Lecithin-cholesterol acyltransferase Lcat promotes hepatic steatosis through fatty acid metabolism reprogramming in zebrafish larvae

However, its hepatocyte-autonomous function in fatty acid metabolism remains elusive. Here, we established a hepatocyte-specific lcat-overexpressing zebrafish model (Tg(fabp10a:lcat-T2A-mCherry)) and integrated transcriptomic with metabolic phenotyping to reveal that lcat overexpression in zebrafish hepatocytes directly drives early-stage hepatic steatosis. lcat overexpression induces triglyceride (TG)-specific accumulation and cytoplasmic lipid droplet deposition.

Surprisingly, transcriptomic profiling revealed unexpected upregulation of fatty acid elongation pathway. Crucially, genetic knockdown of hsd17b12a or pharmacological inhibition of Elovl1 partially rescued Lcat-induced hepatic steatosis. These findings decouple Lcat from classical RCT function, thereby providing a molecular rationale for targeted metabolic interventions in metabolic dysfunction-associated steatotic liver disease (MASLD).