2026-04-27T03:43:13Zhttps://repisalud.isciii.es/rest/oai/requestoai:repisalud.isciii.es:20.500.12105/163532025-06-25T09:57:17Zcom_20.500.12105_15322com_20.500.12105_2051com_20.500.12105_2052col_20.500.12105_16963col_20.500.12105_19616col_20.500.12105_25179
Repisalud
author
Perez-Luz, Sara
author
Lalchandani, Jaanam
author
Matamala, Nerea
author
Barrero, Maria
author
Gil-MartÃn, Sara
author
Ramos-Del Saz, Sheila
author
Varona Fernandez, Sarai
author
Monzon-Fernandez, Sara
author
Cuesta de la Plaza, Isabel
author
Justo, Iago
author
Marcacuzco, Alberto
author
Hierro, Loreto
author
Garfia, Cristina
author
Gomez-Mariano, Gema Maria
author
Janciauskiene, Sabina
author
Martinez-Delgado, Beatriz
funder
Instituto de Salud Carlos III
2023-08-28T08:14:05Z
2023-08-28T08:14:05Z
2023-08-05
Int J Mol Sci. 2023 Aug 5;24(15):12472.
http://hdl.handle.net/20.500.12105/16353
37569847
10.3390/ijms241512472
1422-0067
International journal of molecular sciences
Different mutations in the SERPINA1 gene result in alpha-1 antitrypsin (AAT) deficiency and in an increased risk for the development of liver diseases. More than 90% of severe deficiency patients are homozygous for Z (Glu342Lys) mutation. This mutation causes Z-AAT polymerization and intrahepatic accumulation which can result in hepatic alterations leading to steatosis, fibrosis, cirrhosis, and/or hepatocarcinoma. We aimed to investigate lipid status in hepatocytes carrying Z and normal M alleles of the SERPINA1 gene. Hepatic organoids were developed to investigate lipid alterations. Lipid accumulation in HepG2 cells overexpressing Z-AAT, as well as in patient-derived hepatic organoids from Pi*MZ and Pi*ZZ individuals, was evaluated by Oil-Red staining in comparison to HepG2 cells expressing M-AAT and liver organoids from Pi*MM controls. Furthermore, mass spectrometry-based lipidomics analysis and transcriptomic profiling were assessed in Pi*MZ and Pi*ZZ organoids. HepG2 cells expressing Z-AAT and liver organoids from Pi*MZ and Pi*ZZ patients showed intracellular accumulation of AAT and high numbers of lipid droplets. These latter paralleled with augmented intrahepatic lipids, and in particular altered proportion of triglycerides, cholesterol esters, and cardiolipins. According to transcriptomic analysis, Pi*ZZ organoids possess many alterations in genes and cellular processes of lipid metabolism with a specific impact on the endoplasmic reticulum, mitochondria, and peroxisome dysfunction. Our data reveal a relationship between intrahepatic accumulation of Z-AAT and alterations in lipid homeostasis, which implies that liver organoids provide an excellent model to study liver diseases related to the mutation of the SERPINA1 gene.
eng
AAT aggregates
Alpha-1 antitrypsin (AAT)
Alpha-1 antitrypsin deficiency (AATD)
Lipid accumulation
Liver organoids
Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin.
research article
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QuantitativeLipidProfilingReveals_2023.pdf.txt