The DOI matches its Crossref record; 50 of the 51 references it cites were found in a registry or an index.
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.
Overview
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
The cited source says what the claim attributes to it.
In the citing paper
“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]
The cited source says what the claim attributes to it.
In the citing paper
“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]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Citations
Cites
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
Self-citation
Cited by
Sorted by citations
Items 101–200 of 577
Fecal microbiota transplantation as a promising treatment option for osteoporosis
Zhang, Y., Cao, M., Li, Y., Zhang, R., Wu, M., Yu, Q., & Rui, Y. (2022) · Journal of Bone and Mineral Metabolism · doi:10.1007/s00774-022-01375-x · Cited by 60
Ma, N., Ma, D., Liu, X., Zhao, L., Ma, L., Ma, D., & Dong, S. (2023) · Environment International · doi:10.1016/j.envint.2023.107949 · Cited by 57
Li, Y., Ji, X., Wu, H., Xiang, L., Zhang, H., & Tang, D. (2021) · Journal of Ethnopharmacology · doi:10.1016/j.jep.2021.114207 · Cited by 55
The Immunomodulatory Potential of Short-Chain Fatty Acids in Multiple Sclerosis
Bărcuţean, L., Maier, S., Patrascu, M. B., Farczádi, L., & Bălașa, R. (2024) · International Journal of Molecular Sciences · doi:10.3390/ijms25063198 · Cited by 62
“In terms of metabolic processes, a significant contrast between glucose and fructose metabolism lies in the rapid breakdown of high sugar consumption in the small intestine, while fructose consumption generates acetate through the gut microbiome [100].”
BackgroundCao, C., Yue, S., Lü, A., & Liang, C. (2024) · Pharmacological Research · doi:10.1016/j.phrs.2024.107321 · Cited by 64
ACLY inhibition promotes tumour immunity and suppresses liver cancer
Gautam, J., Wu, J., Lally, J., McNicol, J. D., Fayyazi, R., Ahmadi, E., Oniciu, D. C., Heaton, S., Newton, R. S., Rehal, S., et al. (2025) · Nature · doi:10.1038/s41586-025-09297-0 · Cited by 64
“In contrast to previous reports in hepatocytes 26,40 , but similar to findings in pancreatic islets 41 , the expression of Acss2 was not significantly upregulated at either timepoint (Fig.”
Metabolism and Health Impacts of Dietary Sugars
Alam, Y. H., Kim, R., & Jang, C. (2022) · Journal of Lipid and Atherosclerosis · doi:10.12997/jla.2022.11.1.20 · Cited by 54
Self-citationRoles of gut microbiota and metabolites in overweight and obesity of children
Zhang, S., & Dang, Y. (2022) · Frontiers in Endocrinology · doi:10.3389/fendo.2022.994930 · Cited by 58
Yarahmadi, A., Afkhami, H., Javadi, A., & Kashfi, M. (2024) · Diabetology & Metabolic Syndrome · doi:10.1186/s13098-024-01561-z · Cited by 61
“The ever-increasing prevalence of NAFLD and obesity can be ascribed to the excessive generation of acetate [182–185].”
Jadhav, K. S., & Cohen, T. S. (2020) · Frontiers in Endocrinology · doi:10.3389/fendo.2020.592157 · Cited by 55
“set out to tease apart the relative contribution of these two pathways in fructose consumption-mediated increases in hepatic DNL (45).”
BackgroundWang, Y., Li, Y., Lin, Y., Cao, C.-Y., Chen, D., Huang, X., Li, C., Xu, H., Lai, H., Chen, H., et al. (2025) · Cell Death Discovery · doi:10.1038/s41420-025-02413-z · Cited by 60
“The acetate served as a major hepatic acetyl-CoA donor [150], which increased glutamine synthesis, leading to higher O-GlcNAcylation in fructose-rich environments.”
Shao, M., Ye, Z., Qin, Y., & Wu, T. (2020) · Experimental and Therapeutic Medicine · doi:10.3892/etm.2020.9154 · Cited by 52
“A recent study demonstrated that dietary fructose promoted hepatic lipogenesis via microbiota‐derived acetate (17).”
BackgroundSun, M., Li, D., Mei, H., Miao, X., Su, Y., Chi, Y., Li, Y., Sun, R., Niu, H., & Wang, J. (2022) · Food & Function · doi:10.1039/d2fo01165d · Cited by 52
The intestinal microbiome associated with lipid metabolism and obesity in humans and animals
Jian, Z., Zeng, L., Xu, T., Sun, S., Yan, S., Zhao, S., Su, Z., Ge, C., Zhang, Y., Jia, J., et al. (2022) · Journal of Applied Microbiology · doi:10.1111/jam.15740 · Cited by 55
“Studies have shown that fructose ingested in large doses is converted into acetic acid by intestinal microbes, which is then converted into acetyl- CoA by ACSS2 (acyl- CoA synthetase short- chain family member 2) in the liver to promote the production of fatty acids (Zhao et al., 2020).”
