膳食果糖通過微生物來源的醋酸鹽促進肝臟脂肪生成
作者：
小柯機器人發布時間：2020/3/24 15:23:48
美國賓夕法尼亞大學Kathryn E. Wellen團隊取得一項新進展。他們的最新研究表明，膳食果糖通過微生物來源的醋酸鹽為肝臟脂肪生成提供原料。該項研究成果於2020年3月18日在線發表在《自然》雜誌上。
使用體內同位素示蹤，研究人員表明小鼠中ATP檸檬酸裂解酶（Acly）的肝臟特異性缺失無法抑制果糖誘導的脂肪生成。飲食中的果糖通過腸道菌群轉化為乙酸鹽，從而不依賴於ACLY提供脂肪生成的乙醯輔酶A。微生物的耗竭或肝臟ACSS2的沉默會從乙酸鹽生成乙醯輔酶A，從而有效地抑制大劑量果糖向肝乙醯輔酶A和脂肪酸的轉化。
當果糖被逐漸消耗以促進其在小腸中的吸收時，肝細胞中的檸檬酸鹽裂解和微生物來源的乙酸鹽都會促進脂肪形成。相比之下，脂肪果糖轉錄程序以一種與乙醯輔酶A代謝無關的方式響應果糖而被激活。這些數據揭示了調節肝脂肪生成的雙重機制，其中肝細胞內的果糖分解提供了促進脂肪生成基因表達的信號，而微生物乙酸鹽的產生則為乙醯輔酶A的脂肪生成池提供原料。
據了解，近幾十年來，由於在飲料和加工食品中使用蔗糖和高果糖玉米糖漿，果糖的消費量顯著增加，這導致肥胖症和非酒精性脂肪肝的發病率上升。果糖的攝入會觸發肝臟中新生脂肪的形成，其中乙醯輔酶A的碳前體被轉化為脂肪酸。ACLY裂解胞質檸檬酸生成乙醯輔酶A，在消耗碳水化合物後被上調。目前，臨床試驗正在尋求抑制ACLY作為代謝性疾病的治療方法。然而，從飲食果糖到肝乙醯輔酶A和脂質的途徑仍然未知。
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