Pregnane X Receptor Regulates Human Endocrine System by Inducing Sex Hormone-Binding Globulin Expression

Area of Science:

• Endocrinology
• Pharmacology
• Hepatology

Background:

• Sex hormone-binding globulin (SHBG) is a key carrier protein for sex hormones.
• The pregnane X receptor (PXR) is a critical regulator of drug metabolism and xenobiotic response.
• The role of PXR in SHBG regulation is not well understood.

Purpose of the Study:

• To investigate the role of PXR in the regulation of SHBG in humans.
• To characterize the molecular mechanisms underlying PXR-mediated SHBG regulation.

Main Methods:

• Clinical trials involving healthy volunteers treated with a PXR ligand (rifampicin).
• In vitro experiments using human 3D hepatocyte spheroids and HepG2 cells.
• Analysis of previously published chromatin immunoprecipitation sequencing (ChIP-seq) data.

Main Results:

• Rifampicin administration significantly increased serum SHBG levels in healthy volunteers.
• PXR activation induced SHBG mRNA expression in human hepatocyte spheroids.
• PXR antagonist SPA70 decreased SHBG mRNA expression.
• ChIP-seq analysis revealed a PXR binding site within the SHBG gene.

Conclusions:

• PXR is a novel regulator of serum SHBG in humans.
• PXR-mediated regulation of SHBG may influence sex hormone balance.
• This finding has implications for understanding the effects of PXR-activating drugs on metabolic health.