BackgroundSelf-citationXie, Y., Pei, F., Liu, Y., Liu, Z., Chen, X., & Xue, D. (2023) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2023.121122 · Cited by 50
Thing, M., Werge, M. P., Kimer, N., Hetland, L. E., Rashu, E. B., Nabilou, P., Junker, A. E., Galsgaard, E. D., Bendtsen, F., Laupsa‐Borge, J., et al. (2024) · BMC Gastroenterology · doi:10.1186/s12876-024-03129-7 · Cited by 56
“In hepatic cells, propionate can be used for gluconeogenesis and acetate for de novo lipogenesis [2, 7, 9].”
BackgroundInsulin Regulation of Hepatic Lipid Homeostasis
Uehara, K., Santoleri, D., Whitlock, A. E. G., & Titchenell, P. M. (2023) · Comprehensive Physiology · doi:10.1002/cphy.c220015 · Cited by 49
Self-citationAcetyl-CoA and Metabolite Fluxes Regulate White Adipose Tissue Expansion
Felix, J. B., Cox, A. R., & Hartig, S. M. (2021) · Trends in Endocrinology and Metabolism · doi:10.1016/j.tem.2021.02.008 · Cited by 52
Gut Microbiome in Non-Alcoholic Fatty Liver Disease: From Mechanisms to Therapeutic Role
Gupta, H., Min, B.-H., Ganesan, R., Gebru, Y. A., Sharma, S. P., Park, E., Won, S., Jeong, J., Lee, S.-B., Cha, M., et al. (2022) · Biomedicines · doi:10.3390/biomedicines10030550 · Cited by 50
“Abolishing the microbiome or suppressing ACSS2 significantly suppresses hepatic lipogenesis in mice [51].”
BackgroundCyanobacteria as cell factories for the photosynthetic production of sucrose
Santos‐Merino, M., Yun, L., & Ducat, D. C. (2023) · Frontiers in Microbiology · doi:10.3389/fmicb.2023.1126032 · Cited by 51
“, 2016), as it has been proposed for one of these SPP isoforms in sorghum seed germination (Jiang et al., 2015).”
BackgroundMultiple omics study identifies an interspecies conserved driver for nonalcoholic steatohepatitis
Zhang, X., She, Z., Wang, J., Sun, D., Shen, L., Xiang, H., Cheng, X., Ji, Y., Huang, Y., Li, P., et al. (2021) · Science Translational Medicine · doi:10.1126/scitranslmed.abg8117 · Cited by 49
He, L., Yao, D.-H., Wang, L., Zhang, L., & Bai, X. (2021) · Frontiers in Microbiology · doi:10.3389/fmicb.2021.761836 · Cited by 49
Gut microbiota and their metabolites in the progression of non-alcoholic fatty liver disease
Zhou, J., Tripathi, M., Sinha, R. A., Singh, B. K., & Yen, P. M. (2021) · Hepatoma Research · doi:10.20517/2394-5079.2020.134 · Cited by 49
“Acetate can be converted to acetyl-CoA by hepatic acetyl-coenzyme a synthetase cytoplasmic (ACSS2)[100] and used as one of the major sources for de novo lipogenesis[100,101].”
BackgroundG protein-coupled receptors as potential targets for nonalcoholic fatty liver disease treatment
Yang, M. J., & Zhang, C. (2021) · World Journal of Gastroenterology · doi:10.3748/wjg.v27.i8.677 · Cited by 49
A two-way relationship between histone acetylation and metabolism
Charidemou, E., & Kirmizis, A. (2024) · Trends in Biochemical Sciences · doi:10.1016/j.tibs.2024.10.005 · Cited by 49
Mitochondria homeostasis: Biology and involvement in hepatic steatosis to NASH
Li, Y., Xie, Z., Song, Q., & Li, J.-Y. (2022) · Acta Pharmacologica Sinica · doi:10.1038/s41401-022-00864-z · Cited by 49
“During a feeding state, mitochondrial citrate is transported to cytoplasm and leads to cytosolic acetyl-CoA formation catalyzed by ATP citrate lyase (ACLY), which is used for de novo lipogenesis (DNL) or epigenetic histone acetylation [21, 22].”
