title: Disrupted signaling and inhibited regeneration in obese mice with fatty livers: implications for nonalcoholic fatty liver disease pathophysiology.
abstract: The impaired regenerative capacity of fatty livers might promote the progression of nonalcoholic fatty liver disease (NAFLD). To identify mechanisms involved, regenerative responses were compared in normal mice and ob/ob mice (a model for NAFLD) after partial hepatectomy (PH). We hypothesized that the usual PH activation of oxidant-sensitive, growth-regulatory kinase cascades would be abnormal in fatty hepatocytes, which have adapted to chronic oxidant stress, and expected that this might interfere with the induction of proliferative- and stress-related genes. The normal coordinated induction of Jun N-terminal kinases (Jnks) and extracellular regulated kinases (Erks) does not occur after PH in ob/ob mice, which cannot activate Jnks but can superinduce Erks. Jnk inhibition is associated with enhanced activation of Akt, which inhibits phosphoenolpyruvate carboxykinase (PEPCK) induction, causing severe hypoglycemia and increased lethality in the ob/ob group. Activation of nuclear factor kappaB (NF-kappaB) is also inhibited, but liver damage is increased only modestly, perhaps because Akt-regulated survival factors are protective. Despite enhanced Erk activity, induction of cyclin D-1, an NF-kappaB target gene, is abolished and this, together with hyperphosphorylated signal transducer and activator of transcription-3 (Stat-3) and reduced adenosine triphosphate (ATP) levels, arrests fatty hepatocytes in G(1). Thus, in mice with NAFLD that have adapted hepatocyte signaling mechanisms to survive chronic oxidative stress, the cellular response to an acute regenerative stimulus is altered. This contributes to NAFLD pathophysiology by inhibiting proliferation, increasing injury, and limiting function in fatty livers.
authors.affiliation: Department of Medicine, The Johns Hopkins University, Baltimore, MD 21205, USA.
authors.forename: S Q
authors.initials: SQ
authors.lastname: Yang
authors.forename: H Z
authors.initials: HZ
authors.lastname: Lin
authors.forename: A K
authors.initials: AK
authors.lastname: Mandal
authors.forename: J
authors.initials: J
authors.lastname: Huang
authors.forename: A M
authors.initials: AM
authors.lastname: Diehl
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000818:Animals; D005234:Fatty Liver / Q000503:physiopathology*; D016193:G1 Phase; D015850:Interleukin-6 / Q000096:biosynthesis; D007473:Ion Channels; D008112:Liver Glycogen / Q000378:metabolism; D008115:Liver Regeneration; D008297:Male; D026901:Membrane Transport Proteins; D051379:Mice; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D024101:Mitochondrial Proteins; D020928:Mitogen-Activated Protein Kinases / Q000096:biosynthesis; D009765:Obesity / Q000150:complications*; D018384:Oxidative Stress; D019764:Phosphoenolpyruvate Carboxykinase (ATP) / Q000378:metabolism; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D017346:Protein Serine-Threonine Kinases; D011506:Proteins / Q000378:metabolism; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis; D000071246:Uncoupling Protein 2
chemical_list: D015850:Interleukin-6; D007473:Ion Channels; D008112:Liver Glycogen; D026901:Membrane Transport Proteins; D024101:Mitochondrial Proteins; D018809:Proliferating Cell Nuclear Antigen; D011506:Proteins; D011518:Proto-Oncogene Proteins; D014409:Tumor Necrosis Factor-alpha; D000071246:Uncoupling Protein 2; D000255:Adenosine Triphosphate; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt; D020928:Mitogen-Activated Protein Kinases; D019764:Phosphoenolpyruvate Carboxykinase (ATP)