Cited by 232Diet, Metabolism, and DiseaseLipid metabolism and disordersEstrogen and related hormone effects

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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

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Selva, David M., Hogeveen, Kevin N., Innis, Sheila M., Hammond, Geoffrey L.·2007·Journal of Clinical Investigation

DOI 10.1172/jci32249PMC PMC2066187

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Abstract

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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Background
Urate Transport in Health and Disease
Kuhns, V. L. H., & Woodward, O. (2021) · Baillière's Best Practice & Research : Clinical Rheumatology · doi:10.1016/j.berh.2021.101717 · Cited by 42
Associations of Fatty Liver Disease and Other Factors Affecting Serum SHBG Concentrations: A Population Based Study on 1657 Subjects
Flechtner-Mors, M., Schick, A., Oeztuerk, S., Haenle, M., Wilhelm, M., Koenig, W., Imhof, A., Boehm, B. O., Graeter, T., Mason, R., et al. (2013) · Hormone and Metabolic Research · doi:10.1055/s-0033-1354369 · Cited by 42
The contribution of SHBG to the variation in HOMA‐IR is not dependent on endogenous oestrogen or androgen levels in postmenopausal women
Davis, S. R., Robinson, P. J., Moufarege, A., & Bell, R. J. (2011) · Clinical Endocrinology · doi:10.1111/j.1365-2265.2011.04301.x · Cited by 38
Association of sex hormone-binding globulin with nonalcoholic fatty liver disease in Chinese adults
Luo, J., Chen, Q., Shen, T.-R., Wang, X., Fang, W.-J., Wu, X., Yuan, Z.-N., Chen, G.-D., Ling, W., & Chen, Y. (2018) · Nutrition and Metabolism · doi:10.1186/s12986-018-0313-8 · Cited by 40
Endometrial Cancer as a Metabolic Disease with Dysregulated PI3K Signaling: Shedding Light on Novel Therapeutic Strategies
Kyo, S., & Nakayama, K. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21176073 · Cited by 44
“Exposure of hepatic cells to glucose significantly reduces SHBG mRNA expression via decreased hepatocyte nuclear factor-4 alpha (HNF-4α), which is the key transcription factor that binds the SHBG promoter and is down-regulated by glucose-induced de novo lipogenesis in the liver [58].”
Background
Sex hormone-binding globulin overexpression protects against high-fat diet-induced obesity in transgenic male mice
Saez-Lopez, C., Villena, J. A., Simó, R., & Selva, D. M. (2020) · The Journal of Nutritional Biochemistry · doi:10.1016/j.jnutbio.2020.108480 · Cited by 38
Self-citation
Sex Hormone–Binding Globulin Expression Correlates With Acetyl-Coenzyme A Carboxylase and Triglyceride Content in Human Liver
Sáez‐López, C., Salcedo, M. T., Hernández, C., Simó‐Servat, O., Simó, R., & Selva, D. M. (2018) · The Journal of Clinical Endocrinology & Metabolism · doi:10.1210/jc.2018-00740 · Cited by 40
Self-citation
Determinants of testosterone recovery after bariatric surgery: is it only a matter of reduction of body mass index?
Luconi, M., Samavat, J., Seghieri, G., Iannuzzi, G., Lucchese, M., Rotella, C. M., Forti, G., Maggi, M., & Mannucci, E. (2013) · Fertility and Sterility · doi:10.1016/j.fertnstert.2013.02.039 · Cited by 33
Cross-sectional and longitudinal determinants of serum sex hormone binding globulin (SHBG) in a cohort of community-dwelling men
Gyawali, P., Martin, S. A., Heilbronn, L. K., Vincent, A. D., Jenkins, A. J., Januszewski, A. S., Taylor, A. W., Adams, R. J. T., O’Loughlin, P. D., & Wittert, G. A. (2018) · PLOS ONE · doi:10.1371/journal.pone.0200078 · Cited by 35
“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].”
BackgroundInfluential
Comments on ‘Low serum sex hormone binding globulin is associated with nonalcoholic fatty liver disease in type 2 diabetic patients’
Wang, C., & Swerdloff, R. S. (2014) · Clinical Endocrinology · doi:10.1111/cen.12430 · Cited by 3
Androgen therapy in women, beyond libido
