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Cited by 5Diet, Metabolism, and DiseaseLiver Disease Diagnosis and TreatmentLipid metabolism and biosynthesis

Effects of Fructose on Features of Steatotic Liver Disease in HepG2 Cells

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Howes, Matthew Thomas, King, Jessie, Rosengren, Rhonda Joy·2025·Nutrients
DOI 10.3390/nu17172762PMC PMC12430389
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Abstract

Background/Objectives: Metabolic (dysfunction)-associated steatotic liver disease (MASLD), the hepatic consequence of metabolic syndrome, affects 30% of the global population. Studies in animals and humans investigating the effect of fructose on MASLD present conflicting findings, while in vitro methods often fail to add meaningful evidence due to acute exposures (<72 h) and non-physiological concentrations. This study aimed to determine the effect of fructose on triglyceride (TG) accumulation in HepG2 cells following acute and chronic exposures and assess its effect on the expression of genes related to de novo lipogenesis (DNL). Methods: TG concentration was measured after 48 h in response to fructose (20 mM) or glucose (20 mM), with or without a fatty acid mixture (oleic acid/palmitic acid 110 µM/55 µM), in low (5.5 mM)- and high (25.5 mM)-glucose media. To model chronic exposure, cells were maintained in fructose, glucose, or fatty acids for 28 days and the TG concentration was determined every 7 days. The effect of fructose on DNL regulators (SREBPF1, NR1H3, FASN, and ACACA) was determined using qPCR. Results: Neither fructose nor glucose, with or without fatty acids, changed the TG levels in cells at 48 h and the media glucose concentration had no effect on this result. Similarly, fructose did not increase TG levels after 28 days. While fructose and glucose did not affect key DNL genes at 6 h, the fatty acid mixture reduced FASN by 41%. Conclusions: This study shows that fructose did not significantly impact TG synthesis or DNL gene expression in the HepG2 cell model. Future studies should consider using primary human hepatocytes or more complex in vitro models.

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  • The absence of expected steatogenic response to fructose in HepG2 may be due to low aldolase B expression, glycolytic phenotype, and basal glucose in the medium negating fructose effect.

    “The absence of the expected steatogenic response in HepG2 may be due to the metabolic characteristics of this cell line, in particular the low expression of aldolase B and the predominance of the glycolytic phenotype [122], as well as the fact that the basal glucose level in the medium may negate the effect of fructose [123].”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [122]

  • Fructose alone does not reliably induce de novo lipogenesis or triglyceride accumulation in HepG2, even at concentrations up to 20-25 mM and incubation times from 48 h to 28 days.

    “The limited reproducibility of fructose-induced DNL is a particularly significant limitation for MASLD studies, where sugar/fructose loading is considered one of the key pathogenic factors, as the ability of fructose to induce steatosis directly in HepG2 hepatoma cells remains controversial.”

    From The HepG2 Cell Line as a Model for Studying Metabolic Dysfunction-Associated Steatotic Liver Disease (2026) · cites this paper as [122]

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Research works printed but not linked: 38

