Myristic acid potentiates palmitic acid-induced lipotoxicity and steatohepatitis associated with lipodystrophy by sustaning de novo ceramide synthesis

摘要: Palmitic acid (PA) induces hepatocyte apoptosis and fuels de novo ceramide synthesis in the endoplasmic reticulum (ER). Myristic (MA), a free fatty highly abundant copra/palmist oils, is predictor of nonalcoholic steatohepatitis (NASH) stimulates synthesis. Here we investigated synergism between MA PA synthesis, ER stress, lipotoxicity NASH. Unlike PA, not lipotoxic but potentiated PA-mediated lipoapoptosis, caspase-3 activation cytochrome c release primary mouse hepatocytes (PMH). Moreover, kinetically sustained PA-induced total content by stimulating dehydroceramide desaturase switched profile from decreased to increased 14:0/ceramide16:0, without changing medium long-chain species. PMH were more sensitive equimolar ceramide14:0/ceramide16:0 exposure, which mimics outcome plus treatment on homeostasis, than either alone. Treatment with myriocin inhibit tauroursodeoxycholic prevent stress ameliorated induced apoptosis, similar protection afforded antioxidant BHA, pan-caspase inhibitor z-VAD-Fmk JNK inhibition. ruthenium red protected against MA-induced cell death. Recapitulating vitro findings, mice fed diet enriched exhibited lipodystrophy, hepatosplenomegaly, liver cholesterol levels, damage, inflammation fibrosis compared diets or The deleterious effects MA-enriched largely prevented vivo treatment. These findings indicate causal link lipotoxicity, imply that consumption can cause NASH associated lipodystrophy.