Saturated fatty acid-mediated endoplasmic reticulum stress and apoptosis are augmented by trans-10, cis-12-conjugated linoleic acid in liver cells.
Lipid accumulation in non-adipose tissues leads to cell dysfunction and apoptosis, a phenomenon known as lipotoxicity. Recent evidence suggests that lipotoxicity in hepatocytes involves endoplasmic reticulum (ER) stress and c-Jun NH(2)-terminal kinase-mediated apoptosis. The present study examined (1) the dose-response and time course characteristics of fatty acid-mediated ER stress and apoptosis in H4IIE liver cells; (2) whether saturated fatty acid-induced apoptosis involved the ER-associated caspase-12; and (3) whether trans-10, cis-12-conjugated linoleic acid, an inhibitor of stearoyl-CoA desaturase, influenced fatty acid-mediated ER stress and apoptosis. Saturated fatty acids induced ER stress in a dose-dependent manner with a time course that was delayed relative to chemical-induction of ER stress. Saturated fatty acids increased caspase-9 and caspase-3 activity, however increased caspase-12 activity was not observed. Inhibition of stearoyl-CoA desaturase, using conjugated linoleic acid (trans-10, cis-12), augmented saturated fatty acid-induced ER stress and apoptosis. These data suggest that saturated fatty acids induce ER stress and apoptosis at physiologic concentrations and with a relatively rapid time course. It would appear that saturated fatty acid-mediated apoptosis occurs independently of caspase-12 activation. Since conjugated linoleic acid inhibited stearoyl-CoA desaturase activity, it is hypothesized that saturation, per se, plays a role in lipotoxicity in liver cells.
Wei
Yuren
Y
Department of Food Science and Human Nutrition, Colorado State University, Gifford 234, Campus Delivery 1571, Fort Collins, CO 80523-1571, USA.
Wang
Dong
D
Pagliassotti
Michael J
MJ
D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D053454:Caspase 12 / Q000378:metabolism; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004721:Endoplasmic Reticulum / Q000187:drug effects* / Q000378:metabolism; D005227:Fatty Acids / Q000008:administration & dosage*; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism*; D044243:Linoleic Acids, Conjugated / Q000494:pharmacology*; D018384:Oxidative Stress / Q000187:drug effects*; D051381:Rats; D013230:Stearoyl-CoA Desaturase / Q000037:antagonists & inhibitors / Q000378:metabolism
D005227:Fatty Acids; D044243:Linoleic Acids, Conjugated; C496197:trans-10,cis-12-conjugated linoleic acid; D013230:Stearoyl-CoA Desaturase; D053454:Caspase 12