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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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Cited by
Sorted by citations
Hepatokines: Linking nonalcoholic fatty liver disease and insulin resistance
Meex, R. C. R., & Watt, M. J. (2017) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2017.56 · Cited by 631
The effect of obesity on polycystic ovary syndrome: a systematic review and meta‐analysis
Lim, S. S., Norman, R. J., Davies, M. J., & Moran, L. J. (2013) · Obesity Reviews · doi:10.1111/j.1467-789x.2012.01053.x · Cited by 539
“Alternatively, the regulation of SHBG may occur independent of insulin (59) with dietary influences such as monosaccharide-induced lipogenesis also attenuating SHBG levels (60).”
BackgroundThe role of hepatokines in metabolism
Stefan, N., & Häring, H.-U. (2013) · Nature Reviews Endocrinology · doi:10.1038/nrendo.2012.258 · Cited by 500
Rojas, J., Chávez-Castillo, M., Olivar, L. C., Rojas, M., Morillo, J., Mejias, J. A., Calvo, M. C. C., & Bermúdez, V. (2014) · International Journal of Reproductive Medicine · doi:10.1155/2014/719050 · Cited by 504
“Although insulin and the insulin-like growth factor 1 (IGF-1) have been demonstrated unable to directly repress shbg [75], they may be key indirect mediators, as they have been associated with decreased total protein secretion in human hepatic cells [76].”
Plasma steroid-binding proteins: primary gatekeepers of steroid hormone action
Hammond, G. L. (2016) · Journal of Endocrinology · doi:10.1530/joe-16-0070 · Cited by 356
“This provided the first explanation for why low plasma SHBG is a hallmark of the metabolic syndrome and its associated diseases, such as type 2 diabetes and cardiovascular disease (Selva et al. 2007 ).”
Self-citation
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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