Novel insights in SHBG regulation and clinical implications

• Hyperinsulinemia does not downregulate hepatic SHBG production in obesity.
• Proinflammatory cytokines and hepatic steatosis downregulate SHBG in obesity.
• Monosaccharides and palmitate downregulate and oleate upregulates hepatic SHBG.
• Plasma SHBG could be a biomarker of the degree of inflammation in metabolic disorders.

Sex hormone-binding globulin (SHBG) is produced and secreted by the liver into the bloodstream where it binds sex steroids and regulates their bioavailability. Traditionally, body mass index (BMI) was thought to be the major determinant of SHBG concentrations and hyperinsulinemia the main cause for low SHBG levels found in obesity. However, no mechanisms have ever been described. Emerging evidence now shows that liver fat content rather than BMI is a strong determinant of circulating SHBG. In this review we discuss evidence demonstrating that insulin might not regulate SHBG production, describe putative molecular mechanisms by which proinflammatory cytokines downregulate SHBG, and comment on recent findings suggesting dietary SHBG regulation. Finally, clinical implications of all of these findings and future perspectives are discussed.