolysis within hepatocytes provides a signal to promote the expression of lipogenic genes, and the generation of microbial acetate feeds lipogenic pools of acetyl-CoA.
First Authors:
Steven Zhao,Cholsoon Jang
Correspondence Authors:
Kathryn E Wellen
All Authors:
Steven Zhao,Cholsoon Jang,Joyce Liu,Kahealani Uehara,Michael Gilbert,Luke Izzo,Xianfeng Zeng,Sophie Trefely,Sully Fernandez,Alessandro Carrer,Katelyn D Miller,Zachary T Schug,Nathaniel W Snyder,Terence P Gade,Paul M Titchenell,Joshua D Rabinowitz,Kathryn E Wellen
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