Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome

Michel Pugeat , Nancy Nader , Kevin Hogeveen , Gérald Raverot , Henri Déchaud , Catherine Grenot

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 gene promoter activity. In contrast, monosaccharides (glucose or fructose) effectively decrease expression by inducing lipogenesis, which reduces hepatic HNF-4α levels, a transcription factor that play a critical role in controlling the promoter. Interestingly, diminishing hepatic lipogenesis and free fatty acid liver biosynthesis also appear to be associated with the positive effects of thyroid hormones and PPARγ antagonists on 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 expression in the liver open new approaches for identifying and preventing metabolic disorder associated diseases early in life.

Mots clés: Life Sciences

Michel Pugeat, Nancy Nader, Kevin Hogeveen, Gérald Raverot, Henri Déchaud, et al.. Sex hormone-binding globulin gene expression in the liver: drugs and the metabolic syndrome. Molecular and Cellular Endocrinology, 2009, 316 (1), pp.53. ⟨10.1016/j.mce.2009.09.020⟩. ⟨hal-00550180⟩