Fatty acid ethyl esters decrease human hepatoblastoma cell proliferation and protein synthesis.
OBJECTIVE
Fatty acid ethyl esters (FAEEs) are nonoxidative products 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 proliferation was measured by [methyl-3H]thymidine incorporation. Protein synthesis was determined using L-[35S]methionine.


RESULTS
Incubation of cells with 600 mumol/L ethyl oleate or 800 mumol/L ethyl arachidonate decreased [methyl-3H]thymidine incorporation into HepG2 cells by 31% and 37%, respectively. LDL reconstituted with 400 mumol/L ethyl oleate decreased protein synthesis in intact HepG2 cells by 41%. Electron microscopy revealed significant changes in cell morphology, particularly involving the cell nucleus. FAEE delivered in reconstituted LDL were rapidly hydrolyzed and the fatty acids re-esterified into phospholipids, triglycerides, and cholesterol esters, with preference for triglycerides.


CONCLUSIONS
These findings provide evidence that FAEE are toxic for intact human hepatoblastoma cells and that they or their metabolites may be an important causative agent in ethanol-induced liver damage.
Department of Pathology, Massachusetts General Hospital, Boston.
Z M
ZM
Szczepiorkowski
G R
GR
Dickersin
M
M
Laposata
D002455:Cell Division / Q000187:drug effects; D000431:Ethanol / Q000008:administration & dosage / Q000009:adverse effects*; D005227:Fatty Acids / Q000494:pharmacology*; D018197:Hepatoblastoma / Q000378:metabolism* / Q000473:pathology*; D006801:Humans; D008077:Lipoproteins, LDL / Q000494:pharmacology; D008113:Liver Neoplasms / Q000378:metabolism* / Q000473:pathology*; D008854:Microscopy, Electron; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000187:drug effects; D014407:Tumor Cells, Cultured
D005227:Fatty Acids; D008077:Lipoproteins, LDL; D009363:Neoplasm Proteins; D000431:Ethanol