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 disease^2,3,4. Fructose intake triggers de novo lipogenesis in the liver^4,5,6, 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.

近几十年来，由于饮料和加工食品中使用蔗糖和高果糖玉米糖浆¹，果糖的消费量显着增加，这导致肥胖和非酒精性脂肪肝发病率增加^2,3,4。果糖摄入会触发肝脏中的从头脂肪生成^4,5,6，其中乙酰辅酶A的碳前体转化为脂肪酸。ATP 柠檬酸裂解酶 (ACLY) 裂解胞质柠檬酸生成乙酰辅酶 A，并在消耗碳水化合物后上调⁷。目前临床试验正在探索抑制 ACLY 作为代谢疾病的治疗方法⁸。然而，从膳食果糖到肝脏乙酰辅酶A和脂质的途径仍然未知。在这里，利用体内同位素示踪，我们发现小鼠肝脏特异性删除Acly无法抑制果糖诱导的脂肪生成。膳食果糖被肠道微生物群转化为乙酸盐⁹，并且这独立于 ACLY ¹⁰提供脂肪生成乙酰辅酶A。微生物群的耗竭或肝脏 ACSS2（从乙酸盐生成乙酰辅酶A）的沉默，可有效抑制大剂量果糖转化为肝乙酰辅酶A和脂肪酸。当果糖逐渐被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衍生的乙酸盐都有助于脂肪生成。相比之下，脂肪生成转录程序以独立于乙酰辅酶A代谢的方式响应果糖而被激活。这些数据揭示了调节肝脏脂肪生成的双管齐下的机制，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，并且微生物乙酸盐的产生为乙酰辅酶A的脂肪生成池提供营养。