α-Crystallin is a target gene of the farnesoid X-activated receptor in human livers

alpha-Crystallins comprise 35% of soluble proteins in the ocular lens and possess chaperone-like functions. Furthermore, the alpha A subunit ( alpha A-crystallin) of alpha 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 alpha A-crystallin is expressed in human livers and is regulated by farnesoid X-activated receptor ( FXR) in response to FXR agonists. alpha A-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 realtime PCR analyses confirmed that alpha A-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 alpha A-crystallin gene. Importantly, immunohistochemical staining of human liver sections showed increased alpha A-crystallin expression in cholangiocytes and hepatocytes. As a member of the small heat shock protein family possessing chaperone-like activity, alpha A-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.