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Zhao, Steven; Jang, Cholsoon; Liu, Joyce; Uehara, Kahealani; Gilbert, Michael; Izzo, Luke; Zeng, Xianfeng; Trefely, Sophie; Fernandez, Sully; Carrer, Alessandro; Miller, Katelyn D; Schug, Zachary T; Snyder, Nathaniel W; Gade, Terence P; Titchenell, Paul M; Rabinowitz, Joshua D; Wellen, Kathryn E
Nature (London), 03/2020, Volume: 579, Issue: 7800Journal Article
Consumption of fructose has risen markedly in recent decades owing to the use of sucrose and high-fructose corn syrup in beverages and processed foods , and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease . Fructose intake triggers de novo lipogenesis in the liver , 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 carbohydrates . Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases . 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 microbiota , and this supplies lipogenic acetyl-CoA independently of ACLY . 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.
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