BackgroundDiet-microbiota associations in gastrointestinal research: a systematic review
Duncanson, K., Williams, G. M., Hoedt, E. C., Collins, C. E., Keely, S., & Talley, N. J. (2024) · Gut Microbes · doi:10.1080/19490976.2024.2350785 · Cited by 48
Lu, S., Wang, C., Ma, J., & Wang, Y. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1456030 · Cited by 49
Saccharide Characteristics and Their Potential Health Effects in Perspective
Brouns, F. J. P. H. (2020) · Frontiers in Nutrition · doi:10.3389/fnut.2020.00075 · Cited by 47
The Gut–Brain–Microbiota Connection and Its Role in Autism Spectrum Disorders
Młynarska, E., Barszcz, E., Budny, E., Gajewska, A., Kopeć, K., Wasiak, J., Rysz, J., & Franczyk, B. (2025) · Nutrients · doi:10.3390/nu17071135 · Cited by 44
“In mice, dietary fructose is metabolized by gut microbes into acetate, serving as a source of acetyl-CoA for lipid synthesis [61].”
Zhou, T., Cao, L., Du, Y., Qin, L., Lu, Y., Zhang, Q., He, Y., & Tan, D. (2023) · PeerJ · doi:10.7717/peerj.15225 · Cited by 44
“ACSS2 can also convert acetate acid to acetyl-CoA ( Zhao et al., 2020 ), which is then converted to malonyl-CoA by ACACA.”
Dietary and metabolic effects on intestinal stem cells in health and disease
Shay, J. E. S., & Yilmaz, Ö. H. (2024) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-024-00980-7 · Cited by 47
“In addition to direct absorption and metabolism by host tissues, fructose can also be converted to the SCFA acetate, which can, in turn, contribute to increased acetyl-CoA pools driving hepatic lipogenesis 216 .”
Upregulation of WDR6 drives hepatic de novo lipogenesis in insulin resistance in mice
Yao, Z., Gong, Y., Chen, W., Shao, S., Song, Y., Guo, H., Li, Q., Liu, S., Wang, X., Zhang, Z., et al. (2023) · Nature Metabolism · doi:10.1038/s42255-023-00896-7 · Cited by 48
“To establish the HFrD model, mice were placed on either a CD or a HFrD (60% fructose; Jiangsu Xietong Pharmaceutical Bio-engineering) for 4 weeks 70 .”
MethodSelf-citationLu, J., Li, X., Chen, P., Zhang, J.-X., Li, L., Wang, G., Liu, X.-Q., Jiang, C., & Ma, K. (2023) · Acta Pharmacologica Sinica · doi:10.1038/s41401-023-01160-0 · Cited by 44
“However, when antibiotics were used to interfere with the micro-biome ’ s fermentation to produce acetate, hepatic lipid synthesis was inhibited [34].”
Recent advances in age-related metabolic dysfunction-associated steatotic liver disease
He, Q.-J., Li, Y., Zhao, L.-T., Lin, C.-T., Yu, C., & Wang, D. (2024) · World Journal of Gastroenterology · doi:10.3748/wjg.v30.i7.652 · Cited by 51
“Altered intestinal permeability, gut dysbiosis, and increased fructose intake exacerbate hepatic lipid accumulation and contribute to the development of MASLD in elderly patients[54].”
Non-Alcoholic Fatty Liver Disease or Type 2 Diabetes Mellitus—The Chicken or the Egg Dilemma
Kosmalski, M., Śliwińska, A., & Drzewoski, J. (2023) · Biomedicines · doi:10.3390/biomedicines11041097 · Cited by 44
Li, J., Zhao, J., Tian, C., Dong, L., Kang, Z., Wang, J., Zhao, S., Li, M., & Tong, X. (2024) · Nutrition & Metabolism · doi:10.1186/s12986-024-00829-5 · Cited by 43
“Acetic acid may also be produced from microbial fermentation of residual peptides and fats [35, 41–45].”
BackgroundSelf-citationFeng, X., Zhang, R., Yang, Z., Zhang, K., & Xing, J. (2024) · Journal of Clinical and Translational Hepatology · doi:10.14218/jcth.2024.00019 · Cited by 45
Bempedoic acid suppresses diet-induced hepatic steatosis independently of ATP-citrate lyase
Liu, J. Y., Kuna, R. S., Pinheiro, L. V., Nguyen, P. T., Welles, J. E., Drummond, J. M., Murali, N., Sharma, P. V., Supplee, J., Shiue, M., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.10.014 · Cited by 42
“Considering the reports that ACLY deficiency has varying effects on hepatic lipid homeostasis under different dietary and experimental conditions, 16,20,21,23 we first asked if nutritional components could regulate ACSS2 in the absence of ACLY.”
