α-Crystallin Is a Target Gene of the Farnesoid X-activated Receptor in Human Livers

Abstract α-Crystallins comprise 35% of soluble proteins in the ocular lens and possess chaperone-like functions. Furthermore, the αA subunit (αA-crystallin) of α crystallin is thought to be “lens-specific” as only very low levels of expression were detected in a few non-lenticular tissues. Here we report that human αA-crystallin is expressed in human livers and is regulated by farnesoid X-activated receptor (FXR) in response to FXR agonists. αA-Crystallin was identified in a microarray screen as one of the most highly induced genes after treatment of HepG2 cells with the synthetic FXR ligand GW4064. Northern blot and quantitative real-time PCR analyses confirmed that αA-crystallin expression was induced in HepG2-derived cell lines and human primary hepatocytes and hepatic stellate cells in response to either natural or synthetic FXR ligands. Transient transfection studies and electrophoretic mobility shift assays revealed a functional FXR response element located in intron 1 of the human αA-crystallin gene. Importantly, immunohistochemical staining of human liver sections showed increased αA-crystallin expression in cholangiocytes and hepatocytes. As a member of the small heat shock protein family possessing chaperone-like activity, αA-crystallin may be involved in protection of hepatocytes from the toxic effects of high concentrations of bile acids, as would occur in disease states such as cholestasis.