title: 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-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.
authors.affiliation: Department of Obstetrics and Gynecology, University of British Columbia, Child and Family Research Institute, Vancouver, British Columbia, Canada.
authors.forename: David M
authors.initials: DM
authors.lastname: Selva
authors.forename: Kevin N
authors.initials: KN
authors.lastname: Hogeveen
authors.forename: Sheila M
authors.initials: SM
authors.lastname: Innis
authors.forename: Geoffrey L
authors.initials: GL
authors.lastname: Hammond
mesh_terms: D000328:Adult; D000818:Animals; D015415:Biomarkers / Q000097:blood; D045744:Cell Line, Tumor; D002645:Chickens / Q000235:genetics; D002648:Child; D002675:Child, Preschool; D005632:Fructose / Q000009:adverse effects / Q000494:pharmacology*; D005786:Gene Expression Regulation / Q000187:drug effects / Q000235:genetics; D005947:Glucose / Q000009:adverse effects / Q000494:pharmacology*; D012739:Gonadal Steroid Hormones / Q000097:blood; D051538:Hepatocyte Nuclear Factor 1-alpha / Q000235:genetics / Q000378:metabolism; D051557:Hepatocyte Nuclear Factor 4 / Q000378:metabolism*; D006801:Humans; D050155:Lipogenesis / Q000187:drug effects* / Q000235:genetics; D024821:Metabolic Syndrome / Q000097:blood / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D050177:Overweight / Q000097:blood / Q000235:genetics / Q000473:pathology; D012738:Sex Hormone-Binding Globulin / Q000096:biosynthesis* / Q000235:genetics; D013549:Sweetening Agents / Q000009:adverse effects / Q000494:pharmacology*
chemical_list: D015415:Biomarkers; D012739:Gonadal Steroid Hormones; C496487:HNF1A protein, human; C496592:HNF4A protein, human; D051538:Hepatocyte Nuclear Factor 1-alpha; D051557:Hepatocyte Nuclear Factor 4; C496488:Hnf1a protein, mouse; D012738:Sex Hormone-Binding Globulin; D013549:Sweetening Agents; D005632:Fructose; D005947:Glucose