title: Cdc42 and Rac1 are major contributors to the saturated fatty acid-stimulated JNK pathway in hepatocytes.
abstract: OBJECTIVE
  Saturated free fatty acid (SFA)-stimulated c-Jun NH(2)-terminal kinase (JNK) activation is associated with the pathogenesis of non-alcoholic fatty liver disease (NAFLD). However, the mechanisms responsible for the effects of SFA are incompletely understood. The goal of this study was to determine the molecular mechanisms by which SFA induce JNK activation in hepatocytes.
  
  
  METHODS
  We used siRNA-mediated knockdown in Hepa1c1c7 and AML12 cell lines, as well as primary mouse hepatocytes for these studies.
  
  
  RESULTS
  The current model for JNK activation by SFA involves endoplasmic reticulum (ER) stress, which induces JNK activation through an inositol requiring enzyme 1 (IRE1α) Apoptosis Regulating Kinase 1 (ASK1)-dependent mechanism. Here, we find that SFA-induced JNK activation is not inhibited in the absence of IRE1α and ASK1. Instead we show that activation of the small GTP-binding proteins Cdc42 and Rac1 is required for SFA-stimulated MLK3-dependent activation of JNK in hepatocytes. In addition, we demonstrate that SFA-induced cell death in hepatocytes is independent of IRE1α, but dependent on Cdc42, Rac1, and MLK3.
  
  
  CONCLUSIONS
  Our results demonstrate that Cdc42 and Rac1, rather than ER stress, are important components of a SFA-stimulated signaling pathway that regulates MLK3-dependent activation of JNK in hepatocytes.
authors.affiliation: Department of Pathology, Metabolic Diseases Institute, University of Cincinnati, Cincinnati, OH 45237, USA.
authors.forename: Manju
authors.initials: M
authors.lastname: Sharma
authors.forename: Fumihiko
authors.initials: F
authors.lastname: Urano
authors.forename: Anja
authors.initials: A
authors.lastname: Jaeschke
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects / Q000502:physiology; D001483:Base Sequence; D002460:Cell Line; D002478:Cells, Cultured; D059865:Endoplasmic Reticulum Stress / Q000187:drug effects; D004722:Endoribonucleases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D005227:Fatty Acids / Q000494:pharmacology*; D055785:Gene Knockdown Techniques; D022781:Hepatocytes / Q000166:cytology / Q000187:drug effects* / Q000378:metabolism*; D048848:MAP Kinase Kinase Kinase 5 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System / Q000187:drug effects* / Q000502:physiology; D051379:Mice; D008954:Models, Biological; D009479:Neuropeptides / Q000378:metabolism*; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism; D034741:RNA, Small Interfering / Q000235:genetics; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism*; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D004722:Endoribonucleases; D005227:Fatty Acids; D048848:MAP Kinase Kinase Kinase 5; D020930:MAP Kinase Kinase Kinases; D009479:Neuropeptides; D017346:Protein Serine-Threonine Kinases; D034741:RNA, Small Interfering; D020764:cdc42 GTP-Binding Protein; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C484602:Rac1 protein, mouse; C510185:Ern1 protein, mouse; C482859:Map3k5 protein, mouse