Davis, S. R. (2013) · Climacteric · doi:10.3109/13697137.2013.801736 · Cited by 39
Intra-abdominal adipose tissue is independently associated with sex-hormone binding globulin in premenopausal women
Azrad, M., Gower, B. A., Hunter, G. R., & Nagy, T. R. (2012) · Obesity · doi:10.1038/oby.2011.375 · Cited by 33
Insulin resistance and sex hormone-binding globulin are independently correlated with low free testosterone levels in obese males
Souteiro, P., Belo, S., Oliveira, S. C., Neves, J. S., Magalhães, D. M. D. S., Pedro, J. M. P., Bettencourt‐Silva, R., Costa, M. M., Varela, A. T. I. F., Queirós, J., et al. (2018) · Andrologia · doi:10.1111/and.13035 · Cited by 31
Combined Association of Vitamin D and Sex Hormone Binding Globulin With Nonalcoholic Fatty Liver Disease in Men and Postmenopausal Women
Wang, N., Zhai, H., Zhu, C., Qin, L., Han, B., Chen, Y., Zhu, C., Chen, Y., Xia, F., Lin, D., et al. (2016) · Medicine · doi:10.1097/md.0000000000002621 · Cited by 35
Impact of Metabolic Syndrome Factors on Testosterone and SHBG in Type 2 Diabetes Mellitus and Metabolic Syndrome
Mohammed, M., Al‐Habori, M., Abdullateef, A. A., & Saif-Ali, R. (2018) · Journal of Diabetes Research · doi:10.1155/2018/4926789 · Cited by 29
“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…”
Background
Cross‐sectional association between testosterone, sex hormone‐binding globulin and metabolic syndrome: The Healthy Twin Study
Moon, 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
Comparison of hormonal and metabolic markers after a high-fat, Western meal versus a low-fat, high-fiber meal in women with polycystic ovary syndrome
Katcher, H. I., Kunselman, A. R., Dmitrović, R., Demers, L. M., Gnatuk, C. L., Kris‐Etherton, P. M., & Legro, R. S. (2008) · Fertility and Sterility · doi:10.1016/j.fertnstert.2008.01.035 · Cited by 32
“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).”
Role of sex steroids, intrahepatic fat and liver enzymes in the association between SHBG and metabolic features
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
SHBG-C57BL/ksJ-db/db: A New Mouse Model to Study SHBG Expression and Regulation During Obesity Development
Sáez‐López, C., Rivera-Giménez, M., Hernández, C., Simó, R., & Selva, D. M. (2015) · Endocrinology · doi:10.1210/en.2015-1677 · Cited by 29
Self-citation
The hepatic lipidome and HNF4α and SHBG expression in human liver
Winters, S. J., Scoggins, C. R., Appiah, D., & Ghooray, D. T. (2020) · Endocrine Connections · doi:10.1530/ec-20-0401 · Cited by 28
“In other experiments using HepG2 cells, however, palmitoyl-CoA was reported to suppress HNF4 transcription (25).”
Background
Non-alcoholic fatty liver disease is an influencing factor for the association of SHBG with metabolic syndrome in diabetes patients
Hua, X., Li, M., Pan, F., Xiao, Y., Cui, W., & Hu, Y. (2017) · Scientific Reports · doi:10.1038/s41598-017-15232-9 · Cited by 28
Metabolic syndrome, circulating RBP4, testosterone, and SHBG predict weight regain at 6 months after weight loss in men
Wang, P., Menheere, P. P. C. A., Astrup, A. V., Andersen, M. R., van Baak, M. A., Larsen, T. M., Jebb, S. A., Kafatos, A., Pfeiffer, A. F. H., Martínez, J. A., et al. (2013) · Obesity · doi:10.1002/oby.20311 · Cited by 28
“SHBG is produced in the liver, and its production is inhibited by the monosaccharide-induced lipogenesis (35).”
Background
Effect of subcutaneous depo-medroxyprogesterone acetate (DMPA-SC) on serum androgen markers in normal-weight, obese, and extremely obese women
Segall‐Gutierrez, P., Du, J., Niu, C., Ge, M. X., Tilley, I., Mizraji, K., & Stanczyk, F. Z. (2012) · Contraception · doi:10.1016/j.contraception.2012.05.148 · Cited by 26
Resveratrol Increases Hepatic SHBG Expression through Human Constitutive Androstane Receptor: a new Contribution to the French Paradox
