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 1

Hepatic production of SHBG in mice expressing human SHBG transgenes (21) is reduced after feeding diets with high monosaccharide content or increasing blood glucose levels by streptozotocin treatment.

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Hepatic production of SHBG in mice expressing human SHBG transgenes (21)...
(A and B) Mice were fed high-sucrose or isocaloric basal diets for 7 days (3 per group), and the diets were then reversed in two 7-day cycles. Serum SHBG levels are expressed as mean ± SEM relative to pretreatment levels to compensate for between-animal variability (A). At day 21, human SHBG mRNA abundance was determined in relation to 18S RNA (mean ± SEM) in liver and kidney; **P < 0.01 compared with basal diet values (B). (C) Serum SHBG levels in mice expressing a human SHBG transgene lacking a USF-binding site in the promoter (24) were reduced by feeding a high-sucrose diet. Animals (3 per group) were fed a basal diet (squares) or a high-sucrose diet (diamonds) for 7 days, and diets were then reversed for 7 days. Serum SHBG measurements (mean ± SEM) are expressed relative to pretreatment levels. (D) Serum SHBG levels (mean ± SEM) were reduced relative to pretreatment levels in human SHBG transgenic mice (3–4 per group) fed equicaloric diets containing high glucose, sucrose, or fructose, when compared with a basal diet. (E) Human SHBG transgenic mice treated with streptozotocin were maintained on a basal diet for 11 days, followed by a high-sucrose diet (phase I) and the basal diet (phase II). Serum SHBG levels (mean ± SEM) are expressed relative to pretreatment values.