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Dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate
Open accessAbstract
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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“an animal study found that dietary fructose could be converted to microbial acetate by the gut microbiota, which may enhance hepatic lipogenesis by supplying lipogenic acetyl-CoA independently of ATP citrate lyase.96”
From Dietary sugar consumption and health: umbrella review (2023) · cites this paper as [96]
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“In mice, dietary fructose is metabolized by gut microbes into acetate, serving as a source of acetyl-CoA for lipid synthesis [61].”
From The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders (2025) · cites this paper as [61]
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MetaboAnalyst 4.0: towards more transparent and integrative metabolomics analysis
Chong, J., Soufan, O., Li, C., Caraus, I., Li, S., Bourque, G., Wishart, D. S., & Xia, J. (2018) · Nucleic Acids Research · doi:10.1093/nar/gky310 · Cited by 3,637
Donnelly, K. L., Smith, C. I., Schwarzenberg, S. J., Jessurun, J., Boldt, M. D., & Parks, E. J. (2005) · Journal of Clinical Investigation · doi:10.1172/jci23621 · Cited by 3,604
Consumption of high-fructose corn syrup in beverages may play a role in the epidemic of obesity
Bray, G. A., Nielsen, S. J., & Popkin, B. M. (2004) · The American Journal of Clinical Nutrition · doi:10.1093/ajcn/79.4.537 · Cited by 1,990
Nadkarni, M. A., Martin, F. E., Jacques, N. A., & Hunter, N. (2002) · Microbiology · doi:10.1099/00221287-148-1-257 · Cited by 1,931
Postic, C., Shiota, M., Niswender, K. D., Jetton, T. L., Chen, Y., Moates, J. M., Shelton, K. D., Lindner, J., Cherrington, A. D., & Magnuson, M. A. (1999) · Journal of Biological Chemistry · doi:10.1074/jbc.274.1.305 · Cited by 1,302
Lambert, J. E., Ramos–Roman, M. A., Browning, J. D., & Parks, E. J. (2014) · Gastroenterology · doi:10.1053/j.gastro.2013.11.049 · Cited by 1,069
Donohoe, D. R., Collins, L. B., Wali, A., Bigler, R., Sun, W., & Bultman, S. J. (2012) · Molecular Cell · doi:10.1016/j.molcel.2012.08.033 · Cited by 993
Fructose and sugar: A major mediator of non-alcoholic fatty liver disease
Jensen, T., Abdelmalek, M. F., Sullivan, S. A., Nadeau, K. J., Cree‐Green, M., Roncal, C., Nakagawa, T., Kuwabara, M., Sato, Y., Kang, D., et al. (2018) · Journal of Hepatology · doi:10.1016/j.jhep.2018.01.019 · Cited by 993
Role of Dietary Fructose and Hepatic De Novo Lipogenesis in Fatty Liver Disease
Softic, S., Cohen, D. E., & Kahn, C. R. (2016) · Digestive Diseases and Sciences · doi:10.1007/s10620-016-4054-0 · Cited by 709
The Small Intestine Converts Dietary Fructose into Glucose and Organic Acids
Jang, C., Hui, S., Lu, W., Cowan, A. J., Morscher, R. J., Lee, G., Liu, W., Tesz, G. J., Birnbaum, M. J., & Rabinowitz, J. D. (2018) · Cell Metabolism · doi:10.1016/j.cmet.2017.12.016 · Cited by 639
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“…bodies (Xia et al., 2017; Hopkins et al., 2018), choline (Romano et al., 2017), arginine (PoilletPerez et al., 2018), glutamine (Ishak Gabra et al., 2020), fructose (Goncalves et al., 2019; Zhao et al., 2020), or cysteine (Badgley et al., 2020) mediates the progression of multiple types of cancer.”
Background
Metadata
- 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
- Venue
- Nature
- Published
- 2020-03-18
- Volume
- 579
- Issue
- 7800
- Pages
- 586-591
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- 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
- 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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