Endocrine Abstracts

Human sex hormone-binding globulin (SHBG) is produced and secreted by the liver and it binds androgens and estrogens with high affinity. In blood, SHBG acts as a carrier of these sex steroids and regulates their bioavailability. Low plasma SHBG levels are associated with obesity, abdominal adiposity and metabolic syndrome, and predict the development of type 2 diabetes. In addition, an inverse relationship between plasma SHBG levels and risk of cardiovascular disease has been reported.

The SHBG gene has changed its tissue expression and therefore its function during the evolution. Rodents express the SHBG gene in the Sertoli cells of the testis. While in humans, the SHBG gene is expressed in the liver and in the germ cells of the testis. This change of function and tissue expression can be explained by the appearance during evolution of new footprinted regions in the human promoter and an alternative promoter. The generation of the human SHBG transgenic mice has allowed us to study the SHBG expression and regulation in vivo. We have used these mice and HepG2 cells to provide evidence that SHBG expression is downregulated by monosaccharides describing the underlying molecular mechanism. We have also demonstrated that proinflammatory cytokines (TNFα and IL1β) downregulates SHBG production by reducing HNF4α levels. These findings give a new explanation by which those patients suffering from chronic inflammation diseases such as obesity and type 2 diabetes have also low levels of SHBG. Noteworthy, our in vitro and in vivo studies showed that insulin does not regulate hepatic SHBG production. This finding contravenes the classic assumption that insulin is the primary regulator of SHBG production in the liver.

Finally, we have generated a new mouse model by crossing the human SHBG transgenic mice with the db/db mice. The generation of these mice has allowed us to study the regulation of the human SHBG during the development of obesity. As occurs in human obese subjects, these mice showed low plasma SHBG levels as well as low total and free testosterone levels. This model will permit us to further explore SHBG regulation and to design new therapeutic approaches.