Quantitative Lipid Profiling Reveals Major Differences between Liver Organoids with Normal Pi*M and Deficient Pi*Z Variants of Alpha-1-antitrypsin

Author:

Pérez-Luz Sara1ORCID,Lalchandani Jaanam1,Matamala Nerea1,Barrero Maria Jose2ORCID,Gil-Martín Sara13,Saz Sheila Ramos-Del1ORCID,Varona Sarai4ORCID,Monzón Sara4,Cuesta Isabel4,Justo Iago5,Marcacuzco Alberto5,Hierro Loreto6,Garfia Cristina7,Gomez-Mariano Gema1,Janciauskiene Sabina8,Martínez-Delgado Beatriz13ORCID

Affiliation:

1. Molecular Genetics and Genetic Diagnostic Units, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain

2. Models and Mechanisms Unit, Institute of Rare Diseases Research (IIER), Spanish National Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain

3. Centro de Investigación Biomédica en Red de Enfermedades Raras, CIBERER U758, 28029 Madrid, Spain

4. Bioinformatics Unit, Institute of Health Carlos III (ISCIII), 28220 Madrid, Spain

5. General and Digestive Surgery Department, Hospital 12 de Octubre, 28041 Madrid, Spain

6. Paediatric Hepatology Service, Research Institute of University Hospital La Paz, (IdiPAZ), 28046 Madrid, Spain

7. Digestive Department, Hospital 12 de Octubre, 28041 Madrid, Spain

8. Department of Respiratory Medicine, Member of the German Center for Lung Research (DZL), Biomedical Research in Endstage and Obstructive Lung Disease Hannover (BREATH), Hannover Medical School, 30625 Hannover, Germany

Abstract

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.

Funder

INSTITUTO DE SALUD CARLOS III

AESI

Publisher

MDPI AG

Subject

Inorganic Chemistry,Organic Chemistry,Physical and Theoretical Chemistry,Computer Science Applications,Spectroscopy,Molecular Biology,General Medicine,Catalysis

Reference55 articles.

1. The Discovery of A1-Antitrypsin and Its Role in Health and Disease;Janciauskiene;Respir. Med.,2011

2. Variants of SERPINA1 and the Increasing Complexity of Testing for Alpha-1 Antitrypsin Deficiency;Foil;Ther. Adv. Chronic Dis.,2021

3. α-1-Antitrypsin Variants and the Proteinase/Antiproteinase Imbalance in Chronic Obstructive Pulmonary Disease;Sinden;Am. J. Physiol. Lung Cell. Mol. Physiol.,2015

4. Alpha-1-Antitrypsin and Other Proteinase Inhibitors;Miravitlles;Curr. Opin. Pharmacol.,2012

5. Neutrophilic Panniculitis Associated with Alpha-1-Antitrypsin Deficiency: An Update;Blanco;Br. J. Dermatol.,2016

Cited by 5 articles. 订阅此论文施引文献 订阅此论文施引文献,注册后可以免费订阅5篇论文的施引文献,订阅后可以查看论文全部施引文献

同舟云学术

1.学者识别学者识别

2.学术分析学术分析

3.人才评估人才评估

"同舟云学术"是以全球学者为主线,采集、加工和组织学术论文而形成的新型学术文献查询和分析系统,可以对全球学者进行文献检索和人才价值评估。用户可以通过关注某些学科领域的顶尖人物而持续追踪该领域的学科进展和研究前沿。经过近期的数据扩容,当前同舟云学术共收录了国内外主流学术期刊6万余种,收集的期刊论文及会议论文总量共计约1.5亿篇,并以每天添加12000余篇中外论文的速度递增。我们也可以为用户提供个性化、定制化的学者数据。欢迎来电咨询!咨询电话:010-8811{复制后删除}0370

www.globalauthorid.com

TOP

Copyright © 2019-2024 北京同舟云网络信息技术有限公司
京公网安备11010802033243号  京ICP备18003416号-3