BackgroundInfluentialSelf-citationEating, diet, and nutrition for the treatment of non-alcoholic fatty liver disease
Semmler, G., Datz, C., & Trauner, M. (2022) · Clinical and Molecular Hepatology · doi:10.3350/cmh.2022.0364 · Cited by 43
“Also, epigenetic changes occur,(117) and the role of the microbiome, metabolizing fructose to acetate being an additional substrate for DNL—is being increasingly understood.(118) Despite incompletely understood, dietary fructose even seems to increase nutrient absorption via improving survival of intestinal cells and…”
BackgroundPessoa, J., Belew, G. D., Barroso, C., Egas, C., & Jones, J. G. (2023) · Nutrients · doi:10.3390/nu15092097 · Cited by 40
“For example, the conjunction of dietary fructose and gut microbiome-produced acetate enhances hepatic lipogenesis and consequent fat accumulation in the liver [8].”
BackgroundCurrent and Future Treatments in the Fight against Non-Alcoholic Fatty Liver Disease
Smeuninx, B., Boslem, E., & Febbraio, M. A. (2020) · Cancers · doi:10.3390/cancers12071714 · Cited by 39
“Interestingly, high fructose consumption has been associated with liver disease and two recent studies have demonstrated a link between high fructose consumption, gut dysbiosis and liver steatosis and inflammation [115,116].”
BackgroundZhu, Z., Zhang, X., Pan, Q., Zhang, L., & Chai, J. (2023) · Liver Research · doi:10.1016/j.livres.2023.11.003 · Cited by 38
“32 In conclusion, the increased intake of fructose stimulates the transcriptional activation of DNL and provides essential substrates, both of which signi fi cantly contribute to the development of he-patic steatosis.”
Deng, X., Ye, Z., Cao, H., Bai, Y., Che, Q., Guo, J., & Su, Z. (2020) · Food & Function · doi:10.1039/d0fo01107j · Cited by 39
Acetylation-mediated remodeling of the nucleolus regulates cellular acetyl-CoA responses
Houston, R., Sekine, S., Calderon, M. J., Seifuddin, F., Wang, G., Kawagishi, H., Malide, D. A., Li, Y., Guček, M., Pirooznia, M., et al. (2020) · PLoS Biology · doi:10.1371/journal.pbio.3000981 · Cited by 37
Hu, Y., He, J., Zheng, P., Mao, X., Huang, Z., Yan, H., Luo, Y., Yu, J., Luo, J., Yu, B., et al. (2021) · Critical Reviews in Food Science and Nutrition · doi:10.1080/10408398.2021.1955654 · Cited by 39
“However, several studies demonstrated that SCFAs possessed some detrimental effects, as an example, the fructose-derived acetate was a substrate of hepatic acetylCoA synthesis, contributing to energy accumulation and fatty liver disease occurrence (Serino 2019; Tirosh et al. 2019; Zhao et al. 2020).”
BackgroundAllulose in human diet: the knowns and the unknowns
Daniel, H., Hauner, H., Hornef, M. W., & Clavel, T. (2021) · British Journal Of Nutrition · doi:10.1017/s0007114521003172 · Cited by 39
“Although SCFA are considered to be beneficial, studies with 13C-labelled fructose in mice(22) have shown that the acetate as the dominant SCFA species of colonic fermentation can be utilised by rodent liver fatty acid synthase as a starter substrate which could be one mechanism by which high doses of fructose in roden…”
BackgroundZhang, N., Wáng, Q., Lin, F., Zheng, B.-D., Huang, Y., Yang, Y., Xue, C., Xiao, M., & Ye, J. (2022) · Carbohydrate Polymers · doi:10.1016/j.carbpol.2022.119903 · Cited by 37
Rauckhorst, A. J., Sheldon, R. D., Pape, D. J., Ahmed, A., Falls-Hubert, K. C., Merrill, R. A., Brown, R. F., Deshmukh, K., Vallim, T., Deja, S., et al. (2024) · Cell Metabolism · doi:10.1016/j.cmet.2024.10.013 · Cited by 40
Zhang, H., Léveillé, M., Courty, É., Güneş, A., Nguyen, B., & Estall, J. L. (2020) · American Journal of Physiology-Endocrinology and Metabolism · doi:10.1152/ajpendo.00321.2020 · Cited by 35
Park, G. S. H., Jung, S., Wellen, K. E., & Jang, C. (2021) · Experimental & Molecular Medicine · doi:10.1038/s12276-021-00614-x · Cited by 37
Self-citationJacquier, E. F., van de Wouw, M., Nekrasov, E., Contractor, N., Kassis, A. N., & Marcu, D. E. (2024) · Foods · doi:10.3390/foods13050739 · Cited by 42
“…exemplified by initiatives such as the American Gut Project, which found associations between an increased variety of plant species (participants consuming > 30 different plant species per week) and microbiota diversity versus those participants consuming 10 different plant species per week [60].”
