TY - JOUR
T1 - Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
AU - Zhao, Steven
AU - Jang, Cholsoon
AU - Liu, Joyce
AU - Uehara, Kahealani
AU - Gilbert, Michael
AU - Izzo, Luke
AU - Zeng, Xianfeng
AU - Trefely, Sophie
AU - Fernandez, Sully
AU - Carrer, Alessandro
AU - Miller, Katelyn D.
AU - Schug, Zachary T.
AU - Snyder, Nathaniel W.
AU - Gade, Terence P.
AU - Titchenell, Paul M.
AU - Rabinowitz, Joshua D.
AU - Wellen, Kathryn E.
N1 - Funding Information:
Acknowledgements This work was supported by grants R01CA174761, R01CA228339 and R01DK116005 to K.E.W. S.Z. is supported by pre-doctoral fellowship F99CA222741. C.J. is supported by the American Diabetes Association through post-doctoral fellowship 1-17-PDF-076. K.U. is supported by NIAMS training grant T32AR053461. L.I. is supported by NIGMS training grant T32GM07229. S.T. is supported by the American Diabetes Association through post-doctoral fellowship 1-18-PDF-144. S.F. is supported through the Penn-PORT IRACDA grant K12 GM081259. P.M.T. is supported by K01DK111715. N.W.S. is supported by the NIH grant R03HD092630 and R01GM132261. J.D.R. is supported by the NIH Pioneer Award 1DP1DK113643 and Diabetes Research Center P30 DK019525. We thank S. Berger and P. Mews for providing the AAV.U6.shAcss2.CMV. eGFP.SV40 vector. We thank G. Wu and Y. Saimon for discussions on the microbiome.
Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2020/3/26
Y1 - 2020/3/26
N2 - 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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=85082197388&partnerID=8YFLogxK
U2 - 10.1038/s41586-020-2101-7
DO - 10.1038/s41586-020-2101-7
M3 - Article
C2 - 32214246
AN - SCOPUS:85082197388
SN - 0028-0836
VL - 579
SP - 586
EP - 591
JO - Nature
JF - Nature
IS - 7800
ER -