title: Lipotoxic lethal and sublethal stress signaling in hepatocytes: relevance to NASH pathogenesis.
abstract: The accumulation of lipids is a histologic and biochemical hallmark of obesity-associated nonalcoholic fatty liver disease (NAFLD). A subset of NALFD patients develops progressive liver disease, termed nonalcoholic steatohepatitis, which is characterized by hepatocellular apoptosis and innate immune system-mediated inflammation. These responses are orchestrated by signaling pathways that can be activated by lipids, directly or indirectly. In this review, we discuss palmitate- and lysophosphatidylcholine (LPC)-induced upregulation of p53-upregulated modulator of apoptosis and cell-surface expression of the death receptor TNF-related apoptosis-inducing ligand receptor 2. Next, we review the activation of stress-induced kinases, mixed lineage kinase 3, and c-Jun N-terminal kinase, and the activation of endoplasmic reticulum stress response and its downstream proapoptotic effector, CAAT/enhancer binding homologous protein, by palmitate and LPC. Moreover, the activation of these stress signaling pathways is linked to the release of proinflammatory, proangiogenic, and profibrotic extracellular vesicles by stressed hepatocytes. This review discusses the signaling pathways induced by lethal and sublethal lipid overload that contribute to the pathogenesis of NAFLD.
authors.affiliation: Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905.
authors.forename: Petra
authors.initials: P
authors.lastname: Hirsova
authors.affiliation: Pediatric Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN 55905.
authors.forename: Samar H
authors.initials: SH
authors.lastname: Ibrabim
authors.affiliation: Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905. Electronic address: Gores.gregory@mayo.edu.
authors.forename: Gregory J
authors.initials: GJ
authors.lastname: Gores
authors.affiliation: Divisions of Gastroenterology and Hepatology Mayo Clinic, Rochester, MN 55905. Electronic address: Malhi.harmeet@mayo.edu.
authors.forename: Harmeet
authors.initials: H
authors.lastname: Malhi
mesh_terms: D000818:Animals; D022762:CCAAT-Enhancer-Binding Proteins / Q000235:genetics / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D048031:JNK Mitogen-Activated Protein Kinases / Q000235:genetics / Q000378:metabolism; D008244:Lysophosphatidylcholines / Q000235:genetics / Q000378:metabolism; D020930:MAP Kinase Kinase Kinases / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D065626:Non-alcoholic Fatty Liver Disease / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010168:Palmitates / Q000378:metabolism; D013312:Stress, Physiological; D047992:TNF Receptor-Associated Factor 2 / Q000235:genetics / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics; D015854:Up-Regulation; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11
chemical_list: D022762:CCAAT-Enhancer-Binding Proteins; D048031:JNK Mitogen-Activated Protein Kinases; D008244:Lysophosphatidylcholines; D020930:MAP Kinase Kinase Kinases; D010168:Palmitates; D047992:TNF Receptor-Associated Factor 2; D016159:Tumor Suppressor Protein p53; D000097767:Mitogen-Activated Protein Kinase Kinase Kinase 11; C101338:PSMD2 protein, human; C495901:TP53 protein, human
keywords: apoptosis; cell death; cell signaling; exosomes; extracellular vesicles; fatty acids; lipotoxicity; lysophosphatidylcholine; nonalcoholic fatty liver disease; nonalcoholic steatohepatitis; steatohepatitis