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膳食果糖通过微生物来源的醋酸盐促进肝脏脂肪生成
2020-03-19 15:23

美国宾夕法尼亚大学Kathryn E. Wellen团队取得一项新进展。他们的最新研究表明,膳食果糖通过微生物来源的醋酸盐为肝脏脂肪生成提供原料。该项研究成果于2020年3月18日在线发表在《自然》杂志上。

使用体内同位素示踪,研究人员表明小鼠中ATP柠檬酸裂解酶(Acly)的肝脏特异性缺失无法抑制果糖诱导的脂肪生成。饮食中的果糖通过肠道菌群转化为乙酸盐,从而不依赖于ACLY提供脂肪生成的乙酰辅酶A。微生物的耗竭或肝脏ACSS2的沉默会从乙酸盐生成乙酰辅酶A,从而有效地抑制大剂量果糖向肝乙酰辅酶A和脂肪酸的转化。
 
当果糖被逐渐消耗以促进其在小肠中的吸收时,肝细胞中的柠檬酸盐裂解和微生物来源的乙酸盐都会促进脂肪形成。相比之下,脂肪果糖转录程序以一种与乙酰辅酶A代谢无关的方式响应果糖而被激活。这些数据揭示了调节肝脂肪生成的双重机制,其中肝细胞内的果糖分解提供了促进脂肪生成基因表达的信号,而微生物乙酸盐的产生则为乙酰辅酶A的脂肪生成池提供原料。
 
据了解,近几十年来,由于在饮料和加工食品中使用蔗糖和高果糖玉米糖浆,果糖的消费量显著增加,这导致肥胖症和非酒精性脂肪肝的发病率上升。果糖的摄入会触发肝脏中新生脂肪的形成,其中乙酰辅酶A的碳前体被转化为脂肪酸。ACLY裂解胞质柠檬酸生成乙酰辅酶A,在消耗碳水化合物后被上调。目前,临床试验正在寻求抑制ACLY作为代谢性疾病的治疗方法。然而,从饮食果糖到肝乙酰辅酶A和脂质的途径仍然未知。
 
附:英文原文

Title: Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

Author: 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

Issue&Volume: 2020-03-18

Abstract: 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.

DOI: 10.1038/s41586-020-2101-7

Source: https://www.nature.com/articles/s41586-020-2101-7

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:43.07
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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