FATTY-ACID ETHYL-ESTERS DECREASE HUMAN HEPATOBLASTOMA CELL-PROLIFERATION AND PROTEIN-SYNTHESIS

Background/Aims: Fatty acid ethyl esters (FAEEs) are nonoxidative prod ucts of ethanol metabolism. They have been implicated as mediators of ethanol-induced organ damage because FAEE and FAEE synthase have been found specifically in the organs damaged by ethanol abuse. This study showed toxicity specifically related to FAEE or their metabolites for intact human hepatoblastoma-derived cells (HepG2). Methods: The lipid core of human low-density lipoprotein (LDL) was extracted and the LDL particle reconstituted with either ethyl oleate or ethyl arachidonate. Cultured HepG2 cells were incubated with LDL containing FAEE. Cell pr oliferation was measured by [methyl-H-3]thymidine incorporation. Prote in synthesis was determined using L-[S-35]methionine. Results: Incubat ion of cells with 600 mu mol/L ethyl oleate or 800 mu mol/L ethyl arac hidonate decreased [methyl-H-3]thymidine incorporation into HepG2 cell s by 31% and 37%, respectively. LDL reconstituted with 400 mu mol/L et hyl oleate decreased protein synthesis in intact HepG2 cells by 41%. E lectron microscopy revealed significant changes in cell morphology, pa rticularly involving the cell nucleus. FAEE delivered in reconstituted LDL were rapidly hydrolyzed and the fatty acids re-esterified into ph ospholipids, triglycerides, and cholesterol esters, with preference fo r triglycerides. Conclusions: These findings provide evidence that FAE E are toxic for intact human hepatoblastoma cells and that they or the ir metabolites may be an important causative agent in ethanol-induced liver damage.