Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome.
Sex hormone-binding globulin (SHBG) is the main transport binding protein for sex steroid hormones in plasma and regulates their accessibility to target cells. Plasma SHBG is secreted by the liver under the control of hormones and nutritional factors. In the human hepatoma cell line (HepG2), thyroid and estrogenic hormones, and a variety of drugs including the antioestrogen tamoxifen, the phytoestrogen, genistein and mitotane (Op'DDD) increase SHBG production and SHBG gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease SHBG expression by inducing lipogenesis, which reduces hepatic HNF-4alpha levels, a transcription factor that play a critical role in controlling the SHBG promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARgamma antagonists on SHBG expression. This mechanism provides a biological explanation for why SHBG is a sensitive biomarker of insulin resistance and the metabolic syndrome, and why low plasma SHBG levels are a risk factor for developing hyperglycemia and type 2 diabetes, especially in women. These important advances in our knowledge of the regulation of SHBG expression in the liver open new approaches for identifying and preventing metabolic disorder-associated diseases early in life.
Pugeat
Michel
M
Hospices Civils de Lyon, Fédération d'Endocrinologie, Groupement Hospitalier Est, Bron, France. michel.pugeat@chu-lyon.fr
Nader
Nancy
N
Hogeveen
Kevin
K
Raverot
Gérald
G
Déchaud
Henri
H
Grenot
Catherine
C
D017398:Alternative Splicing; D000818:Animals; D003924:Diabetes Mellitus, Type 2 / Q000378:metabolism; D012739:Gonadal Steroid Hormones / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism; D008099:Liver / Q000378:metabolism*; D024821:Metabolic Syndrome / Q000378:metabolism*; D009005:Monosaccharides / Q000378:metabolism; D047495:PPAR gamma / Q000378:metabolism; D012738:Sex Hormone-Binding Globulin / Q000235:genetics / Q000378:metabolism*; D013963:Thyroid Hormones / Q000378:metabolism
D012739:Gonadal Steroid Hormones; D007328:Insulin; D009005:Monosaccharides; D047495:PPAR gamma; D012738:Sex Hormone-Binding Globulin; D013963:Thyroid Hormones