title: JNK1 but not JNK2 promotes the development of steatohepatitis in mice.
abstract: Nonalcoholic fatty liver disease (NAFLD) is characterized by hepatic steatosis and varying degrees of necroinflammation. Although chronic oxidative stress, inflammatory cytokines, and insulin resistance have been implicated in the pathogenesis of NAFLD, the mechanisms that underlie the initiation and progression of this disease remain unknown. c-Jun N-terminal kinase (JNK) is activated by oxidants and cytokines and regulates hepatocellular injury and insulin resistance, suggesting that this kinase may mediate the development of steatohepatitis. The presence and function of JNK activation were therefore examined in the murine methionine- and choline-deficient (MCD) diet model of steatohepatitis. Activation of hepatic JNK, c-Jun, and AP-1 signaling occurred in parallel with the development of steatohepatitis in MCD diet-fed mice. Investigations in jnk1 and jnk2 knockout mice demonstrated that jnk1, but not jnk2, was critical for MCD diet-induced JNK activation. JNK promoted the development of steatohepatitis as MCD diet-fed jnk1 null mice had significantly reduced levels of hepatic triglyceride accumulation, inflammation, lipid peroxidation, liver injury, and apoptosis compared with wild-type and jnk2 -/- mice. Ablation of jnk1 led to an increase in serum adiponectin but had no effect on serum levels of tumor necrosis factor-alpha. In conclusion, JNK1 is responsible for JNK activation that promotes the development of steatohepatitis in the MCD diet model. These findings also provide additional support for the critical mechanistic involvement of JNK1 overactivation in conditions associated with insulin resistance and the metabolic syndrome.
authors.affiliation: Department of Medicine, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
authors.forename: Jörn M
authors.initials: JM
authors.lastname: Schattenberg
authors.forename: Rajat
authors.initials: R
authors.lastname: Singh
authors.forename: Yongjun
authors.initials: Y
authors.lastname: Wang
authors.forename: Jay H
authors.initials: JH
authors.lastname: Lefkowitch
authors.forename: Raina M
authors.initials: RM
authors.lastname: Rigoli
authors.forename: Philipp E
authors.initials: PE
authors.lastname: Scherer
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Czaja
mesh_terms: D052242:Adiponectin / Q000097:blood; D000410:Alanine Transaminase / Q000097:blood; D000818:Animals; D017209:Apoptosis; D002796:Choline Deficiency / Q000150:complications; D004789:Enzyme Activation; D005234:Fatty Liver / Q000209:etiology*; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics; D015227:Lipid Peroxidation; D008099:Liver / Q000473:pathology; D008297:Male; D008715:Methionine / Q000172:deficiency; D051379:Mice; D008810:Mice, Inbred C57BL; D048055:Mitogen-Activated Protein Kinase 8 / Q000502:physiology*; D048056:Mitogen-Activated Protein Kinase 9 / Q000502:physiology*; D014280:Triglycerides / Q000032:analysis
chemical_list: D052242:Adiponectin; D014280:Triglycerides; D018799:Intercellular Adhesion Molecule-1; D008715:Methionine; D000410:Alanine Transaminase; D048056:Mitogen-Activated Protein Kinase 9; D048055:Mitogen-Activated Protein Kinase 8