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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Monosaccharides seem to decrease SHBG levels in a dose-dependent manner after supplementation of either glucose or fructose by reducing SHBG promotor activity.
“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]
Monosaccharides, also abundantly present in a state of IR, explain low levels of SHBG in this state of disease.
“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]
In transgenic mice expressing human SHBG, fructose can effectively further reduce SHBG levels below decreased SHBG levels by glucose, confirming the limited role of insulin in this process.
“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]
Experimental research in rodents demonstrated that the presence of monosaccharides, and not insulin, quickly regulates hepatic SHBG expression by altering hepatic HNF-4α levels.
“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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“Factors shown to be inversely associated with SHBG levels include growth hormone [14], oestrogen (oestradiol) [15, 16], insulin [15, 17], body composition [15, 18, 19], intrahepatic fat [8, 18, 20], triglycerides [21, 22], monosaccharides [23], C-reactive protein (CRP) [24], and moderate alcohol consumption [25].”
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Androgen therapy in women, beyond libido
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“Moreover, an in vitro study has shown that SHBG is not regulated by insulin but rather repressed by monosaccharide-induced lipogenesis in human HepG2 cells [55], suggesting that fatty liver or liver dysfunction which is usually associated with insulin resistance and diabetes might be a mechanism for the lower SHBG lev…”
BackgroundMoon, H., Choi, I., Kim, S., Ko, H., Shin, J., Lee, K., Sung, J., & Song, Y. (2017) · Clinical Endocrinology · doi:10.1111/cen.13390 · Cited by 28 · see citing works
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“Although we did not observe a change in postprandial SHBG levels after the two test meals, there is evidence that dietary factors including fructose, glucose, sucrose, and insulin affect SHBG expression and secretion (33, 34).”
Bonnet, F., Velayoudom Cephise, F., Gautier, A., Dubois, S., Massart, C., Camara, A., Larifla, L., Balkau, B., & Ducluzeau, P. (2013) · Clinical Endocrinology · doi:10.1111/cen.12089 · Cited by 28 · see citing works
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Self-citationThe hepatic lipidome and HNF4α and SHBG expression in human liver
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“In other experiments using HepG2 cells, however, palmitoyl-CoA was reported to suppress HNF4 transcription (25).”
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“SHBG is produced in the liver, and its production is inhibited by the monosaccharide-induced lipogenesis (35).”
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Self-citationPre‐diabetes and serum sex steroid hormones among US men
Arthur, R., Rohrmann, S., Møller, H., Selvin, E., Dobs, A., Kanarek, N., Nelson, W., Platz, E., & Hemelrijck, M. V. (2017) · Andrology · doi:10.1111/andr.12287 · Cited by 24 · see citing works
“Moreover, another study showed that glucose and fructose inhibited human SHBG production in the liver cells by inhibiting production of hepatic HNF-4 levels, while triggering an increase in cellular palmitate levels (Selva et al., 2007).”
BackgroundNuclear Receptor HNF4α Binding Sequences are Widespread in Alu Repeats
Bolotin, E., Chellappa, K., Hwang-Verslues, W., Schnabl, J., Yang, C., & Sladek, F. (2011) · BMC Genomics · doi:10.1186/1471-2164-12-560 · Cited by 24 · see citing works
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“However, considering insulin resistance, it is associated with elevated concentrations of these monosaccharides as a result of impaired insulin signalling and without insulin action by itself (15,16).”
BackgroundNew Insights in the Diagnostic Potential of Sex Hormone-Binding Globulin (SHBG)—Clinical Approach
Szybiak, W., Cyna, W., & Łącka, K. (2025) · Biomedicines · doi:10.3390/biomedicines13051207 · Cited by 23 · see citing works
“These studies indicate that decreased insulin levels do not cause an increase in SHBG [38].”
InfluentialSimons, P. I. H. G., Valkenburg, O., Bons, J. A. P., Stehouwer, C. D. A., & Brouwers, M. C. G. J. (2021) · Endocrinology Diabetes & Metabolism · doi:10.1002/edm2.267 · Cited by 23 · see citing works
Stasi, V. D., Maseroli, E., Rastrelli, G., Scavello, I., Cipriani, S., Todisco, T., Marchiani, S., Sorbi, F., Fambrini, M., Petraglia, F., et al. (2021) · Frontiers in Endocrinology · doi:10.3389/fendo.2021.641446 · Cited by 30 · see citing works
“secretion downregulates SHBG production (63).”
Rojas, J., Chávez-Castillo, M., & Bermúdez, V. (2014) · International Journal of Reproductive Medicine · doi:10.1155/2014/797681 · Cited by 26 · see citing works
“Hepatocyte Nuclear Factor 4-α downregulation [39].”
Oleic acid increases hepatic sex hormone binding globulin production in men
Sáez‐López, C., Soriguer, F., Hernández, C., Rojo‐Martínez, G., Rubio‐Martín, E., Simó, R., & Selva, D. M. (2013) · Molecular Nutrition & Food Research · doi:10.1002/mnfr.201300304 · Cited by 24 · see citing works
“Furthermore, we have also demonstrated that palmitate, a saturated fatty acid, downregulates human SHBG production by affecting HNF-4A gene expression [10].”
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“Although it is assumed that there is a causal association between IHL content, serum SHBG and type 2 diabetes (an assumption that is supported by experimental and genetic studies [13, 15, 16]) we cannot exclude the possibility that the associations are in fact bi-directional.”
BackgroundWang, N., Zhang, K., Han, B., Qin, L., Chen, Y., Zhu, C., Chen, Y., Xia, F., Zhai, H., Jiang, B., et al. (2017) · Endocrine · doi:10.1007/s12020-017-1272-y · Cited by 21 · see citing works
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Camajani, E., Feraco, A., Verde, L., Moriconi, E., Marchetti, M., Colao, A., Caprio, M., Muscogiuri, G., & Barrea, L. (2023) · Current Obesity Reports · doi:10.1007/s13679-023-00516-1 · Cited by 22 · see citing works
Dysregulated Liver Metabolism and Polycystic Ovarian Syndrome
Khan, M. S., Kim, H., Kim, R., Yoon, S. H., & Kim, S. G. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms24087454 · Cited by 25 · see citing works
- 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 › Genetics › 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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