PMID- 21941003 OWN - NLM STAT- MEDLINE DCOM- 20111227 LR - 20220310 IS - 1083-351X (Electronic) IS - 0021-9258 (Print) IS - 0021-9258 (Linking) VI - 286 IP - 45 DP - 2011 Nov 11 TI - Death receptor 5 signaling promotes hepatocyte lipoapoptosis. PG - 39336-48 LID - 10.1074/jbc.M111.280420 [doi] AB - Nonalcoholic steatohepatitis is characterized by hepatic steatosis, elevated levels of circulating free fatty acids (FFA), endoplasmic reticulum (ER) stress, and hepatocyte lipoapoptosis. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) death receptor 5 (DR5) is significantly elevated in patients with nonalcoholic steatohepatitis, and steatotic hepatocytes demonstrate increased sensitivity to TRAIL-mediated cell death. Nonetheless, a role for TRAIL and/or DR5 in mediating lipoapoptotic pathways is unexplored. Here, we examined the contribution of DR5 death signaling to lipoapoptosis by free fatty acids. The toxic saturated free fatty acid palmitate induces an increase in DR5 mRNA and protein expression in Huh-7 human hepatoma cells leading to DR5 localization into lipid rafts, cell surface receptor clustering with subsequent recruitment of the initiator caspase-8, and ultimately cellular demise. Lipoapoptosis by palmitate was not inhibited by a soluble human recombinant DR5-Fc chimera protein suggesting that DR5 cytotoxic signaling is ligand-independent. Hepatocytes from murine TRAIL receptor knock-out mice (DR(-/-)) displayed reduced palmitate-mediated lipotoxicity. Likewise, knockdown of DR5 or caspase-8 expression by shRNA technology attenuated palmitate-induced Bax activation and apoptosis in Huh-7 cells, without altering induction of ER stress markers. Similar observations were verified in other cell models. Finally, knockdown of CHOP, an ER stress-mediated transcription factor, reduced DR5 up-regulation and DR5-mediated caspase-8 activation upon palmitate treatment. Collectively, these results suggest that ER stress-induced CHOP activation by palmitate transcriptionally up-regulates DR5, likely resulting in ligand-independent cytotoxic signaling by this death receptor. FAU - Cazanave, Sophie C AU - Cazanave SC AD - Division of Gastroenterology and Hepatology, College of Medicine, Mayo Clinic, Rochester, Minnesota 55905, USA. FAU - Mott, Justin L AU - Mott JL FAU - Bronk, Steven F AU - Bronk SF FAU - Werneburg, Nathan W AU - Werneburg NW FAU - Fingas, Christian D AU - Fingas CD FAU - Meng, X Wei AU - Meng XW FAU - Finnberg, Niklas AU - Finnberg N FAU - El-Deiry, Wafik S AU - El-Deiry WS FAU - Kaufmann, Scott H AU - Kaufmann SH FAU - Gores, Gregory J AU - Gores GJ LA - eng GR - DK079875/DK/NIDDK NIH HHS/United States GR - CA123258/CA/NCI NIH HHS/United States GR - CA69008/CA/NCI NIH HHS/United States GR - R01 DK069757/DK/NIDDK NIH HHS/United States GR - R01 DK041876/DK/NIDDK NIH HHS/United States GR - K01 DK079875/DK/NIDDK NIH HHS/United States GR - P30DK084567/DK/NIDDK NIH HHS/United States GR - R37 DK041876/DK/NIDDK NIH HHS/United States GR - DK069757/DK/NIDDK NIH HHS/United States GR - P30 DK084567/DK/NIDDK NIH HHS/United States GR - R01 CA069008/CA/NCI NIH HHS/United States GR - DK41876/DK/NIDDK NIH HHS/United States GR - R01 CA123258/CA/NCI NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural DEP - 20110922 PL - United States TA - J Biol Chem JT - The Journal of biological chemistry JID - 2985121R RN - 0 (BAX protein, human) RN - 0 (Bax protein, mouse) RN - 0 (DDIT3 protein, human) RN - 0 (Ddit3 protein, mouse) RN - 0 (Enzyme Inhibitors) RN - 0 (Receptors, TNF-Related Apoptosis-Inducing Ligand) RN - 0 (bcl-2-Associated X Protein) RN - 147336-12-7 (Transcription Factor CHOP) RN - 2V16EO95H1 (Palmitic Acid) RN - EC 3.4.22.- (CASP8 protein, human) RN - EC 3.4.22.- (Casp8 protein, mouse) RN - EC 3.4.22.- (Caspase 8) SB - IM MH - Animals MH - *Apoptosis MH - Caspase 8/genetics/metabolism MH - Cell Line, Tumor MH - Enzyme Inhibitors/pharmacology MH - Fatty Liver/genetics/*metabolism/pathology MH - Gene Knockdown Techniques MH - Hepatocytes/*metabolism/pathology MH - Humans MH - Membrane Microdomains/genetics/metabolism/pathology MH - Mice MH - Mice, Knockout MH - Palmitic Acid/pharmacology MH - Receptors, TNF-Related Apoptosis-Inducing Ligand/genetics/*metabolism MH - Transcription Factor CHOP/genetics/metabolism MH - Transcription, Genetic/drug effects/genetics MH - Up-Regulation/drug effects/genetics MH - bcl-2-Associated X Protein/genetics/metabolism PMC - PMC3234758 EDAT- 2011/09/24 06:00 MHDA- 2011/12/28 06:00 PMCR- 2012/11/11 CRDT- 2011/09/24 06:00 PHST- 2011/09/24 06:00 [entrez] PHST- 2011/09/24 06:00 [pubmed] PHST- 2011/12/28 06:00 [medline] PHST- 2012/11/11 00:00 [pmc-release] AID - S0021-9258(20)50592-9 [pii] AID - M111.280420 [pii] AID - 10.1074/jbc.M111.280420 [doi] PST - ppublish SO - J Biol Chem. 2011 Nov 11;286(45):39336-48. doi: 10.1074/jbc.M111.280420. Epub 2011 Sep 22.