  1. [1]Rinella M.E. Lazarus J.V. Ratziu V. Francque S.M. Sanyal A.J. Kanwal F. Romero D. Abdelmalek M.F. Anstee Q.M. Arab J.P. A Multi-Society Delphi Consensus Statement on New Fatty Liver Disease Nomenclature Ann. Hepatol. 2023 29 101133 10.1016/j.aohep.2023.101133 37364816 · DOI · Paper page
  2. [2]Younossi Z. Anstee Q.M. Marietti M. Hardy T. Henry L. Eslam M. George J. Bugianesi E. Global Burden of NAFLD and NASH: Trends, Predictions, Risk Factors and Prevention Nat. Rev. Gastroenterol. Hepatol. 2018 15 11 20 10.1038/nrgastro.2017.109 28930295 · DOI · Paper page
  3. [3]Malhi H. Bronk S.F. Werneburg N.W. Gores G.J. Free Fatty Acids Induce JNK-dependent Hepatocyte Lipoapoptosis J. Biol. Chem. 2006 281 12093 12101 10.1074/jbc.M510660200 16505490 · DOI
  4. [5]Stanhope K.L. Schwarz J.M. Keim N.L. Griffen S.C. Bremer A.A. Graham J.L. Hatcher B. Cox C.L. Dyachenko A. Zhang W. Consuming Fructose-Sweetened, Not Glucose-Sweetened, Beverages Increases Visceral Adiposity and Lipids and Decreases Insulin Sensitivity in Overweight/Obese Humans J. Clin. Investig. 2009 119 1322 1334 10.1172/JCI37385 19381015 PMC2673878 · DOI · Paper page
  5. [7]Chung M. Ma J. Patel K. Berger S. Lau J. Lichtenstein A.H. Fructose, High-Fructose Corn Syrup, Sucrose, and Nonalcoholic Fatty Liver Disease or Indexes of Liver Health: A Systematic Review and Meta-Analysis Am. J. Clin. Nutr. 2014 100 833 849 10.3945/ajcn.114.086314 25099546 PMC4135494 · DOI
  6. [8]Spruss A. Kanuri G. Stahl C. Bischoff S.C. Bergheim I. Metformin Protects against the Development of Fructose-Induced Steatosis in Mice: Role of the Intestinal Barrier Function Lab. Investig. 2012 92 1020 1032 10.1038/labinvest.2012.75 22525431 · DOI · Paper page
  7. [9]Todoric J. Di Caro G. Reibe S. Henstridge D.C. Green C.R. Vrbanac A. Ceteci F. Conche C. McNulty R. Shalapour S. Fructose Stimulated de Novo Lipogenesis Is Promoted by Inflammation Nat. Metab. 2020 2 1034 1045 10.1038/s42255-020-0261-2 32839596 PMC8018782 · DOI · Paper page
  8. [11]Herman M.A. Samuel V.T. The Sweet Path to Metabolic Demise: Fructose and Lipid Synthesis Trends Endocrinol. Metab. 2016 27 719 730 10.1016/j.tem.2016.06.005 27387598 PMC5035631 · DOI
  9. [12]Arzumanian V.A. Kiseleva O.I. Poverennaya E.V. The Curious Case of the HepG2 Cell Line: 40 Years of Expertise Int. J. Mol. Sci. 2021 22 13135 10.3390/ijms222313135 34884942 PMC8658661 · DOI · Paper page
  10. [13]Hart S.N. Li Y. Nakamoto K. Subileau E. Steen D. Zhong X. A Comparison of Whole Genome Gene Expression Profiles of HepaRG Cells and HepG2 Cells to Primary Human Hepatocytes and Human Liver Tissues Drug Metab. Dispos. 2010 38 988 994 10.1124/dmd.109.031831 20228232 PMC2879958 · DOI
  11. [14]Gerets H.H.J. Tilmant K. Gerin B. Chanteux H. Depelchin B.O. Dhalluin S. Atienzar F.A. Characterization of Primary Human Hepatocytes, HepG2 Cells, and HepaRG Cells at the mRNA Level and CYP Activity in Response to Inducers and Their Predictivity for the Detection of Human Hepatotoxins Cell Biol. Toxicol. 2012 28 69 87 10.1007/s10565-011-9208-4 22258563 PMC3303072 · DOI · Paper page
  12. [15]Yu X. Ren L.P. Wang C. Zhu Y.J. Xing H.Y. Zhao J. Song G.Y. Role of X-Box Binding Protein-1 in Fructose-Induced de Novo Lipogenesis in HepG2 Cells Chin. Med. J. 2018 131 2310 2319 10.4103/0366-6999.241799 30246717 PMC6166463 · DOI
  13. [16]Lanaspa M.A. Sanchez-Lozada L.G. Choi Y.J. Cicerchi C. Kanbay M. Roncal-Jimenez C.A. Ishimoto T. Li N. Marek G. Duranay M. Uric Acid Induces Hepatic Steatosis by Generation of Mitochondrial Oxidative Stress: Potential Role in Fructose-Dependent and -Independent Fatty Liver J. Biol. Chem. 2012 287 40732 40744 10.1074/jbc.M112.399899 23035112 PMC3504786 · DOI
  14. [17]Montesano A. Senesi P. Vacante F. Mollica G. Benedini S. Mariotti M. Luzi L. Terruzzi I. L-Carnitine Counteracts in Vitro Fructose-Induced Hepatic Steatosis through Targeting Oxidative Stress Markers J. Endocrinol. Investig. 2020 43 493 503 10.1007/s40618-019-01134-2 31705397 PMC7067714 · DOI
  15. [18]Zhao L. Guo X. Wang O. Zhang H. Wang Y. Zhou F. Liu J. Ji B. Fructose and Glucose Combined with Free Fatty Acids Induce Metabolic Disorders in HepG2 Cell: A New Model to Study the Impacts of High-Fructose/Sucrose and High-Fat Diets in Vitro Mol. Nutr. Food Res. 2016 60 909 921 10.1002/mnfr.201500635 26763130 · DOI
  16. [20]Huggett Z.J. Smith A. De Vivo N. Gomez D. Jethwa P. Brameld J.M. Bennett A. Salter A.M. A Comparison of Primary Human Hepatocytes and Hepatoma Cell Lines to Model the Effects of Fatty Acids, Fructose and Glucose on Liver Cell Lipid Accumulation Nutrients 2023 15 40 10.3390/nu15010040 PMC9824391 36615698 · DOI · Paper page
  17. [21]Nawroth J.C. Petropolis D.B. Manatakis D.V. Maulana T.I. Burchett G. Schlünder K. Witt A. Shukla A. Kodella K. Ronxhi J. Modeling Alcohol-Associated Liver Disease in a Human Liver-Chip Cell Rep. 2021 36 109393 10.1016/j.celrep.2021.109393 34289365 PMC8342038 · DOI · Paper page
  18. [23]Ricchi M. Odoardi M.R. Carulli L. Anzivino C. Ballestri S. Pinetti A. Fantoni L.I. Marra F. Bertolotti M. Banni S. Differential Effect of Oleic and Palmitic Acid on Lipid Accumulation and Apoptosis in Cultured Hepatocytes J. Gastroenterol. Hepatol. 2009 24 830 840 10.1111/j.1440-1746.2008.05733.x 19207680 · DOI
