Metformin protects against the development of fructose-induced steatosis in mice: role of the intestinal barrier function
Open accessAbstract
To test the hypothesis that metformin protects against fructose-induced steatosis, and if so, to elucidate underlying mechanisms, C57BL/6J mice were either fed 30% fructose solution or plain water for 8 weeks. Some of the animals were concomitantly treated with metformin (300 mg/kg body weight/day) in the drinking solution. While chronic consumption of 30% fructose solution caused a significant increase in hepatic triglyceride accumulation and plasma alanine-aminotransferase levels, this effect of fructose was markedly attenuated in fructose-fed mice concomitantly treatment with metformin. The protective effects of the metformin treatment on the onset of fructose-induced non-alcoholic fatty liver disease (NAFLD) were associated with a protection against the loss of the tight junction proteins occludin and zonula occludens 1 in the duodenum of fructose-fed mice and the increased translocation of bacterial endotoxin found in mice only fed with fructose. In line with these findings, in metformin-treated fructose-fed animals, hepatic expression of genes of the toll-like receptor-4-dependent signalling cascade as well as the plasminogen-activator inhibitor/cMet-regulated lipid export were almost at the level of controls. Taken together, these data suggest that metformin not only protects the liver from the onset of fructose-induced NAFLD through mechanisms involving its direct effects on hepatic insulin signalling but rather through altering intestinal permeability and subsequently the endotoxin-dependent activation of hepatic Kupffer cells.
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
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?
Nonalcoholic substances including fructose promote gut leakiness.
“binge alcohol exposure [232], [233], [234], [235], [236], [237], [238], [239] and nonalcoholic substances including fructose [240], [241], [242] are known to promote gut leakiness, contributing to more severe inflammatory liver disease.”
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cani, P. D., Bibiloni, R., Knauf, C., Waget, A., Neyrinck, A. M., Delzenne, N. M., & Burcelin, R. (2008) · Diabetes · doi:10.2337/db07-1403 · Cited by 4,819 · see citing works
Increased intestinal permeability and tight junction alterations in nonalcoholic fatty liver disease
Miele, L., Valenza, V., La Torre, G., Montalto, M., Cammarota, G., Ricci, R., Mascianà, R., Forgione, A., Gabrieli, M. L., Perotti, G., et al. (2009) · Hepatology · doi:10.1002/hep.22848 · Cited by 1,434 · see citing works
Bedogni, G., Miglioli, L., Masutti, F., Tiribelli, C., Marchesini, G., & Bellentani, S. (2005) · Hepatology · doi:10.1002/hep.20734 · Cited by 1,250 · see citing works
Fructose consumption as a risk factor for non-alcoholic fatty liver disease
Ouyang, X., Cirillo, P., Sautin, Y. Y., McCall, S. J., Bruchette, J. L., Diehl, A. M., Johnson, R. J., & Abdelmalek, M. F. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.02.011 · Cited by 862 · see citing works
Metformin reverses fatty liver disease in obese, leptin-deficient mice.