Sáez‐López, C., Briansó‐Llort, L., Torres‐Torronteras, J., Simó, R., Hammond, G. L., & Selva, D. M. (2017) · Scientific Reports · doi:10.1038/s41598-017-12509-x · Cited by 25
Self-citation
Pre‐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
“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).”
Background
Nuclear 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
Influence of Insulin on LH, Testosterone and SHBG in Various PCOS Categories Based on the Mode of Secretion of LH in Relation to FSH Levels
Malini, N. (2021) · Acta Endocrinologica (Bucharest) · doi:10.4183/aeb.2021.313 · Cited by 33
“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).”
Background
New 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
“These studies indicate that decreased insulin levels do not cause an increase in SHBG [38].”
Influential
The relationships of sex hormone‐binding globulin, total testosterone, androstenedione and free testosterone with metabolic and reproductive features of polycystic ovary syndrome
Simons, 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
SHBG as a Marker of NAFLD and Metabolic Impairments in Women Referred for Oligomenorrhea and/or Hirsutism and in Women With Sexual Dysfunction
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
“secretion downregulates SHBG production (63).”
The Role of Metformin in Metabolic Disturbances during Pregnancy: Polycystic Ovary Syndrome and Gestational Diabetes Mellitus
Rojas, J., Chávez-Castillo, M., & Bermúdez, V. (2014) · International Journal of Reproductive Medicine · doi:10.1155/2014/797681 · Cited by 26
“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
“Furthermore, we have also demonstrated that palmitate, a saturated fatty acid, downregulates human SHBG production by affecting HNF-4A gene expression [10].”
BackgroundMethodInfluentialSelf-citation
Plasma Sex Hormone-binding Globulin, Corticosteroid-binding Globulin, Cortisol, and Free Cortisol Levels in Outpatients Attending a Lipid Disorders Clinic: A Cross-sectional Study of 1137 Subjects
Lewis, J. G., Borowski, K. K., Shand, B. I., George, P. M., & Scott, R. S. (2010) · Hormone and Metabolic Research · doi:10.1055/s-0029-1243260 · Cited by 22
Serum sex hormone-binding globulin is a mediator of the association between intrahepatic lipid content and type 2 diabetes: the Maastricht Study
Simons, P. I. H. G., Valkenburg, O., van de Waarenburg, M. P. H., van Greevenbroek, M. M. J., Kooi, M. E., Jansen, J. F. A., Schalkwijk, C. G., Stehouwer, C. D. A., & Brouwers, M. C. G. J. (2022) · Diabetologia · doi:10.1007/s00125-022-05790-7 · Cited by 26
“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.”
Background
Follicle stimulating hormone, its novel association with sex hormone binding globulin in men and postmenopausal women
Wang, 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
Intensive insulin therapy increases sex hormone-binding globulin in newly diagnosed type 2 diabetic patients
Tong, G., Hua, X., Zhong, Y., Zhang, K., Gu, G., Feng, W., Huang, H., Wang, W., Li, L., Sun, Y., et al. (2013) · European Journal of Endocrinology · doi:10.1530/eje-13-0557 · Cited by 23
Ketogenic Diet as a Possible Non-pharmacological Therapy in Main Endocrine Diseases of the Female Reproductive System: A Practical Guide for Nutritionists
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 25
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 26

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.
ORCID: Selva, David M.
Hogeveen, Kevin N.
Hammond, Geoffrey L.
Venue: Journal of Clinical Investigation
Publisher: American Society for Clinical Investigation
Published: 2007-11-08
Volume: 117
Issue: 12
Pages: 3979-87
ISSN: 0021-9738 (ISSN-L)
DOI: 10.1172/jci32249
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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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

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