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.
Highlights
Cachexia is a wasting syndrome observed during the later stages of chronic diseases like cancer, Acquired Immunodeficiency Syndrome and Chronic Obstructive Pulmonary Disease [1], and greatly hampers quality of life in patients under remission
A subset of WT, non—cachectic and severely—cachectic mice were perfused using 4% paraformaldehyde fixative and stained with the hematoxylin and eosin stain to determine if cachexia progression leads to liver pathology
Since it is likely that the liver is a pathological target of cachexia progression, our study under took the novel examination of the liver in a cancerous state combined with cachexia
Summary
Cachexia is a wasting syndrome observed during the later stages of chronic diseases like cancer, Acquired Immunodeficiency Syndrome and Chronic Obstructive Pulmonary Disease [1], and greatly hampers quality of life in patients under remission. No pharmacological treatments are currently approved for cachexia [2]. This may be due to its multifactorial and systemic nature which could serve to limit the effectiveness of a single drug or therapy. It is important to study the effect of cachexia progression in terms of loss of body mass, evident only in advanced stages of the disease, and on initial systemic events that initiate and lead to wasting. The visceral organs such as heart, spleen, and liver maintain mass or even hypertrophy with cachexia [1]
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