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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene
Open accessAbstract
The liver produces plasma sex hormone-binding globulin (SHBG), which transports sex steroids and regulates their access to tissues. In overweight children and adults, low plasma SHBG levels are a biomarker of the metabolic syndrome and its associated pathologies. Here, we showed in transgenic mice and HepG2 hepatoblastoma cells that monosaccharides (glucose and fructose) reduce human SHBG production by hepatocytes. This occurred via a downregulation of hepatocyte nuclear factor-4alpha (HNF-4alpha) and replacement of HNF-4alpha by the chicken OVA upstream promoter-transcription factor 1 at a cis-element within the human SHBG promoter, coincident with repression of its transcriptional activity. The dose-dependent reduction of HNF-4alpha levels in HepG2 cells after treatment with glucose or fructose occurred in concert with parallel increases in cellular palmitate levels and could be mimicked by treatment with palmitoyl-CoA. Moreover, inhibition of lipogenesis prevented monosaccharide-induced downregulation of HNF-4alpha and reduced SHBG expression in HepG2 cells. Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4alpha levels, which in turn attenuated SHBG expression. This provides a biological explanation for why SHBG is a sensitive biomarker of the metabolic syndrome and the metabolic disturbances associated with increased fructose consumption.
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“Additionally, monosaccharides seem to decrease SHBG levels in a dose-dependent manner after supplementation of either glucose or fructose by reducing SHBG promotor activity.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [131]
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“Monosaccharides, also abundantly present in a state of IR, thus explain low levels of SHBG in this state of disease [131].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [131]
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“In fact, in transgenic mice expressing human SHBG, fructose, which as opposed to glucose fails to stimulate pancreatic insulin secretion, can effectively further reduce SHBG levels below decreased SHBG levels by glucose, confirming the limited role of insulin in this process [131].”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [131]
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“Experimental research in rodents demonstrated that the presence of monosaccharides, and not insulin, quickly regulates hepatic SHBG expression by altering hepatic HNF-4α levels.”
From Role of sex hormone-binding globulin in the free hormone hypothesis and the relevance of free testosterone in androgen physiology (2022) · cites this paper as [131]
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Citations
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Cited by
Sorted by citations
Items 201–219 of 219
Miao, R. (2026) · doi:10.48550/arxiv.2610.37675
“Forty biomarkers were organized a priori into four blocks: hormones (12), biochemistry (18), complete blood counts (7), and inflammation/lipids (3).”
Beneficial Hepatokines in MASLD/MASH: Therapeutic Potentials and Drug Delivery Challenges
Amatya, R., Min, K. A., & Shin, M. C. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27167118
“Hepatic SHBG expression is suppressed by insulin resistance, inflammation, and hepatic lipid accumulation, and it is enhanced by estrogens and HNF-4 α activity, thus making circulating SHBG a sensitive marker of hepatic metabolic health [35,92].”
Zhou, Y.-H., Lee, Y. A., Tang, Y.-X., Dai, Y., Chiu, P. K. F., Teoh, J., & Ng, C. (2026) · Asian Journal of Andrology · doi:10.4103/aja202614
Purc-Bandurko, K., Trojnar, K., Masiarz, A., Bandurko, A., Kimber-Trojnar, Ż., & Leszczyńska‐Gorzelak, B. (2026) · Biomolecules · doi:10.3390/biom16070998
“Clinical and experimental studies have shown that low SHBG concentrations are associated with insulin resistance, obesity, T2DM, metabolic dysfunction-associated steatotic liver disease (MASLD), and polycystic ovary syndrome (PCOS) [69,75,83–85].”
An HMMR-derived SHBG genetic score predicts lower type 2 diabetes risk
Zhuang, J., Ku, C., Wu, M., Xie, J., Li, C., Qin, Z., Abdrakhmanov, A. S., Zheng, J., & Zhang, Y. (2026) · Regenesis repair rehabilitation. · doi:10.1016/j.rerere.2026.05.001
Álvarez-Guaita, A., Cabrera-Serra, J., Perez-Gonzalez, B., Salcedo, M. T., Fuertes‐Rioja, L., Ramos‐Perez, L., Hernández, C., Simó, R., & Selva, D. M. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-08305-9
“Our studies have demonstrated that hepatic SHBG production is reduced by high carbohydrate diets (associated with hepatic lipid accumulation) by reducing hepatocyte nuclear factor alpha (HNF4α) levels [9], the most important transcription factor activating SHBG gene expression [10].”
