title: Free fatty acids induce transglutaminase 2-dependent apoptosis in hepatocytes via ER stress-stimulated PERK pathways.
abstract: Non-alcoholic steatohepatitis (NASH), a progressive form of fatty liver, shares histological similarities with alcoholic steatohepatitis (ASH), including accumulated fat, hepatic apoptosis, and fibrous tissues in the liver, but the molecular mechanisms responsible for hepatic apoptosis remain unclear. We previously reported that transglutaminase 2 (TG2), induced in the nuclei of ethanol-treated hepatocytes, crosslinks and inactivates the transcription factor Sp1, leading to hepatic apoptosis. In this study, we investigated whether a similar change is involved in NASH, and if so, how TG2 and crosslinked Sp1 (CLSp1) are induced. Elevated nuclear TG2 and CLSp1 formation was demonstrated in NASH patients, as well as increased activation of apoptosis inducing factor (AIF) and release of cytochrome c. In Hc human normal hepatocytes treated with free fatty acids (FFAs), biochemical analyses revealed that ethanol and FFAs provoked fat accumulation, endoplasmic reticulum (ER) stress, increased nuclear factor kappa B (NFκB), and nuclear TG2. Salubrinal, a selective inhibitor of the ER stress-induced pancreatic ER kinase (PERK) signaling pathway, inhibited NFκB activation, nuclear TG2 expression, and apoptosis only if it was induced by FFAs, but not by ethanol. These results suggest that FFAs could increase ER stress and lead to nuclear NFκB activation and TG2 induction through PERK-dependent pathways, resulting in TG2-mediated apoptosis accompanying crosslinking and inactivation of Sp1, activation of AIF, and release of cytochrome c.
authors.affiliation: Chemical Biology Department, RIKEN Advanced Science Institute, Wako, Saitama, Japan.
authors.forename: Ting-Fang
authors.initials: TF
authors.lastname: Kuo
authors.forename: Hideki
authors.initials: H
authors.lastname: Tatsukawa
authors.forename: Tomokazu
authors.initials: T
authors.lastname: Matsuura
authors.forename: Keisuke
authors.initials: K
authors.lastname: Nagatsuma
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Hirose
authors.forename: Soichi
authors.initials: S
authors.lastname: Kojima
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D002934:Cinnamates / Q000494:pharmacology; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects / Q000502:physiology*; D000431:Ethanol / Q000494:pharmacology; D005230:Fatty Acids, Nonesterified / Q000502:physiology*; D005234:Fatty Liver / Q000201:enzymology* / Q000473:pathology; D019204:GTP-Binding Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D016328:NF-kappa B / Q000096:biosynthesis; D065626:Non-alcoholic Fatty Liver Disease; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000037:antagonists & inhibitors; D013890:Thiourea / Q000031:analogs & derivatives / Q000494:pharmacology; D011503:Transglutaminases / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015854:Up-Regulation / Q000187:drug effects / Q000502:physiology; D019892:eIF-2 Kinase / Q000037:antagonists & inhibitors / Q000502:physiology*
chemical_list: D002934:Cinnamates; D000431:Ethanol; D005230:Fatty Acids, Nonesterified; D019204:GTP-Binding Proteins; D016328:NF-kappa B; D000091345:Protein Glutamine gamma Glutamyltransferase 2; D016329:Sp1 Transcription Factor; D013890:Thiourea; D011503:Transglutaminases; D019892:eIF-2 Kinase; C496827:salubrinal