Lin, H. Z., Yang, S. Q., Chuckaree, C., Kuhajda, F., Ronnet, G., & Diehl, A. M. (2000) · Nature Medicine · doi:10.1038/79697 · Cited by 673 · see citing works
Toll-Like Receptor 4 Is Involved in the Development of Fructose-Induced Hepatic Steatosis in Mice†
Spruss, A., Kanuri, G., Wagnerberger, S., Haub, S., Bischoff, S. C., & Bergheim, I. (2009) · Hepatology · doi:10.1002/hep.23122 · Cited by 563 · see citing works
Self-citationAntibiotics protect against fructose-induced hepatic lipid accumulation in mice: Role of endotoxin
Bergheim, I., Weber, S., Vos, M. B., Krämer, S., Volynets, V., Kaserouni, S., McClain, C. J., & Bischoff, S. C. (2008) · Journal of Hepatology · doi:10.1016/j.jhep.2008.01.035 · Cited by 523 · see citing works
Self-citationThuy, S., Ladurner, R., Volynets, V., Wagner, S., Strahl, S., Königsrainer, A., Maier, K., Bischoff, S., & Bergheim, I. (2008) · Journal of NutriLife · doi:10.1093/jn/138.8.1452 · Cited by 432 · see citing works
Self-citationConsuming Fructose‐sweetened Beverages Increases Body Adiposity in Mice
Jürgens, H. S., Haaß, W., Castañeda, T. R., Schürmann, A., Koebnick, C., Dombrowski, F., Otto, B., Nawrocki, A. R., Scherer, P. E., Spranger, J., et al. (2005) · Obesity Research · doi:10.1038/oby.2005.136 · Cited by 340 · see citing works
Sabaté, J., Jouët, P., Harnois, F., Mechler, C., Msika, S., Grossin, M., & Coffin, B. (2008) · Obesity Surgery · doi:10.1007/s11695-007-9398-2 · Cited by 251 · see citing works
Yang, S. Q., Lin, H. Z., Mandal, A. K., Huang, J., & Diehl, A. M. (2001) · Hepatology · doi:10.1053/jhep.2001.28054 · Cited by 237 · see citing works
Fructose-Induced Fatty Liver Disease
Ackerman, Z., Oron‐Herman, M., Grozovski, M., Rosenthal, T., Pappo, O., Link, G., & Sela, B. (2005) · Hypertension · doi:10.1161/01.hyp.0000164570.20420.67 · Cited by 223 · see citing works
Bergheim, I., Guo, L., Davis, M. A., Lambert, J. C., Beier, J. I., Duveau, I., Luyendyk, J. P., Roth, R. A., & Arteel, G. E. (2006) · Gastroenterology · doi:10.1053/j.gastro.2006.03.020 · Cited by 204 · see citing works
Self-citationChen, F., Ohashi, N., Li, W., Eckman, C. B., & Nguyen, J. H. (2009) · Hepatology · doi:10.1002/hep.23203 · Cited by 165 · see citing works
Spruss, A., & Bergheim, I. (2009) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2009.05.006 · Cited by 162 · see citing works
Alisi, A., Manco, M., Vito, R. D., Piemonte, F., & Nobili, V. (2010) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e3181c7bdf1 · Cited by 147 · see citing works
Metformin versus dietary treatment in nonalcoholic hepatic steatosis: a randomized study
Garinis, G. A., Fruci, B., Mazza, A., Siena, M. D., Abenavoli, S., Gulletta, E., Ventura, V., Greco, M., Abenavoli, L., & Belfiore, A. (2010) · International Journal of Obesity · doi:10.1038/ijo.2010.40 · Cited by 127 · see citing works
Kanuri, G., Spruss, A., Wagnerberger, S., Bischoff, S. C., & Bergheim, I. (2010) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2010.04.007 · Cited by 112 · see citing works
Self-citationNadeau, K. J., Ehlers, L. B., Zeitler, P. S., & Love‐Osborne, K. (2008) · Pediatric Diabetes · doi:10.1111/j.1399-5448.2008.00450.x · Cited by 106 · see citing works
Thymosin alpha 1 attenuates lipid peroxidation and improves fructose-induced steatohepatitis in rats
Armutçu, F., Çoşkun, Ö., Gürel, A., Kanter, M., Can, M., Uçar, F., & Ünalacak, M. (2005) · Clinical Biochemistry · doi:10.1016/j.clinbiochem.2005.01.013 · Cited by 102 · see citing works
Lund, S. S., Tarnow, L., Stehouwer, C. D. A., Schalkwijk, C. G., Teerlink, T., Gram, J., Winther, K., Frandsen, M., Smidt, U., Pedersen, O. B., et al. (2008) · European Journal of Endocrinology · doi:10.1530/eje-07-0815 · Cited by 100 · see citing works
Lischper, M., Beuck, S., Thanabalasundaram, G., Pieper, C., & Galla, H. (2010) · Brain Research · doi:10.1016/j.brainres.2010.02.054 · Cited by 96 · see citing works
Matrix Metalloproteinase-9 Is Increased in Obese Subjects and Decreases in Response to Pioglitazone
Ünal, R., Yao‐Borengasser, A., Varma, V., Rasouli, N., Labbate, C. V., Kern, P. A., & Ranganathan, G. (2010) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2009-2623 · Cited by 87 · see citing works
Therapy of nonalcoholic fatty liver disease: current status.