BackgroundExcessive Intake of Longan Arillus Alters gut Homeostasis and Aggravates Colitis in Mice
Huang, H., Li, M., Wang, Y., Wu, X., Shen, J., Xiao, Z., Zhao, Y., Du, F., Chen, Y., Wu, Z., et al. (2021) · Frontiers in Pharmacology · doi:10.3389/fphar.2021.640417 · Cited by 34
“Free sugars, fructose in particular, were demonstrated to disrupt the gut-liver axis, possibly through increased gut permeability and altered gut microbiota (Todoric et al., 2020; Zhao et al., 2020).”
BackgroundThe multifaceted therapeutic value of targeting ATP-citrate lyase in atherosclerosis
Verberk, S. G. S., Kuiper, K. L., Lauterbach, M., Latz, E., & den Bossche, J. V. (2021) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2021.09.004 · Cited by 37
Richard, G. M., Blondin, D. P., Syed, S. A., Rossi, L., Fontes, M. E., Fortin, M., Phoenix, S., Frisch, F., Dubreuil, S., Guérin, B., et al. (2022) · Cell Reports Medicine · doi:10.1016/j.xcrm.2022.100742 · Cited by 37
Bhat, S., Pinney, S. E., Kennedy, K. M., McCourt, C. R., Mundy, M. A., Surette, M. G., Sloboda, D. M., & Simmons, R. A. (2021) · The Journal of Physiology · doi:10.1113/jp280034 · Cited by 35
“Although Bifidobacteria are typically associated with intestinal health (Leahy et al. 2005), they may also contribute to hepatic lipogenesis (Zhao et al. 2020) by metabolising fructose to acetate (Falony et al. 2006), which we found to be increased in both male and female livers at 6 weeks (Fig.”
BackgroundFructose and metabolic diseases: too much to be good
Shi, Y.-N., Liu, Y., Xie, Z., & Zhang, W. J. (2021) · Chinese Medical Journal · doi:10.1097/cm9.0000000000001545 · Cited by 40
“Very recently, Zhao et al([68]) report that dietary fructose feeds hepatic lipogenesis via microbiota-derived acetate, indicating a potential role of microbiota in the pathogenesis of fructoseinduced metabolic disease.”
BackgroundHallmarks of the human intestinal microbiome on liver maturation and function
Almeida, J. I., Tenreiro, M. F., Martínez‐Santamaría, L., Guerrero‐Aspizua, S., Gisbert, J. P., Alves, P. M., Serra, M., & Baptista, P. M. (2021) · Journal of Hepatology · doi:10.1016/j.jhep.2021.10.015 · Cited by 37
High fructose diet: A risk factor for immune system dysregulation
Cheng, H., Zhou, J., Sun, Y., Zhan, Q., & Zhang, D. (2022) · Human Immunology · doi:10.1016/j.humimm.2022.03.007 · Cited by 37
“Zhao et al. proposed a dual mechanism that might explain hepatic fat accumulation, whereby fructolysis within hepatocytes promotes the expression of adipogenic genes including ChREBP-b , Acaca , Fasn, and Aldob , and microbial fructose metabolism provides acetate lipogenic pools of acetyl-CoA [42].”
Yenilmez, B., Kelly, M., Zhang, G., Wetoska, N., Ilkayeva, O., Min, K., Rowland, L. A., DiMarzio, C., He, W., Raymond, N., et al. (2022) · Journal of Biological Chemistry · doi:10.1016/j.jbc.2022.102401 · Cited by 36
“when D2O was used for measurements of DNL, no effect of ACLY depletion was observed, in contrast with the marked increase we reported here (34).”
BackgroundResultInfluentialDietary fibre-adapted gut microbiome clears dietary fructose and reverses hepatic steatosis
Jung, S., Bae, H., Song, W., Chun, Y., Le, J., Alam, Y. H., Verlande, A., Chun, S. K., Kim, J., Kelly, M. E., et al. (2025) · Nature Metabolism · doi:10.1038/s42255-025-01356-0 · Cited by 38
“No statistical methods were used to predetermine sample sizes, but our sample sizes are similar to those reported in previous publications 15,16 .”