  19. [24]Vichai V. Kirtikara K. Sulforhodamine B Colorimetric Assay for Cytotoxicity Screening Nat. Protoc. 2006 1 1112 1116 10.1038/nprot.2006.179 17406391 · DOI
  20. [25]Zhang Q. Zhao G. Yang N. Zhang L. Chapter Sixteen—Fasting Blood Glucose Levels in Patients with Different Types of Diseases Progress in Molecular Biology and Translational Science Zhang L. Glycans and Glycosaminoglycans as Clinical Biomarkers and Therapeutics—Part A; Academic Press Cambridge, MA, USA 2019 Volume 162 277 292 30905457
  21. [26]Ameer F. Scandiuzzi L. Hasnain S. Kalbacher H. Zaidi N. De Novo Lipogenesis in Health and Disease Metabolism 2014 63 895 902 10.1016/j.metabol.2014.04.003 24814684 · DOI
  22. [27]Livak K.J. Schmittgen T.D. Analysis of Relative Gene Expression Data Using Real-Time Quantitative PCR and the 2− ΔΔCT Method Methods 2001 25 402 408 10.1006/meth.2001.1262 11846609 · DOI · Paper page
  23. [28]Kruszynska Y.T. Meyer-Alber A. Wollen N. McIntyre N. Energy Expenditure and Substrate Metabolism after Oral Fructose in Patients with Cirrhosis J. Hepatol. 1993 19 241 251 10.1016/S0168-8278(05)80578-1 8301057 · DOI
  24. [29]Tran C. Jacot-Descombes D. Lecoultre V. Fielding B.A. Carrel G. Lê K.-A. Schneiter P. Bortolotti M. Frayn K.N. Tappy L. Sex Differences in Lipid and Glucose Kinetics after Ingestion of an Acute Oral Fructose Load Br. J. Nutr. 2010 104 1139 1147 10.1017/S000711451000190X 20540820 · DOI
  25. [30]Le M.T. Frye R.F. Rivard C.J. Cheng J. McFann K.K. Segal M.S. Johnson R.J. Johnson J.A. Effects of High-Fructose Corn Syrup and Sucrose on the Pharmacokinetics of Fructose and Acute Metabolic and Hemodynamic Responses in Healthy Subjects Metabolism 2012 61 641 651 10.1016/j.metabol.2011.09.013 22152650 PMC3306467 · DOI
  26. [31]Hui H. Huang D. McArthur D. Nissen N. Boros L.G. Heaney A.P. Direct Spectrophotometric Determination of Serum Fructose in Pancreatic Cancer Patients Pancreas 2009 38 706 712 10.1097/MPA.0b013e3181a7c6e5 19506535 · DOI
  27. [32]Low W.S. Cornfield T. Charlton C.A. Tomlinson J.W. Hodson L. Sex Differences in Hepatic de Novo Lipogenesis with Acute Fructose Feeding Nutrients 2018 10 1263 10.3390/nu10091263 30205493 PMC6164310 · DOI
  28. [33]Catenacci D.V.T. Chapman C.G. Xu P. Koons A. Konda V.J. Siddiqui U.D. Waxman I. Acquisition of Portal Venous Circulating Tumor Cells from Patients with Pancreaticobiliary Cancers by Endoscopic Ultrasound Gastroenterology 2015 149 1794 1803 10.1053/j.gastro.2015.08.050 26341722 PMC4985007 · DOI
  29. [34]Zhang D. Wei Y. Huang Q. Chen Y. Zeng K. Yang W. Chen J. Chen J. Important Hormones Regulating Lipid Metabolism Molecules 2022 27 7052 10.3390/molecules27207052 36296646 PMC9607181 · DOI
  30. [35]Yellaturu C.R. Deng X. Cagen L.M. Wilcox H.G. Mansbach C.M. Siddiqi S.A. Park E.A. Raghow R. Elam M.B. Insulin Enhances Post-Translational Processing of Nascent SREBP-1c by Promoting Its Phosphorylation and Association with COPII Vesicles * J. Biol. Chem. 2009 284 7518 7532 10.1074/jbc.M805746200 19158095 PMC2658047 · DOI
  31. [36]Hewitt K.N. Pratis K. Jones M.E.E. Simpson E.R. Estrogen Replacement Reverses the Hepatic Steatosis Phenotype in the Male Aromatase Knockout Mouse Endocrinology 2004 145 1842 1848 10.1210/en.2003-1369 14684602 · DOI
  32. [37]Pouwels S. Sakran N. Graham Y. Leal A. Pintar T. Yang W. Kassir R. Singhal R. Mahawar K. Ramnarain D. Non-Alcoholic Fatty Liver Disease (NAFLD): A Review of Pathophysiology, Clinical Management and Effects of Weight Loss BMC Endocr. Disord. 2022 22 63 10.1186/s12902-022-00980-1 35287643 PMC8919523 · DOI
  33. [38]Yoshida R. Sasaki T. Minami Y. Hibino Y. Okumura S. Sado M. Miyokawa N. Hayashi S. Kitada M. Ohsaki Y. Activation of Src Signaling Mediates Acquired Resistance to ALK Inhibition in Lung Cancer Int. J. Oncol. 2017 51 1533 1540 10.3892/ijo.2017.4140 29048652 · DOI
  34. [39]Donato M.T. Tolosa L. Gómez-Lechón M.J. Culture and Functional Characterization of Human Hepatoma HepG2 Cells Protocols in In Vitro Hepatocyte Research Humana Press New York, NY, USA 2015 Volume 1250 77 93 978-1-4939-2074-7 26272135
  35. [40]Klein D. Quantification Using Real-Time PCR Technology: Applications and Limitations Trends Mol. Med. 2002 8 257 260 10.1016/S1471-4914(02)02355-9 12067606 · DOI
  36. [42]Song Z. Xiaoli A.M. Yang F. Regulation and Metabolic Significance of De Novo Lipogenesis in Adipose Tissues Nutrients 2018 10 1383 10.3390/nu10101383 30274245 PMC6213738 · DOI
  37. [44]Zhang M. Bai X. Du Q. Xu J. Wang D. Chen L. Dong K. Chen Z. Yang J. The Different Mechanisms of Lipid Accumulation in Hepatocytes Induced by Oleic Acid/Palmitic Acid and High-Fat Diet Molecules 2023 28 6714 10.3390/molecules28186714 37764494 PMC10536454 · DOI
  38. [45]Favaro E. Bensaad K. Chong M.G. Tennant D.A. Ferguson D.J.P. Snell C. Glucose Utilization via Glycogen Phosphorylase Sustains Proliferation and Prevents Premature Senescence in Cancer Cells Cell Metab. 2012 16 751 764 10.1016/j.cmet.2012.10.017 23177934 · DOI

