RT Journal Article
T1 Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin
A1 Pérez Luz, Sara
A1 Lalchandani, Jaanam
A1 Matamala, Nerea
A1 Barrero, Maria Jose
A1 Gil-Marín, Sara
A1 Ramos Del Saz, Sheila
A1 Varona, Sarai
A1 Monzón, Sara
A1 Cuesta, Isabel
A1 Justo Alonso, Iago
A1 Marcacuzco Quinto, Alberto Alejandro
A1 Hierro, Loreto
A1 Garfia Castillo, María Cristina
A1 Gómez Mariano, Gema
A1 Janciauskiene, Sabina
A1 Martínez Delgado, Beatriz
AB 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 patientderived 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.
PB MDPI
YR 2023
FD 2023-08-05
LK https://hdl.handle.net/20.500.14352/102052
UL https://hdl.handle.net/20.500.14352/102052
LA eng
NO Pérez-Luz, S.; Lalchandani, J.; Matamala, N.; Barrero, M.J.; Gil-Martín, S.; Saz, S.R.-D.; Varona, S.; Monzón, S.; Cuesta, I.; Justo, I.; et al. Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin. Int. J. Mol. Sci. 2023, 24, 12472. https://doi.org/ 10.3390/ijms241512472
NO Author Contributions: S.P.-L., J.L., N.M., S.R.-D.S. and G.G.-M. isolated the organoids; S.P.-L., J.L., S.G.-M. and G.G.-M. performed the experiments; S.V., S.M. and I.C. analyzed data; I.J., A.M., L.H. and C.G. provided liver biopsies; S.P.-L. and G.G.-M. wrote the manuscript; M.J.B. and S.J. analyzed data and contributed to critical data interpretation; B.M.-D. conceived and supervised the study. All authors have provided comments on the manuscript. All authors have read and agreed to the published version of the manuscript.
NO Instituto de Salud Carlos III
DS Docta Complutense
RD 18 abr 2025