InfluentialSelf-citationDiet and gut microbiome in fatty liver and its associated liver cancer
Pan, Y., & Zhang, X. (2021) · Journal of Gastroenterology and Hepatology · doi:10.1111/jgh.15713 · Cited by 35
Saadati, S., Naseri, K., Asbaghi, O., Yousefi, M., Golalipour, E., & de Courten, B. V. (2023) · Obesity Reviews · doi:10.1111/obr.13667 · Cited by 38
Behler-Janbeck, F., Baranowsky, A., Yorgan, T. A., Jaeckstein, M. Y., Worthmann, A., Fuh, M. M., Gunasekaran, K., Tiegs, G., Amling, M., Schinke, T., et al. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1392418 · Cited by 37
“The most abundant SCFA acetate acts as a substrate for hepatic lipogenesis and cholesterol biosynthesis (73, 74).”
Intestinal α1-2-Fucosylation Contributes to Obesity and Steatohepatitis in Mice
Zhou, R., Llorente, C., Cao, J., Zaramela, L. S., Zeng, S.-L., Gao, B., Li, S., Welch, R. D., Huang, F., Qi, L., et al. (2021) · Cellular and Molecular Gastroenterology and Hepatology · doi:10.1016/j.jcmgh.2021.02.009 · Cited by 33
“To further show a contribution of the intestinal microbiota, gut bacteria were reduced with antibiotics.(20,21) WT and Fut2 mice on a Western diet for 12–13 weeks received antibiotics for an additional 5 weeks, while being continued on a Western diet.”
MethodAndersen, M. K., Skotte, L., Jørsboe, E., Polito, R., Stæger, F. F., Aldiss, P., Hanghøj, K., Waples, R. K., Santander, C. G., Grarup, N., et al. (2021) · Gastroenterology · doi:10.1053/j.gastro.2021.12.236 · Cited by 35
“50 The fact that we observed markedly higher levels of acetate in circulation could indicate that acetate bypasses hepatic catabolism and thereby reaches systemic circulation, where it might induce bene fi cial signaling pathways in other tissues, including brain, muscle, and adipose tissue.”
BackgroundIGUDESMAN, D. A., Crandell, J., Corbin, K. D., Hooper, J., Thomas, J. M., Bulik, C. M., Pence, B. W., Pratley, R. E., Kosorok, M. R., Maahs, D. M., et al. (2022) · Journal of Nutrition · doi:10.1016/j.tjnut.2022.12.017 · Cited by 34
Western diet influences on microbiome and carcinogenesis
Newsome, R. C., Yang, Y., & Jobin, C. (2023) · Seminars in Immunology · doi:10.1016/j.smim.2023.101756 · Cited by 35
Positive Regulation of Acetate in Adipocyte Differentiation and Lipid Deposition in Obese Mice
Sun, C., Li, A., Wang, H., Ma, J., & Hou, J. (2023) · Nutrients · doi:10.3390/nu15173736 · Cited by 35
“An analysis of tissue histology was conducted following the modified method as previously described [16,17].”
BackgroundMethodLv, Y., Jiang, L., Zhang, F., Li, M., Yang, B., Zhang, F., & Guo, X. (2020) · Bioscience Reports · doi:10.1042/bsr20200382 · Cited by 33
Irreversible hippocampal changes induced by high fructose diet in rats
Fierros-Campuzano, J., Ballesteros‐Zebadúa, P., Manjarrez-Marmolejo, J., Aguilera, P., Méndez‐Díaz, M., Prospero-Garcia, O. E., & Franco‐Pérez, J. (2020) · Nutritional Neuroscience · doi:10.1080/1028415x.2020.1853418 · Cited by 34
“Some reports also demonstrated that a high fructose diet causes dyslipidemia, increased plasma uric acid, and gut microbiota changes facilitating the generation of acetate and acetyl CoA [3,6,7].”
