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Cited by 55Diet, Metabolism, and DiseaseLipid metabolism and biosynthesisMetabolism, Diabetes, and Cancer

Comparative Effects of Fructose and Glucose on Lipogenic Gene Expression and Intermediary Metabolism in HepG2 Liver Cells

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Hirahatake, Kristin M., Meissen, John K., Fiehn, Oliver, Adams, Sean H.·2011·PLoS ONE
DOI 10.1371/journal.pone.0026583PMC PMC3214012
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Abstract

Consumption of large amounts of fructose or sucrose increases lipogenesis and circulating triglycerides in humans. Although the underlying molecular mechanisms responsible for this effect are not completely understood, it is possible that as reported for rodents, high fructose exposure increases expression of the lipogenic enzymes fatty acid synthase (FAS) and acetyl-CoA carboxylase (ACC-1) in human liver. Since activation of the hexosamine biosynthesis pathway (HBP) is associated with increases in the expression of FAS and ACC-1, it raises the possibility that HBP-related metabolites would contribute to any increase in hepatic expression of these enzymes following fructose exposure. Thus, we compared lipogenic gene expression in human-derived HepG2 cells after incubation in culture medium containing glucose alone or glucose plus 5 mM fructose, using the HBP precursor 10 mM glucosamine (GlcN) as a positive control. Cellular metabolite profiling was conducted to analyze differences between glucose and fructose metabolism. Despite evidence for the active uptake and metabolism of fructose by HepG2 cells, expression of FAS or ACC-1 did not increase in these cells compared with those incubated with glucose alone. Levels of UDP-N-acetylglucosamine (UDP-GlcNAc), the end-product of the HBP, did not differ significantly between the glucose and fructose conditions. Exposure to 10 mM GlcN for 10 minutes to 24 hours resulted in 8-fold elevated levels of intracellular UDP-GlcNAc (P<0.001), as well as a 74-126% increase in FAS (P<0.05) and 49-95% increase in ACC-1 (P<0.01) expression above controls. It is concluded that in HepG2 liver cells cultured under standard conditions, sustained exposure to fructose does not result in an activation of the HBP or increased lipogenic gene expression. Should this scenario manifest in human liver in vivo, it would suggest that high fructose consumption promotes triglyceride synthesis primarily through its action to provide lipid precursor carbon and not by activating lipogenic gene expression.

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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 [123]

    The Discussion reports that fructose did not induce lipogenic gene or protein expression in HepG2 cells, supporting the absence of the expected response. The Results characterize carbohydrate-metabolism enzymes, but our copy does not report low aldolase B expression or attribute the absent response to a predominantly glycolytic phenotype. The basal-glucose explanation is attached to a different citation, [123], and is not judged here. (LLM, conf=0.85)

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  • 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 [123]

    The Results (Effects of fructose on lipogenic gene expression; page not available) report that 5 mM fructose did not induce FAS or ACC-1 expression in HepG2 cells over the tested periods of up to 72 hours. The paper does not establish the claim for 20–25 mM fructose or 28-day incubations, and it did not directly show an absence of de novo lipogenesis or triglyceride accumulation. (LLM, conf=0.88)

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Research works printed but not linked: 2

  1. [22]Nagata R Nishio Y Sekine O Nagai Y Maeno Y 2004 Single nucleotide polymorphism (−468 Gly to A) at the promoter region of SREBP-1c associates with genetic defect of fructose-induced hepatic lipogenesis [corrected]. J Biol Chem 279 29031 29042 15123654
  2. [38]Hers HG 1952 [Liver fructokinase]. Biochim Biophys Acta 8 416 423 13208667

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Authors
Hirahatake, K. M., Meissen, J. K., Fiehn, O., & Adams, S. H.
Affiliations
  • University of California, Davis (US)
  • Agricultural Research Service (US)
Corresponding author
Adams, Sean H.
ORCID
Venue
PLoS ONE
Publisher
Public Library of Science (PLoS)
Published
2011-11-11
Volume
6
Issue
11
Pages
e26583
ISSN
1932-6203 (ISSN-L)
DOI
10.1371/journal.pone.0026583
PMC
PMC3214012
OpenAlex
W2041125527
Cited by
55
References
39
Citations by year
2026: 1 · 2025: 4 · 2024: 4 · 2023: 3 · 2022: 5 · 2021: 4 · 2020: 4 · 2019: 7 · 2018: 4 · 2017: 1 · 2016: 8 · 2015: 3 · 2014: 2 · 2013: 4 · 2012: 1
FWCI
1.84
Type
journal article
Language
en
Open access
Licence
Locations
  • PLoS ONE (publishedVersion, public-domain)
  • PubMed Central (publishedVersion, public-domain)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Figshare (submittedVersion, cc-by)
Funders
  • U.S. Department of Agriculture (5306‐51530‐019‐00, 5306‐51530‐016‐00D, 5306‐51530‐019)
  • Diabetes Action Research and Education Foundation
  • Agricultural Research Service (5306‐51530‐019‐00, 5306‐51530‐016‐00D)
Topics
  • Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Biochemistry › Lipid metabolism and biosynthesis
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Metabolism, Diabetes, and Cancer
Keywords
fructose, glucose, lipogenesis, fatty acid synthase, acetyl-CoA carboxylase, hexosamine biosynthetic pathway, UDP-N-acetylglucosamine, glucosamine, HepG2 cells, hepatic triglyceride synthesis, fructose metabolism
MeSH terms
Acetyl-CoA Carboxylase, Fructose, Glucosamine, Glucose, Humans, Liver, Uridine Diphosphate N-Acetylglucosamine, Gene Expression, Lipogenesis, Hep G2 Cells, Fatty Acid Synthases

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