Biallelic variants in LARS1 induce steatosis in developing zebrafish liver via enhanced autophagy
Authors: Inoue Masanori , Sebastian Wulan Apridita , Sonoda Shota , Miyahara Hiroaki , Shimizu Nobuyuki , Shiraishi Hiroshi , Maeda Miwako , Yanagi Kumiko , Kaname Tadashi , Hanada Reiko , Hanada Toshikatsu , Ihara Kenji 
Published: September 2023

AbstractAcute liver failure is a life-threatening condition during infancy. Biallelic pathogenic variants inLARS1cause infantile liver failure syndrome type 1 (ILFS1), which is characterized by acute hepatic failure in infants. LARS functions as a protein associated with mTORC1 and plays a crucial role in amino acid-triggered mTORC1 activation and autophagy regulation. A previous study demonstrated thatlarsb-knockout zebrafish show a condition resembling ILFS. However, a comprehensive analysis oflarsb-knockout zebrafish has not yet been performed because of early mortality. We herein generated a long-term viable zebrafish model carrying aLARS1variant identified in an ILFS1 patient (larsb-I451F zebrafish) and analyzed the pathogenesis of the affected liver of ILFS1. Hepatic dysfunction is most prominent in ILFS1 patients during infancy; correspondingly, thelarsb-I451Fzebrafish manifested hepatic anomalies during the developmental stages. Thelarsb-I451Fzebrafish demonstrates augmented lipid accumulation within the liver under autophagy activation. Inhibition of DGAT1, which converts fatty acids to triacylglycerols, improved lipid droplets in the liver oflarsb-I451Fzebrafish. Notably, treatment with an autophagy inhibitor ameliorated hepatic lipid accumulation in this model. Our findings suggested that enhanced autophagy caused by biallelicLARS1variants contributes to ILFS1-associated hepatic dysfunction. Furthermore, thelarsb-I451Fzebrafish model, which has a prolonged survival rate compared to thelarsb-knockout model, highlights its potential utility as a tool for investigating the pathophysiology of ILFS1-associated liver dysfunction.Author SummaryInfantile liver failure (ALF) is a rare but life-threatening condition primarily caused by various genetic and infectious factors during infancy. Comprehensive research into its causes is crucial for treatment decisions, including liver transplantation and supportive interventions. While specific therapies exist for some conditions, a significant proportion of infant ALF cases remains unresolved. Recent advances in genetic sequencing have identified congenital disorders, particularly involving theLARS1gene, as contributors to ALF.LARS1is essential for regulating processes related to amino acids and autophagy. To better understand this condition, we created a zebrafish model carrying specificLARS1gene variants seen in ALF patients. These zebrafish displayed liver abnormalities similar to those observed in infants with ALF. Our study revealed that enhanced autophagy, triggered by biallelicLARS1variants, plays a significant role in liver dysfunction associated with ALF. Notably, inhibiting specific enzymes involved in fat metabolism and autophagy showed promising results in reducing hepatic lipid accumulation in our zebrafish model. This research provides insights that may lead to improved understanding and potential treatments for this devastating condition.