Alpha‐1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid–Inducible Manner

• DOI: 10.1111/liv.16207
• Publication Date: 2024-12-12T15:54:28Z
• Authors: Igor Spivak; Nurdan Guldiken; Valentyn Usachov; Frank Schaap; Steven W.M. Olde ...; Marion Bouchecareilh; Alexandra Lehmann; Lei Fu; Fa‐Rong Mo; Gökce Kobazi Ensari; Franziska Hufnagel; Malin Fromme; Christian Preisinger; Pavel Strnad
• Keywords: Male; Adult; 0301 basic medicine; genetic liver disease; Bile Acids and Salts/metabolism; 610; Transgenic; Mice; 03 medical and health sciences; Heat-Shock Proteins/metabolism genetics; Animals; Humans; alpha 1-Antitrypsin Deficiency/genetics metabolism pathology; Endoplasmic Reticulum Chaperone BiP; info:eu-repo/classification/ddc/610; alpha 1-Antitrypsin/genetics metabolism; a-1 antitrypsin deficiency; Liver/metabolism pathology; Hepatocytes/metabolism drug effects pathology; Inclusion Bodies/metabolism pathology; Middle Aged; ER chaperone; Mutation; rare liver disease; Female; Original Article; cholestatic liver injury

ABSTRACT Background and Aims The homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha‐1 antitrypsin (AAT) deficiency leads to liver disease via hepatocellular AAT aggregation. We systematically analysed composition aggregates studied impact bile acids. Methods inclusions were isolated from livers overexpressing mice PIZZ humans fluorescence‐activated immunomagnetic sorting (FACS/MACS), while insoluble proteins obtained Triton‐X extraction. Inclusion was evaluated through mass‐spectrometry (MS), immunoblotting immunostaining. Hepatocytes with versus without microdissection. Serum acids assessed in 57 subjects 19 controls. Mice administered 2% cholic acid (CA)–supplemented chow for 7 days. Results MS identified key endoplasmic reticulum chaperone 78 kDa glucose‐regulated protein (GRP78) FACS/MACS pulldowns. GRP78 also enriched fractions wild types detected fractions/MACS isolates explants. In cultured cells/primary hepatocytes, overexpression associated increased mRNA/protein levels. human livers, hepatocytes had higher levels than without. displayed serum controls highest seen individuals injury/fibrosis. mice, CA‐mediated challenge resulted injury translocation into aggregates. Conclusions Our results demonstrate that is sequestered within inclusions. Bile accumulation, as disease, may promote segregation thereby augment damage. Trial Registration: NCT02929940