ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

Endocrine Abstracts (2019) 63 OC11.2 | DOI: 10.1530/endoabs.63.OC11.2

Molecular mechanisms regulating hepatic sex hormone-binding globulin production: clinical implications in human diseases

David Selva

Vall d’Hebron Research Institute (VHIR), Barcelona, Spain.

Human sex hormone-binding globulin (SHBG) is produced by the liver and secreted it into the circulation where it binds androgens and estrogens with high affinity. Therefore, SHBG acts as a carrier of these sex steroids and regulates their bioavailability. Low plasma SHBG levels are associated with obesity, fatty liver disease, 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 different transgenic mice expressing the human SHBG gene has allowed us to study the SHBG expression and regulation in vivo. We have used these mice and HepG2 cells to provide evidences that SHBG expression is regulated by thyroid hormone, proinflammatory cytokines (TNFα and IL1β), adiponectin, monosaccharides, olive oil and resveratrol (red wine). We have described the underlying molecular mechanisms by which all these factors regulate SHBG gene expression that involve the regulation of several transcription factors, such as HNF4α, PPARγ and CAR. These findings give an explanation of why diseases such as obesity, type 2 diabetes, hyperthyroidism, fatty liver disease and inflammatory disease (rheumatoid arthritis) have altered plasma SHBG levels. Finally, the generation of these mouse models has allowed us to demonstrate that SHBG overexpression can protect against obesity and fatty liver development point-out SHBG modulation as a novel therapeutic strategy for the treatment of these prevalent diseases.

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