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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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“…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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