Duvnjak, M., Tomašić, V., Gomerčić, M., Duvnjak, L. S., Baršić, N., & Lerotić, I. (2009) · PubMed · Cited by 82 · see citing works
Grant, P. J., Stickland, M. H., Booth, N. A., et al. (1991) · Diabetic Medicine · doi:10.1111/j.1464-5491.1991.tb01610.x · Cited by 78 · see citing works
Diabetes of the Liver: The Link Between Nonalcoholic Fatty Liver Disease and HFCS‐55
Collison, K. S., Saleh, S. M., Bakheet, R., Al‐Rabiah, R. K., Inglis, A. L., Makhoul, N. J., Maqbool, Z. M., Zaidi, M. Z., Al‐Johi, M. A., & Al-Mohanna, F. A. (2009) · Obesity · doi:10.1038/oby.2009.58 · Cited by 77 · see citing works
Role of the Inducible Nitric Oxide Synthase in the Onset of Fructose-Induced Steatosis in Mice
Spruss, A., Kanuri, G., Uebel, K., Bischoff, S. C., & Bergheim, I. (2010) · Antioxidants and Redox Signaling · doi:10.1089/ars.2010.3263 · Cited by 77 · see citing works
Self-citationMetformin prevents endotoxin-induced liver injury after partial hepatectomy
Bergheim, I., Luyendyk, J. P., Steele, C., Russell, G. K., Guo, L., Roth, R. A., & Arteel, G. E. (2006) · The Journal of Pharmacology and Experimental Therapeutics · doi:10.1124/jpet.105.092122 · Cited by 75 · see citing works
Self-citationKrakoff, J. A., Clark, J. M., Crandall, J. P., Wilson, C., Molitch, M. E., Brancati, F. L., Edelstein, S. L., & Knowler, W. C. (2010) · Obesity · doi:10.1038/oby.2010.21 · Cited by 58 · see citing works
Protective effect of bile acids on the onset of fructose-induced hepatic steatosis in mice
Volynets, V., Spruss, A., Kanuri, G., Wagnerberger, S., Bischoff, S. C., & Bergheim, I. (2010) · Journal of Lipid Research · doi:10.1194/jlr.m007179 · Cited by 51 · see citing works
Self-citationKanuri, G., Spruss, A., Wagnerberger, S., Bischoff, S. C., & Bergheim, I. (2011) · Laboratory Investigation · doi:10.1038/labinvest.2011.44 · Cited by 49 · see citing works
Self-citationMaury, E., Brichard, S. M., Pataky, Z., Carpentier, A., Golay, A., & Bobbioni‐Harsch, E. (2009) · Obesity · doi:10.1038/oby.2009.464 · Cited by 44 · see citing works
Pandey, M., Tuncman, G., Hotamışlıgil, G. S., & Samad, F. (2003) · American Journal Of Pathology · doi:10.1016/s0002-9440(10)63888-6 · Cited by 42 · see citing works
Chen, C., Wang, H., Shih, H.-C., Sheen, L., Chang, C., Chen, R.-H., & Wang, T.-Y. (2001) · PubMed · Cited by 16 · see citing works
Flagged first, then by citations
Research works printed but not linked: 1
- Lin HZ, Yang SQ, Chuckaree C, et al. Metformin reverses fatty liver disease in obese, leptin-deficient mice. Nat Med 2000;6:998-1003.