BackgroundKhodami, B., Hatami, B., Yari, Z., Alavian, S. M., Sadeghi, A., Kord‐Varkaneh, H., Santos, H. O., & Hekmatdoost, A. (2022) · European Journal of Clinical Nutrition · doi:10.1038/s41430-022-01081-x · Cited by 32
“The reduction in TC levels, in turn, can be justified by a restriction in fructose intake, since fructose surplus can increase TC concentrations due to increased formation of Acetyl-CoA in the liver through fructose, where Acetyl-CoA together with acetoacetyl-CoA are substrates for cholesterol synthesis via the β-hydr…”
BackgroundThe Interaction between the Gut Microbiome and Bile Acids in Cardiometabolic Diseases
Callender, C., Attaye, I., & Nieuwdorp, M. (2022) · Metabolites · doi:10.3390/metabo12010065 · Cited by 33
Standardizing translational microbiome studies and metagenomic analyses
Gambardella, J., Castellanos, V., & Santulli, G. (2020) · Cardiovascular Research · doi:10.1093/cvr/cvaa175 · Cited by 32
Fructose and fructose kinase in cancer and other pathologies
Jiang, H., Lin, Q., Ma, L., Luo, S., Jiang, X., Fang, J., & Lu, Z. (2021) · Journal of genetics and genomics/Journal of Genetics and Genomics · doi:10.1016/j.jgg.2021.06.006 · Cited by 32
Li, G., Chen, H.-Q., Shen, F., Smithson, S. B., Shealy, G. L., Ping, Q., Liang, Z., Han, J., Adams, A. C., Li, Y., et al. (2023) · Hepatology · doi:10.1097/hep.0000000000000433 · Cited by 30
“[24] However, how alcohol intake generates hepatic acetyl-CoA to promote lipid production remains largely unknown.”
Exercise-induced microbial changes in preventing type 2 diabetes
Yao, T., Wang, H., Lin, K., Wang, R., Guo, S., Chen, P., Wu, H., Liu, T., & Wang, R. (2023) · Science China Life Sciences · doi:10.1007/s11427-022-2272-3 · Cited by 31
“…components such as fructose (Egli et al., 2013), a known risk factor for both dyslipidemia and diabetes (Hannou et al., 2018; Ouyang et al., 2008), and recent mice study proved that dietary fructose could be converted to acetate by gut microbiota feeding to hepatic lipogenesis (Zhao et al., 2020).”
Potential therapeutic strategies for MASH: from preclinical to clinical development
Xie, Z., Li, Y., Cheng, L., Huang, Y., Rao, W., Shi, H., & Li, J. (2024) · Life Metabolism · doi:10.1093/lifemeta/loae029 · Cited by 31
You, N., Liu, G., Yu, M., Chen, W., Fei, X., Sun, T., Han, M., Qin, Z., Wei, Z., & Wang, D. (2025) · Journal of Advanced Research · doi:10.1016/j.jare.2024.12.049 · Cited by 31
“Remarkably, acetate metabolism involves a compensatory interaction of ECs on the regulation of ACLY/ACSS2 activity, which in turn alters the source of Ac-CoA and maintains normal levels of Ac-CoA and histone acetylation [204,209] (Fig.”
Yang, J., Zhang, T., Dong, Z., Shi, H.-H., Xu, J., Mao, X., Wang, Y.-M., & Xue, C. (2021) · Journal of Agricultural and Food Chemistry · doi:10.1021/acs.jafc.0c06831 · Cited by 31
Exploration of the link between gut microbiota and purinergic signalling
Li, M., Liu, B., Li, R., Yang, P. C., Leng, P., & Huang, Y. (2022) · Purinergic Signalling · doi:10.1007/s11302-022-09891-1 · Cited by 32
Cui, Y., Liu, H., Wang, Z., Zhang, H., Tian, J., Wang, Z., Song, W., Guo, H., Liu, L., Tian, R., et al. (2023) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-023-02765-3 · Cited by 29
Renal Tubular Handling of Glucose and Fructose in Health and Disease
Vallon, V., & Nakagawa, T. (2021) · Comprehensive physiology · doi:10.1002/cphy.c210030 · Cited by 49
Berdowska, I., Matusiewicz, M., & Fecka, I. (2025) · International Journal of Molecular Sciences · doi:10.3390/ijms26062394 · Cited by 30
Truong, T. M. T., Seo, S. H., Chung, S., & Kang, I. (2022) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2022.109204 · Cited by 29
Ketogenesis supports hepatic polyunsaturated fatty acid homeostasis via fatty acid elongation
Queathem, E. D., Moazzami, Z., Stagg, D. B., Nelson, A. B., Fulghum, K., Hayir, A., Seay, A., Gillingham, J. R., d’Avignon, D. A., Han, X., et al. (2025) · Science Advances · doi:10.1126/sciadv.ads0535 · Cited by 30
“A key source of steatosis in MASLD is increased hepatic DNL, whose carbon sourcing has drawn recent attention ( 4 , 20 – 27 ).”
