Modulation of the longevity proteins FOXO3a and SIRT1 by chorionic gonadotropin prevents hepatocellular injury during acute liver inflammation

During pregnancy, the clinical improvement of autoimmune hepatitis is frequently observed. The understanding of this phenomenon is incomplete both from the side of the immune system and the liver. Using a murine model of autoimmune hepatitis and adult human hepatocytes in primary culture, we could show that the pregnancy hormone, human chorionic gonadotropin (hCG) regulates the longevity proteins FOXO3a and SIRT1, which permit hepatocytes to tolerate destructive T cell attack and protects mice from T cell-dependent liver injury. hCG-signaling induced the nuclear exclusion of wild type, but not phosphorylation-resistant or DNA-binding defective forms of FOXO3a in hepatocytes, decreased its transcriptional activity and concomitantly reduced transcription of its target genes Bim and Puma. The cytoprotective effect of hCG was dependent on the NAD-dependent deacetylase SIRT1, that upon activation of the hCG signaling pathway translocates to the nucleus in its phosphorylated form. Our findings provide novel insights on liver protection during pregnancy. Given that humans tolerate hCG very well, the modulation of FOXO3a and SIRT1 by hCG opens new perspectives for therapeutic intervention in a wide range of liver diseases.

chorionic gonadotropin - cytoprotection - longevity proteins