title: Interruption of triacylglycerol synthesis in the endoplasmic reticulum is the initiating event for saturated fatty acid-induced lipotoxicity in liver cells.
abstract: The aim of the present study was to investigate in detail the molecular mechanisms by which free fatty acids induce liver toxicity in liver cells. HepG2 and Huh7 human liver cell lines were exposed to varying concentrations of stearate (18:0), oleate (18:1), or mixtures of the two fatty acids, and the effects on cell proliferation, lipid droplet accumulation and induction of endoplasmic reticulum stress and apoptosis were evaluated. It was observed that: (a) stearate, but not oleate, inhibited cell proliferation and induced cell death; (b) stearate-induced cell death had the characteristics of endoplasmic reticulum stress-mediated and mitochondrial-mediated apoptosis; (c) the activation of stearate in the form of stearoyl-CoA was a necessary step for the lipotoxic effect; (d) the capacity of cells to produce and accumulate triacylglycerols in the form of lipid droplets was interrupted following exposure to stearate, whereas it proceeded normally in oleate-treated cells; and (e) the presence of relatively low amounts of oleate protected cells from stearate-induced toxicity and restored the ability of the cells to accumulate triacylglycerols. Our data suggest that interruption of triacylglycerol synthesis in the endoplasmic reticulum, apparently because of the formation of a pool of oversaturated intermediates, represents the key initiating event in the mechanism of saturated fatty acid-induced lipotoxicity.
authors.affiliation: Laboratory of Biological Chemistry, University of Ioannina Medical School, Greece.
authors.forename: Michalis D
authors.initials: MD
authors.lastname: Mantzaris
authors.forename: Epameinondas V
authors.initials: EV
authors.lastname: Tsianos
authors.forename: Dimitrios
authors.initials: D
authors.lastname: Galaris
mesh_terms: D000214:Acyl Coenzyme A / Q000378:metabolism; D017209:Apoptosis; D002460:Cell Line; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005227:Fatty Acids / Q000494:pharmacology / Q000633:toxicity*; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000378:metabolism*; D014280:Triglycerides / Q000096:biosynthesis*
chemical_list: D000214:Acyl Coenzyme A; D005227:Fatty Acids; D014280:Triglycerides; C017725:stearoyl-coenzyme A