Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

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

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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 disease2–4. Fructose intake triggers de novo lipogenesis in the liver4–6, 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.

Original languageEnglish (US)
Pages (from-to)586-591
Number of pages6
JournalNature
Volume579
Issue number7800
DOIs
StatePublished - Mar 26 2020

All Science Journal Classification (ASJC) codes

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    Zhao, S., Jang, C., Liu, J., Uehara, K., Gilbert, M., Izzo, L., Zeng, X., Trefely, S., Fernandez, S., Carrer, A., Miller, K. D., Schug, Z. T., Snyder, N. W., Gade, T. P., Titchenell, P. M., Rabinowitz, J. D., & Wellen, K. E. (2020). Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate. Nature, 579(7800), 586-591. https://doi.org/10.1038/s41586-020-2101-7