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

Lecithin-cholesterol acyltransferase (LCAT), the key enzyme in reverse cholesterol transport (RCT), has been traditionally recognized for playing roles in high-density lipoprotein (HDL) maturation and systemic cholesterol homeostasis. However, its function in liver disease remains elusive. Here, we identify the role of LCAT in driving hepatic steatosis. Using a hepatocyte-specific lcat-overexpressing zebrafish model combined with transcriptomic and metabolic phenotyping, we demonstrated that lcat overexpression induces triglyceride (TG) accumulation and cytoplasmic lipid droplet deposition in the liver. Unexpectedly, transcriptomic profiling revealed an upregulation of fatty acid elongation pathway genes in lcat-overexpressed hepatocytes. Crucially, genetic knockdown or pharmacological inhibition of fatty acid elongation enzymes (hsd17b12a and Elovl1) alleviated LCAT-induced hepatic steatosis. Furthermore, overexpression of hsd17b12a and elovl1 resulted in hepatic steatosis similar to that of lcat-overexpressing larvae. These findings establish a novel role for LCAT in hepatic steatosis through regulating fatty acid metabolism, providing a mechanistic basis for targeting Lcat/fatty acid elongation axis in metabolic dysfunction-associated steatotic liver disease (MASLD).