Self-citationLiu, X., Chen, M., Dai, W., Gao, H., Chen, X., & Gao, R. (2026) · Journal of Thoracic Disease · doi:10.21037/jtd-2026-0787
Lyu, J., Luo, Y., Qian, Y.-W., Gu, J., Miao, M.-Y., Chen, G., & Yin, G. (2026) · Biology of Sex Differences · doi:10.1186/s13293-026-00884-y
Pan, P., Liang, H., & Li, M. (2025) · Current Issues in Molecular Biology · doi:10.3390/cimb47070494
“In addition, monosaccharide-induced lipogenesis could downregulate HNF-4 α levels in HepG2 cells, which in turn reduced hep-atic SHBG expression [64].”
Farrah, A. M. E. (2018) · Journal of Clinical Case Reports and Case Studies · doi:10.29199/2637-9309/cccs-101014
“This now forged androgen pathway is formed with bound up testosterone and increased levels of estradiol in the obese patient [4,5].”
BackgroundSex Hormone-Binding Globulin in Obese Type 2 Diabetics
Salam, E. M. A. E., Mohamed, N., Maghraby, H., & Mohamed, R. (2016) · doi:10.12816/0033774
SEX HORMONE-BINDING GLOBULIN IN OBESE TYPE 2 DIABETES MELLITUS.
Mohamed, R. A. E., Maghrabya, H., Salam., E., & Mohamed, N. (2016) · International Journal of Advanced Research · doi:10.21474/ijar01/1453 · Cited by 1
Stéatose et résistance à l’insuline : implication des hépatokines
Bertrand, C., Valet, P., & Castan‐Laurell, I. (2015) · Obésité · doi:10.1007/s11690-015-0492-7
Effects of Androgen on the Cardiovascular System in the Aging Male
Kim, J. W., Kim, J. J., & Moon, D. G. (2011) · Korean Journal of Andrology · doi:10.5534/kja.2011.29.1.10
Casazza, K., Granger, W., Wallace, S. B., & Gower, B. (2011) · doi:10.1177/1941406410393282
Round, P. (2019) · doi:10.14288/1.0387293
“The interplay between these two transcription factors influences plasma SHBG levels in response to hormonal and metabolic stimuli, including thyroid hormones that increase SHBG expression and numerous metabolic changes that characterize the metabolic syndrome (57,58).”
InfluentialSexualhormon-bindendes Globulin
Bidlingmaier, M. (2019) · Springer Reference Medizin · doi:10.1007/978-3-662-48986-4_2811
The role of FGF21 in regulating energy homeostasis
Ameka, M. K. (2017) · doi:10.17077/etd.vfkd2il1
“Glucose and fructose, which are strong inducers of insulin secretion and de novo hepatic lipogenesis, reduce the expression of SHBG in hepatocytes [771].”
BackgroundMeyers, W. M. (2016) · cIRcle (University of British Columbia) · doi:10.14288/1.0308668
“(glucose and fructose) causes hepatic lipogenesis resulting increased cellular levels of palmitate and downregulation of HNF4A resulting in decreased levels of serum SHBG [74].”
BackgroundMethod
Metadata
- Authors
- Selva, D. M., Hogeveen, K. N., Innis, S. M., & Hammond, G. L.
- Affiliations
- University of British Columbia (CA)
- Western University (CA)
- Corresponding author
- Hammond, Geoffrey L.
- Venue
- Journal of Clinical Investigation
- Published
- 2007-11-08
- Volume
- 117
- Issue
- 12
- Pages
- 3979-87
- ISSN
- 0021-9738 (ISSN-L)
- PMC
- PMC2066187
- OpenAlex
- W2026196869
- Cited by
- 232
- References
- 48
- Citations by year
- 2026: 9 · 2025: 11 · 2024: 13 · 2023: 14 · 2022: 22 · 2021: 15 · 2020: 12 · 2019: 7 · 2018: 11 · 2017: 20 · 2016: 17 · 2015: 8 · 2014: 9 · 2013: 18 · 2012: 18
- FWCI
- 4.16
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Journal of Clinical Investigation (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Child and Family Research Institute
- Michael Smith Health Research BC
- Canadian Institutes of Health Research
- Topics
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diet, Metabolism, and Disease
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Lipid metabolism and disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Endocrinology › Estrogen and related hormone effects
- Keywords
- sex hormone-binding globulin, monosaccharides, glucose, fructose, lipogenesis, HNF4α, promoter cis-acting elements, palmitate, metabolic syndrome, hepatocytes, fructose consumption
- MeSH terms
- Adult, Animals, Chickens, Child, Child, Preschool, Fructose, Gene Expression Regulation, Glucose, Humans, Mice, Transgenic, Sex Hormone-Binding Globulin, Gonadal Steroid Hormones, Sweetening Agents, Biomarkers, Metabolic Syndrome, Cell Line, Tumor, Lipogenesis, Overweight, Mice, Hepatocyte Nuclear Factor 1-alpha, Hepatocyte Nuclear Factor 4
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