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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene
David M. Selva,1,2 Kevin N. Hogeveen,2,3 Sheila M. Innis,4 and Geoffrey L. Hammond1,2
1Department of Obstetrics and Gynecology, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada. 2University of Western Ontario, London, Ontario, Canada. 3UMR-INSERM U449, Faculté de Médecine RTH Laënnec, Lyon, France. 4Department of Pediatrics, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada.
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–4α (HNF-4α) and replacement of HNF-4α 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-4α 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-4α and reduced SHBG expression in HepG2 cells.
Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4α 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.
Published online, November 2007
J. Clin. Invest. doi:10.1172/JCI32249
What this means:
Recent research published in the Journal of Clinical Investigation showed a high-fructose diet (such as high-fructose corn syrup, present in virtually all processed foods and beverages) decreased levels of sex-hormone-binding globulin in the liver by 80%, resulting in higher levels of circulating estrogen.
This has profound implications for breast cancer, since breast cancer's growth can be fueled by estrogen circulating in our blood.
David M. Selva,1,2 Kevin N. Hogeveen,2,3 Sheila M. Innis,4 and Geoffrey L. Hammond1,2
1Department of Obstetrics and Gynecology, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada. 2University of Western Ontario, London, Ontario, Canada. 3UMR-INSERM U449, Faculté de Médecine RTH Laënnec, Lyon, France. 4Department of Pediatrics, University of British Columbia, and Child and Family Research Institute, Vancouver, British Columbia, Canada.
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–4α (HNF-4α) and replacement of HNF-4α 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-4α 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-4α and reduced SHBG expression in HepG2 cells.
Thus, monosaccharide-induced lipogenesis reduced hepatic HNF-4α 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.
Published online, November 2007
J. Clin. Invest. doi:10.1172/JCI32249
What this means:
Recent research published in the Journal of Clinical Investigation showed a high-fructose diet (such as high-fructose corn syrup, present in virtually all processed foods and beverages) decreased levels of sex-hormone-binding globulin in the liver by 80%, resulting in higher levels of circulating estrogen.
This has profound implications for breast cancer, since breast cancer's growth can be fueled by estrogen circulating in our blood.