Sucrose-preferring gut microbes prevent host obesity by producing exopolysaccharides
Shimizu, H., Miyamoto, J., Hisa, K., Ohue‐Kitano, R., Takada, H., Yamano, M., Nishida, A., Sasahara, D., Masujima, Y., Watanabe, K., et al. (2025) · Nature Communications · doi:10.1038/s41467-025-56470-0 · Cited by 29
“Although some reports demonstrate metabolic detriments of fructose intake 38,39 , such effects were not clearly observed in our sugar replacement experiments when compared with those of glucose and sucrosereplacement.”
Strathearn, L. S., Stepanov, A. I., & Font-Burgada, J. (2020) · Nutrients · doi:10.3390/nu12040933 · Cited by 26
“In a dual mechanism, dietary fructose promoted transcriptional up-regulation of DNL genes, while bacterial metabolism of excess fructose into the short-chain fatty acid acetate in the intestine, provided a source of acetyl-CoA in hepatocytes to feed DNL [67]. context of liver cancer.”
BackgroundInfluentialGolonka, R. M., & Vijay–Kumar, M. (2020) · Advances in cancer research · doi:10.1016/bs.acr.2020.10.004 · Cited by 28
Fu, J., Hu, F., Ma, T., Zhao, W., Tian, H., Zhang, Y., Hu, M., Zhou, J., Zhang, Y., Jian, C., et al. (2021) · Hepatology · doi:10.1002/hep.32126 · Cited by 27
ACSS2 controls PPARγ activity homeostasis to potentiate adipose-tissue plasticity
Chen, N., Zhao, M., Wu, N., Guo, Y., Cao, B., Zhan, B., Li, Y., Zhou, T., Zhu, F., Guo, C. H., et al. (2024) · Cell Death and Differentiation · doi:10.1038/s41418-024-01262-0 · Cited by 29
“The acetyl-CoA from ACSS2 can also be utilized for liver lipogenesis with high fructose while in adipocyte, ACSS2 has little effect on adipocyte differentiation and formation [26, 27].”
Paoli, A. (2025) · Nutrients · doi:10.3390/nu17040663 · Cited by 30
“The production of short-chain fatty acids like acetate from microbiota fermentation of dietary fructose further fuels hepatic DNL [26].”
KLF10 integrates circadian timing and sugar signaling to coordinate hepatic metabolism
Ruberto, A. A., Gréchez‐Cassiau, A., Guérin, S., Martin, L., Revel, J. S., Mehiri, M., Subramaniam, M., Delaunay, F., & Teboul, M. (2021) · eLife · doi:10.7554/elife.65574 · Cited by 27
The intestine is a major contributor to circulating succinate in mice
Tong, W., Hannou, S. A., Wang, Y., Astapova, I. I., Sargsyan, A., Monn, R., Thiriveedi, V., Li, D., McCann, J. R., Rawls, J. F., et al. (2022) · The FASEB Journal · doi:10.1096/fj.202200135rr · Cited by 26
Chen, K., Hu, M., Tang, M., Gao, C., Wang, H., Man, S., & Lu, F. (2022) · Food Research International · doi:10.1016/j.foodres.2022.111619 · Cited by 24
Chen, A. S., Liu, D. H., Hou, H. N., Yao, J. N., Xiao, S. C., Xiao, R., Li, P. Z., Cao, Q., Liu, X. K., Zhou, Z. Q., et al. (2022) · The Science of The Total Environment · doi:10.1016/j.scitotenv.2022.159936 · Cited by 25
Hepatic acetyl-CoA metabolism modulates neuroinflammation and depression susceptibility via acetate
Cao, Y., Zhao, Y., Deng, T., Zhou, Q., Hu, G., Hu, Z., Jiang, Y.-Y., Yang, X., Wang, F., Wu, P.-F., et al. (2025) · Cell Metabolism · doi:10.1016/j.cmet.2025.08.010 · Cited by 24
Johnson, R. J., Wilson, W. L., Bland, S. T., & Lanaspa, M. A. (2020) · Evolution and Human Behavior · doi:10.1016/j.evolhumbehav.2020.09.006 · Cited by 28
Debray, F., Seyssel, K., Fadeur, M., Tappy, L., Paquot, N., & Tran, C. (2021) · Clinical Nutrition · doi:10.1016/j.clnu.2021.01.026 · Cited by 24
Zhao, L., Jin, L., Petrick, J. L., Zeng, H., Wang, F., Tang, L., Smith‐Warner, S. A., Eliassen, A. H., Zhang, F. F., Campbell, P. T., et al. (2022) · American Journal of Clinical Nutrition · doi:10.1016/j.ajcnut.2022.12.004 · Cited by 26
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