Cited by

Sorted by citations

Authors
Howes, M. T., King, J., & Rosengren, R. J.
Affiliations
University of Otago (NZ)
Corresponding author
Howes, Matthew Thomas
ORCID
Venue
Nutrients
Publisher
MDPI AG
Published
2025-08-26
Volume
17
Issue
17
Pages
2762
ISSN
2072-6643 (ISSN-L)
DOI
10.3390/nu17172762
PMC
PMC12430389
OpenAlex
W4413657983
Cited by
5
References
5
Citations by year
2026: 5
FWCI
3.41
Type
journal article
Language
en
Open access
Licence
Locations
  • Nutrients (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • PubMed Central (publishedVersion, cc-by)
Funders
a University of Otago Division of Health Sciences Dean’s Bequest Grant
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Health Sciences › Medicine › Epidemiology › Liver Disease Diagnosis and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
Keywords
fructose, non-alcoholic fatty liver disease, hepatic steatosis, triglyceride accumulation, de novo lipogenesis, HepG2 cells, glucose, SREBP1, liver X receptor alpha, fatty acid synthase, ACACA, metabolic syndrome
MeSH terms
Fatty Acids, Fatty Liver, Fructose, Gene Expression Regulation, Glucose, Humans, Triglycerides, Lipogenesis, Hep G2 Cells

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