Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene
David M. Selva, … , Sheila M. Innis, Geoffrey L. Hammond
David M. Selva, … , Sheila M. Innis, Geoffrey L. Hammond
Published November 8, 2007
Citation Information: J Clin Invest. 2007;117(12):3979-3987. https://doi.org/10.1172/JCI32249.
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Monosaccharide-induced lipogenesis regulates the human hepatic sex hormone–binding globulin gene

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–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.

Authors

David M. Selva, Kevin N. Hogeveen, Sheila M. Innis, Geoffrey L. Hammond

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Figure 5

Competition between HNF-4α and COUP-TF1 at a cis-element within the human SHBG promoter regulates its activity.

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Competition between HNF-4α and COUP-TF1 at a cis-element within the huma...
(A) HNF-4α levels were reduced in HepG2 cells after transient transfection of an HNF-4α siRNA versus a control siRNA oligonucleotide (left), and siRNA-mediated downregulation of HNF-4α reduced human SHBG promoter activity in a luciferase reporter gene assay (right). Data points are shown as mean ± SD of triplicates; **P < 0.01 compared with cells treated with an siRNA control. (B) ChIP assays of HNF-4α and COUP-TF1 binding to the human SHBG promoter (top). As a control for the ChIP, anti–RNA polymerase (RNApol) antibodies were used with human-specific oligonucleotide primers to PCR amplify the GAPDH promoter (bottom). A nonspecific mouse IgG was used in ChIP reactions to control for nonspecific immunoprecipitation. Positive PCR controls of sheared genomic DNA templates indicated the integrity of the input DNA used in the ChIP reactions. (C) Reduction of COUP-TF1 mRNA in HepG2 cells after siCOUP-TF1 treatment (left) did not influence the activity of the human SHBG promoter under basal conditions (right). Data points are shown as mean ± SD of triplicates. (D) Reduction of human SHBG promoter activity after treatment with siHNF-4α was mitigated by cotreatment with siCOUP-TF1. Data points are shown as mean ± SD of triplicates; *P < 0.05, **P < 0.01 compared with cells treated with an siRNA control.