Evidence map›Paper›PMID 39665869›Full record

ArticleLiver international : official journal of the International Association for the Study of the Liver2025

Alpha-1 Antitrypsin Inclusions Sequester GRP78 in a Bile Acid-Inducible Manner.

Igor Spivak, Nurdan Guldiken, Valentyn Usachov, Frank Schaap, Steven W M Olde Damink, Marion Bouchecareilh, Alexandra Lehmann, Lei Fu, Fa-Rong Mo, Gökce Kobazi Ensari and 4 more

Registry-linked trialAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Liver international : official journal of the International Association for the Study of the Liver, 2025. The graph could read no effect estimate from its abstract, so it casts no vote on the map. It is linked to trial NCT02929940 (Multi-center Study of the Liver Disease in European Patients With alpha1-antitrypsin Deficiency), which is not on this map. Cited by 3 papers.

0numbers the graph read from it
0cells of the map it votes in
3citing papers in PubMed
–field-weighted citation impact
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

NCT02929940 unknown statusnot on this map

Multi-center Study of the Liver Disease in European Patients With alpha1-antitrypsin Deficiency

Typeobservational_patient_registrySponsorRWTH Aachen UniversityRan2015 to 2020Enrolled500Conditionsalpha1-antitrypsin DeficiencyArmsNo intervention
3 · Its place in the literature

Who cites it

3 citing papers in PubMed.

  1. Article
  2. Article
  3. Review
4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

14 authors.

Igor SpivakMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.ORCID 0009-0000-9446-6458
Nurdan GuldikenMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Valentyn UsachovMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Frank SchaapDepartment of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.
Steven W M Olde DaminkDepartment of Surgery, Maastricht University Medical Center and NUTRIM School of Nutrition and Translational Research in Metabolism, Maastricht University, Maastricht, Netherlands.
Marion BouchecareilhINSERM, CNRS, U1312 BRIC, University Bordeaux, Bordeaux, France.ORCID 0000-0001-9233-4152
Alexandra LehmannINSERM, CNRS, U1312 BRIC, University Bordeaux, Bordeaux, France.
Lei FuMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Fa-Rong MoMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Gökce Kobazi EnsariMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Franziska HufnagelMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.
Malin FrommeMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.ORCID 0000-0003-0382-5705
Christian PreisingerInterdisciplinary Center for Clinical Research (IZKF), University Hospital RWTH Aachen, Aachen, Germany.
Pavel StrnadMedical Department III, Gastroenterology, Metabolic Diseases and Intensive Care, University Hospital RWTH Aachen, Aachen, Germany.ORCID 0000-0002-7122-6379

Funding

ADAAT Alpha-1 FranceDeutsche Forschungsgemeinschaft SFB 1382Deutsche Forschungsgemeinschaft STR 1095/6-1FilfoieMedizinische Fakultät, RWTH Aachen UniversityRégion Nouvelle-Aquitaine
6 · The paper itself

Abstract

BACKGROUND AND

aimsThe homozygous PiZ mutation (PIZZ genotype) constitutes the predominant cause of severe alpha-1 antitrypsin (AAT) deficiency and leads to liver disease via hepatocellular AAT aggregation. We systematically analysed the composition of AAT aggregates and studied the impact of bile acids.

methodsAAT inclusions were isolated from livers of PiZ overexpressing mice and PIZZ humans via fluorescence-activated and immunomagnetic sorting (FACS/MACS), while insoluble proteins were obtained via Triton-X extraction. Inclusion composition was evaluated through mass-spectrometry (MS), immunoblotting and immunostaining. Hepatocytes with versus without AAT aggregates were obtained via microdissection. Serum bile acids were assessed in 57 PIZZ subjects and 19 controls. Mice were administered 2% cholic acid (CA)-supplemented chow for 7 days.

resultsMS identified the key endoplasmic reticulum chaperone 78 kDa glucose-regulated protein (GRP78) in FACS/MACS pulldowns. GRP78 was also enriched in insoluble fractions from PiZ mice versus wild types and detected in insoluble fractions/MACS isolates from PIZZ liver explants. In cultured cells/primary hepatocytes, PiZ overexpression was associated with increased GRP78 mRNA/protein levels. In human livers, hepatocytes with AAT aggregates had higher GRP78 levels than hepatocytes without. PIZZ subjects displayed higher serum bile acid levels than controls and the highest levels were seen in individuals with liver injury/fibrosis. In PiZ mice, CA-mediated bile acid challenge resulted in increased liver injury and translocation of GRP78 into the aggregates.

conclusionsOur results demonstrate that GRP78 is sequestered within AAT inclusions. Bile acid accumulation, as seen in PIZZ subjects with liver disease, may promote GRP78 segregation and thereby augment liver damage.

trial registrationNCT02929940.

Indexed as

alpha 1-Antitrypsinalpha 1-Antitrypsin DeficiencyBile Acids and SaltsEndoplasmic Reticulum Chaperone BiPHeat-Shock ProteinsHepatocytesAdultAnimalsFemaleHumansInclusion BodiesLiverMaleMiceMice, TransgenicMiddle Agedalpha 1-AntitrypsinBile Acids and SaltsEndoplasmic Reticulum Chaperone BiPHeat-Shock ProteinsHSPA5 protein, humanHspa5 protein, mouseSERPINA1 protein, humancholestatic liver injuryER chaperonegenetic liver diseaserare liver diseaseα‐1 antitrypsin deficiency

Identifiers

PMID39665869
PMCPMC11636636

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Registered trials

Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.