PUBLICATION
Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish
- Authors
- Fung, C., Wilding, B., Schittenhelm, R.B., Bryson-Richardson, R.J., Bird, P.I.
- ID
- ZDB-PUB-230212-34
- Date
- 2023
- Source
- International Journal of Molecular Sciences 24(3): (Journal)
- Registered Authors
- Bird, Phillip I., Bryson-Richardson, Robert, Fung, Connie
- Keywords
- ERAD, SERPINA1, liver, zebrafish, α-1-antitrypsin
- Datasets
- GEO:GSE215899
- MeSH Terms
-
- Animals
- Animals, Genetically Modified
- Cell Line
- Cholesterol
- Humans
- Liver
- Proteomics*
- Zebrafish*/genetics
- alpha 1-Antitrypsin/genetics
- PubMed
- 36768797 Full text @ Int. J. Mol. Sci.
Citation
Fung, C., Wilding, B., Schittenhelm, R.B., Bryson-Richardson, R.J., Bird, P.I. (2023) Expression of the Z Variant of α1-Antitrypsin Suppresses Hepatic Cholesterol Biosynthesis in Transgenic Zebrafish. International Journal of Molecular Sciences. 24(3):.
Abstract
Individuals homozygous for the Pi*Z allele of SERPINA1 (ZAAT) are susceptible to lung disease due to insufficient α1-antitrypsin secretion into the circulation and may develop liver disease due to compromised protein folding that leads to inclusion body formation in the endoplasmic reticulum (ER) of hepatocytes. Transgenic zebrafish expressing human ZAAT show no signs of hepatic accumulation despite displaying serum insufficiency, suggesting the defect in ZAAT secretion occurs independently of its tendency to form inclusion bodies. In this study, proteomic, transcriptomic, and biochemical analysis provided evidence of suppressed Srebp2-mediated cholesterol biosynthesis in the liver of ZAAT-expressing zebrafish. To investigate the basis for this perturbation, CRISPR/Cas9 gene editing was used to manipulate ER protein quality control factors. Mutation of erlec1 resulted in a further suppression in the cholesterol biosynthesis pathway, confirming a role for this ER lectin in targeting misfolded ZAAT for ER-associated degradation (ERAD). Mutation of the two ER mannosidase homologs enhanced ZAAT secretion without inducing hepatic accumulation. These insights into hepatic ZAAT processing suggest potential therapeutic targets to improve secretion and alleviate serum insufficiency in this form of the α1-antitrypsin disease.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping