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 Miller, Zachary Schug, Nathaniel Snyder, Terence Gade, Paul Titchenell, Joshua Rabinowitz, Kathryn Wellen Publication Year 2020 Type Journal Article 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 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. Journal Nature Volume 579 Issue 7800 Pages 586-591 Date Published 03/2020 ISSN Number 1476-4687 DOI 10.1038/s41586-020-2101-7 Alternate Journal Nature PMID 32214246 PubMedGoogle ScholarBibTeXEndNote X3 XML