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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Research Article Metabolism

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 6

Increased palmitate levels in HepG2 cells as a result of monosaccharide or palmitoyl-CoA supplementation reduce HNF-4α levels and SHBG production.

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Increased palmitate levels in HepG2 cells as a result of monosaccharide ...
(A) Concentrations of human SHBG in the medium from untreated HepG2 cells and HepG2 cells after 5 days supplementation with 0.1–10 mM glucose or fructose. Data points are shown as mean ± SD of triplicates; *P < 0.05, **P < 0.01 compared with no glucose/fructose supplementation. In addition, the cellular content of palmitate was measured in cells after 5-day treatment with monosaccharides as indicated; **P < 0.01 compared with no glucose/fructose supplementation. (B) Concentrations of SHBG in medium from untreated HepG2 cells and HepG2 cells treated for 5 days with 1 μM or 10 μM palmitoyl-CoA. **P < 0.01 compared with no treatment. (C) HNF-4α and SHBG mRNA levels determined by RT-PCR in untreated HepG2 cells and HepG2 cells treated for 5 days with 1 μM or 10 μM palmitoyl-CoA. Cyclophilin A mRNA was amplified as an internal control. (D) Western blots of HNF-4α and actin in extracts of untreated HepG2 cells and HepG2 cells treated for 5 days with 1 μM or 10 μM palmitoyl-CoA. (E) The effects of 1–10 μM palmitoyl-CoA on human SHBG promoter activity was analyzed in HepG2 cells in the context of a luciferase reporter gene. Data points are mean ± SD of triplicate measurements; **P < 0.01 compared with no treatment.