Alpha-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 alphaA subunit (alphaA-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 alphaA-crystallin is expressed in human livers and is regulated by farnesoid X-activated receptor (FXR) in response to FXR agonists. AlphaA-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 alphaA-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 alphaA-crystallin gene. Importantly, immunohistochemical staining of human liver sections showed increased alphaA-crystallin expression in cholangiocytes and hepatocytes. As a member of the small heat shock protein family possessing chaperone-like activity, alphaA-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.
Lee
Florence Y
FY
Department of Biological Chemistry, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA.
Kast-Woelbern
Heidi R
HR
Chang
Jenny
J
Luo
Guizhen
G
Jones
Stacey A
SA
Fishbein
Michael C
MC
Edwards
Peter A
PA
D001647:Bile Acids and Salts / Q000502:physiology; D002460:Cell Line; D004268:DNA-Binding Proteins / Q000819:agonists / Q000502:physiology*; D004742:Enhancer Elements, Genetic; D005786:Gene Expression Regulation / Q000502:physiology*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007438:Introns / Q000502:physiology; D008024:Ligands; D008099:Liver / Q000378:metabolism*; D018160:Receptors, Cytoplasmic and Nuclear; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014157:Transcription Factors / Q000819:agonists / Q000502:physiology*; D014158:Transcription, Genetic; D014162:Transfection; D038201:alpha-Crystallins / Q000096:biosynthesis / Q000235:genetics*; D000099150:Receptor, Farnesoid X-Activated
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; D008024:Ligands; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D038201:alpha-Crystallins; D000099150:Receptor, Farnesoid X-Activated