SAHA increases chaperone expression and reduces Z-alpha-1-antitrypsin polymers in a patient specific iPSC-based liver model for alpha-1-antitrypsin deficiency

Background The severe phenotype of alpha-1-antitrypsin deficiency (AATD) is typically caused by the Z-mutation within the SERPINA1 gene. The Glu342Lys substitution causes misfolding and polymerisation of the alpha-1-antitrypsin (AAT) protein and its accumulation in the ER. This increases the susceptibility of hepatocytes towards ER-stress. Methods Here, we present an induced pluripotent stem cell (iPSC)-based hepatic model to study AATD. We tested 4 distinct compounds on our cells that have been reported to reduce ZAAT polymers in hepatocytes. We quantified their effect via immunocytochemistry and performed next generation sequencing for the most effective compounds: Carbamazepine (CBZ) and Suberoylanilide hydroxamic acid (SAHA). Results We demonstrate that iPSCs from AATD patients differentiate equally well to hepatocyte-like cells (HLCs) as control iPSCs. We detected ZAAT polymers in patient-derived HLCs which could be reduced by SAHA or CBZ treatment. Transcriptome analyses revealed major differences in metabolism and signalling between control and AATD HLCs and indicated increased stress levels affecting intracellular organelles. Importantly, the transcriptomes of control and patient-derived cells separated into distinct clusters with respect to the expression of Heat-shock protein (HSP) encoding genes. Conclusion SAHA treatment increased expression of various HSPs which might contribute towards reduced ZAAT polymers.