Endocrine Abstracts

Patients suffering from low-grade chronic inflammatory diseases such as rheumatoid arthritis, osteoarthritis, diabetes and obesity have low plasma SHBG levels. These diseases are characterized among other features by high plasma IL1β levels. The aim of the present study is to explore whether IL1β could regulate hepatic SHBG production to account for low SHBG levels in these diseases. We provide evidence that daily IL1β treatment reduces SHBG production in HepG2 cells. The IL1β effect on human SHBG expression was mediated by the downregulation of HNF-4A via the JNK/c-Jun signalling pathway. Daily TNFα treatment of human SHBG transgenic mice reduced plasma SHBG and hepatic HNF-4α mRNA and protein levels. Importantly, SHBG levels were reduced by IL1β within 24 h in vitro in HepG2 cells and in vivo in human SHBG transgenic mice. The human SHBG promoter did not respond directly to c-Jun and its transcription was reduced by the rapid decrease in HNF-4α levels that occurs within 2–4 h of IL1β treatment. Our results show the molecular mechanisms by which IL1β reduces hepatic SHBG production suggesting that IL1β plasma levels are an important factor in accounting for the low SHBG levels in chronic low-grade inflammatory diseases.

Declaration of interest: The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research project.

Funding: This work was supported, however, funding details unavailable.