Cited by 577Diet, Metabolism, and DiseaseLipid metabolism and biosynthesisLiver Disease Diagnosis and Treatment

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Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

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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.·2020·Nature

DOI 10.1038/s41586-020-2101-7PMC PMC7416516

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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 foods 1, and this has contributed to increasing rates of obesity and non-alcoholic fatty liver disease 2-4. Fructose intake triggers de novo lipogenesis in the liver 4-6, 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 carbohydrates 7. Clinical trials are currently pursuing the inhibition of ACLY as a treatment for metabolic diseases 8. 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 9, and this supplies lipogenic acetyl-CoA independently of ACLY 10. 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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EFFECT OF EXTRACT ACALYPHA INDICA L. ON LIPID PROFILE AND CARDIAC TROPONIN-T OF RATS FED WITH HIGH FRUCTOSE AND CHOLESTEROL DIET
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Additional file 6 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532740
Additional file 1 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532725
Additional file 3 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532731
Additional file 7 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532743
Additional file 4 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532734
Additional file 2 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532728
Additional file 5 of Analysis of sex differences in dietary copper-fructose interaction-induced alterations of gut microbial activity in relation to hepatic steatosis
Song, M., Yuan, F., Li, X., Ma, X., Yin, X., Rouchka, E. C., Zhang, X., Deng, Z., Prough, R. A., & McClain, C. J. (2021) · Figshare · doi:10.6084/m9.figshare.13532737
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Authors: 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.
Affiliations: University of Pennsylvania (US)
Princeton University (US)
Veneto Institute of Molecular Medicine (IT)
The Wistar Institute (US)
Temple University (US)
Corresponding author: Wellen, Kathryn E.
ORCID: Zhao, Steven
Jang, Cholsoon
Liu, Joyce
Uehara, Kahealani
Gilbert, Michael
Izzo, Luke
Zeng, Xianfeng
Trefely, Sophie
Carrer, Alessandro
Miller, Katelyn D.
Schug, Zachary T.
Snyder, Nathaniel W.
Gade, Terence P.
Titchenell, Paul M.
Rabinowitz, Joshua D.
Wellen, Kathryn E.
Venue: Nature
Publisher: Springer Science and Business Media LLC
Published: 2020-03-18
Volume: 579
Issue: 7800
Pages: 586-591
ISSN: 0028-0836 (ISSN-L)
1476-4687
DOI: 10.1038/s41586-020-2101-7
PMC: PMC7416516
OpenAlex: W3012090404
Cited by: 553
References: 50
Citations by year: 2026: 61 · 2025: 90 · 2024: 91 · 2023: 96 · 2022: 91 · 2021: 82 · 2020: 42
FWCI: 59.64
Type: journal article
Language: en
Open access: green
www.ncbi.nlm.nih.gov
Licence: www.springer.com/tdm (tdm)
www.springer.com/tdm (vor)
Locations: Nature (publishedVersion)
PubMed (publishedVersion)
PubMed Central (acceptedVersion)
RePEc: Research Papers in Economics (submittedVersion)
eScholarship (California Digital Library) (submittedVersion, cc-by)
Padua Research Archive (University of Padova) (submittedVersion)
Funders: National Cancer Institute (T32CA115299, R01CA174761, F99CA222741, R01CA228339, T32CA009171, P30CA010815)
National Institute of General Medical Sciences (R01GM132261, T32GM007229, K12GM081259)
National Institute of Diabetes and Digestive and Kidney Diseases (R01DK116005, DP1DK113643, K01DK111715, P30DK019525, T32DK007314)
National Institute of Arthritis and Musculoskeletal and Skin Diseases (T32AR053461)
Eunice Kennedy Shriver National Institute of Child Health and Human Development (R03HD092630)
Topics: Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Health Sciences › Medicine › Hepatology › Liver Disease Diagnosis and Treatment
Keywords: dietary fructose, hepatic lipogenesis, de novo lipogenesis, gut microbiota, acetate, acetyl-CoA, ATP citrate lyase, ACSS2, fructolysis, non-alcoholic fatty liver disease, obesity, isotope tracing, lipogenic gene expression, fructose absorption
MeSH terms: Gastrointestinal Microbiome, Dietary Sugars, Acetates, Acetyl Coenzyme A, Acetate-CoA Ligase, Animals, ATP Citrate (pro-S)-Lyase, Fatty Acids, Fructose, Gene Expression Regulation, Isotope Labeling, Liver, Male, Substrate Specificity, Citric Acid, Hepatocytes, Lipogenesis, Mice

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Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate

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