title: Liver inflammation and metabolic signaling in ApcMin/+ mice: the role of cachexia progression.
abstract: The ApcMin/+ mouse exhibits an intestinal tumor associated loss of muscle and fat that is accompanied by chronic inflammation, insulin resistance and hyperlipidemia. Since the liver governs systemic energy demands through regulation of glucose and lipid metabolism, it is likely that the liver is a pathological target of cachexia progression in the ApcMin/+ mouse. The purpose of this study was to determine if cancer and the progression of cachexia affected liver endoplasmic reticulum (ER)-stress, inflammation, metabolism, and protein synthesis signaling. The effect of cancer (without cachexia) was examined in wild-type and weight-stable ApcMin/+ mice. Cachexia progression was examined in weight-stable, pre-cachectic, and severely-cachectic ApcMin/+ mice. Livers were analyzed for morphology, glycogen content, ER-stress, inflammation, and metabolic changes. Cancer induced hepatic expression of ER-stress markers BiP (binding immunoglobulin protein), IRE-1α (endoplasmic reticulum to nucleus signaling 1), and inflammatory intermediate STAT-3 (signal transducer and activator of transcription 3). While gluconeogenic enzyme phosphoenolpyruvate carboxykinase (PEPCK) mRNA expression was suppressed by cancer, glycogen content or protein synthesis signaling remained unaffected. Cachexia progression depleted liver glycogen content and increased mRNA expression of glycolytic enzyme PFK (phosphofrucktokinase) and gluconeogenic enzyme PEPCK. Cachexia progression further increased pSTAT-3 but suppressed p-65 and JNK (c-Jun NH2-terminal kinase) activation. Interestingly, progression of cachexia suppressed upstream ER-stress markers BiP and IRE-1α, while inducing its downstream target CHOP (DNA-damage inducible transcript 3). Cachectic mice exhibited a dysregulation of protein synthesis signaling, with an induction of p-mTOR (mechanistic target of rapamycin), despite a suppression of Akt (thymoma viral proto-oncogene 1) and S6 (ribosomal protein S6) phosphorylation. Thus, cancer induced ER-stress markers in the liver, however cachexia progression further deteriorated liver ER-stress, disrupted protein synthesis regulation and caused a differential inflammatory response related to STAT-3 and NF-κB (Nuclear factor-κB) signaling.
authors: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America; Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America.
authors: Aditi A
authors: AA
authors: Narsale
authors: Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
authors: Reilly T
authors: RT
authors: Enos
authors: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America; Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America.
authors: Melissa J
authors: MJ
authors: Puppa
authors: Environmental Health and Disease Laboratory, Department of Environmental Health Sciences, University of South Carolina, South Carolina, United States of America.
authors: Saurabh
authors: S
authors: Chatterjee
authors: Department of Pathology, Microbiology & Immunology, School of Medicine, University of South Carolina, Columbia, South Carolina, United States of America.
authors: E Angela
authors: EA
authors: Murphy
authors: Center for Colon Cancer Research, Columbia, South Carolina, United States of America; Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America.
authors: Raja
authors: R
authors: Fayad
authors: Center for Colon Cancer Research, Columbia, South Carolina, United States of America.
authors: Majorette O'
authors: MO
authors: Pena
authors: Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America.
authors: J Larry
authors: JL
authors: Durstine
authors: Integrative Muscle Biology Laboratory, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America; Center for Colon Cancer Research, Columbia, South Carolina, United States of America; Division of Applied Physiology, Department of Exercise Science, University of South Carolina, Columbia, South Carolina, United States of America.
authors: James A
authors: JA
authors: Carson
mesh_terms: D000818:Animals; D002100:Cachexia / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D059865:Endoplasmic Reticulum Stress / Q000235:genetics; D017491:Genes, APC; D006003:Glycogen / Q000378:metabolism; D006949:Hyperlipidemias / Q000378:metabolism / Q000473:pathology; D007249:Inflammation / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D007333:Insulin Resistance / Q000235:genetics; D050356:Lipid Metabolism / Q000235:genetics; D008099:Liver / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D014176:Protein Biosynthesis / Q000235:genetics*; D050796:STAT3 Transcription Factor / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D016328:NF-kappa B; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D006003:Glycogen