Cited by
Sorted by citations
Intestinal permeability – a new target for disease prevention and therapy
Bischoff, S. C., Barbara, G., Buurman, W., Ockhuizen, T., Schulzke, J.-D., Serino, M., Tilg, H., Watson, A., & Wells, J. M. (2014) · BMC Gastroenterology · doi:10.1186/s12876-014-0189-7 · Cited by 1,755 · see citing works
Self-citationFructose stimulated de novo lipogenesis is promoted by inflammation
Todoric, J., Di Caro, G., Reibe, S., Henstridge, D. C., Green, C. R., Vrbanac, A., Ceteci, F., Conche, C., McNulty, R., Shalapour, S., et al. (2020) · Nature Metabolism · doi:10.1038/s42255-020-0261-2 · Cited by 328 · see citing works
Chiu, S., Sievenpiper, J. L., de Souza, R. J., Cozma, A. I., Mirrahimi, A., Carleton, A. J., Ha, V, Di Buono, M., Jenkins, A. L., Leiter, L. A., et al. (2014) · European Journal of Clinical Nutrition · doi:10.1038/ejcn.2014.8 · Cited by 314 · see citing works
Microbiota and Gut–Liver Axis: Their Influences on Obesity and Obesity‐Related Liver Disease
Vajro, P., Paolella, G., & Fasano, A. (2013) · Journal of Pediatric Gastroenterology and Nutrition · doi:10.1097/mpg.0b013e318284abb5 · Cited by 201 · see citing works
New mechanisms of metformin action: Focusing on mitochondria and the gut
Hur, K. Y., & Lee, M. (2015) · Journal of Diabetes Investigation · doi:10.1111/jdi.12328 · Cited by 161 · see citing works
Song, B.-J., Akbar, M., Abdelmegeed, M. A., Byun, K., Lee, B., Yoon, S. K., & Hardwick, J. P. (2014) · Redox Biology · doi:10.1016/j.redox.2014.10.004 · Cited by 123 · see citing works
Guru, B., Tamrakar, A. K., Manjula, S. N., & Prashantha Kumar, B. R. (2022) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2022.175322 · Cited by 18 · see citing works
- Authors
- Spruss, A., Kanuri, G., Stahl, C., Bischoff, S. C., & Bergheim, I.
- Affiliations
- University of Hohenheim (DE)
- Corresponding author
- Bergheim, Ina
- Venue
- Laboratory Investigation
- Publisher
- Elsevier BV
- Published
- 2012-07
- Volume
- 92
- Issue
- 7
- Pages
- 1020-1032
- ISSN
- 0023-6837 (ISSN-L)
- OpenAlex
- W2015703748
- Cited by
- 168
- References
- 34
- Citations by year
- 2026: 3 · 2025: 10 · 2024: 11 · 2023: 12 · 2022: 10 · 2021: 14 · 2020: 14 · 2019: 13 · 2018: 19 · 2017: 22 · 2016: 14 · 2015: 8 · 2014: 7 · 2013: 10 · 2012: 1
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Laboratory Investigation (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Deutsche Forschungsgemeinschaft (BE 2376/4-1)
- Bundesministerium für Bildung und Forschung
- Topics
- Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Pharmacology › Drug-Induced Hepatotoxicity and Protection
- Keywords
- metformin, non-alcoholic fatty liver disease, intestinal barrier function, intestinal permeability, tight junction proteins, occludin, zonula occludens-1, TLR4, Kupffer cells, hepatic triglyceride accumulation, plasminogen activator inhibitor, c-Met, lipid export, insulin signaling
- MeSH terms
- Animals, Disease Models, Animal, Endotoxins, Fatty Liver, Fructose, Hypoglycemic Agents, Insulin Resistance, Liver, Metformin, Mice, Inbred C57BL, RNA, Messenger, Triglycerides, Tumor Necrosis Factor-alpha, Signal Transduction, Gene Expression, Plasminogen Activator Inhibitor 1, Tissue Inhibitor of Metalloproteinase-1, Matrix Metalloproteinase 9, Toll-Like Receptor 4, Mice, Matrix Metalloproteinase 13, Non-alcoholic Fatty Liver Disease
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
