PUBLICATION
Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy
- Authors
- Inoue, M., Sebastian, W.A., Sonoda, S., Miyahara, H., Shimizu, N., Shiraishi, H., Maeda, M., Yanagi, K., Kaname, T., Hanada, R., Hanada, T., Ihara, K.
- ID
- ZDB-PUB-240529-11
- Date
- 2024
- Source
- Orphanet journal of rare diseases 19: 219219 (Journal)
- Registered Authors
- Hanada, Reiko, Hanada, Toshikatsu
- Keywords
- Autophagy, DGAT1, Fatty liver, ILFS1, LARS1
- MeSH Terms
-
- Animals
- Autophagy*/genetics
- Disease Models, Animal
- Fatty Liver*/genetics
- Fatty Liver*/metabolism
- Fatty Liver*/pathology
- Humans
- Liver*/metabolism
- Liver*/pathology
- Zebrafish*
- PubMed
- 38807157 Full text @ Orphanet J Rare Dis
Citation
Inoue, M., Sebastian, W.A., Sonoda, S., Miyahara, H., Shimizu, N., Shiraishi, H., Maeda, M., Yanagi, K., Kaname, T., Hanada, R., Hanada, T., Ihara, K. (2024) Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy. Orphanet journal of rare diseases. 19:219219.
Abstract
Background Biallelic pathogenic variants of LARS1 cause infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute hepatic failure with steatosis in infants. LARS functions as a protein associated with mTORC1 and plays a crucial role in amino acid-triggered mTORC1 activation and regulation of autophagy. A previous study demonstrated that larsb-knockout zebrafish exhibit conditions resembling ILFS. However, a comprehensive analysis of larsb-knockout zebrafish has not yet been performed because of early mortality.
Methods We generated a long-term viable zebrafish model carrying a LARS1 variant identified in an ILFS1 patient (larsb-I451F zebrafish) and analyzed the pathogenesis of the affected liver of ILFS1.
Results Hepatic dysfunction is most prominent in ILFS1 patients during infancy; correspondingly, the larsb-I451F zebrafish manifested hepatic anomalies during developmental stages. The larsb-I451F zebrafish demonstrates augmented lipid accumulation within the liver during autophagy activation. Inhibition of DGAT1, which converts fatty acids to triacylglycerols, improved lipid droplets in the liver of larsb-I451F zebrafish. Notably, treatment with an autophagy inhibitor ameliorated hepatic lipid accumulation in this model.
Conclusions Our findings suggested that enhanced autophagy caused by biallelic LARS1 variants contributes to ILFS1-associated hepatic dysfunction. Furthermore, the larsb-I451F zebrafish model, which has a prolonged survival rate compared with the larsb-knockout model, highlights its potential utility as a tool for investigating the pathophysiology of ILFS1-associated liver dysfunction.
Genes / Markers
Expression
Phenotype
Mutations / Transgenics
Human Disease / Model
Sequence Targeting Reagents
Fish
Orthology
Engineered Foreign Genes
Mapping