2026-04-27T03:43:08Zhttps://repisalud.isciii.es/rest/oai/request

oai: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

00925njm 22002777a 4500 dc Perez-Luz, Sara author Lalchandani, Jaanam author Matamala, Nerea author Barrero, Maria author Gil-Martín, 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 author 2023-08-05 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. 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 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.