Liver inflammation and metabolic signaling in ApcMin/+ mice: The role of cachexia progression

Aditi A. Narsale, Reilly T. Enos, Melissa J. Puppa, Saurabh Chatterjee, E. Angela Murphy, Raja Fayad, Majorette O. Pena, J. Larry Durstine, James A. Carson

Research output: Contribution to journalArticle

23 Citations (Scopus)

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, precachectic, 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.

Original languageEnglish (US)
Article numbere0119888
JournalPloS one
Volume10
Issue number3
DOIs
StatePublished - Mar 19 2015

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cachexia
Cachexia
Liver
Endoplasmic Reticulum Stress
endoplasmic reticulum
inflammation
Inflammation
liver
mice
neoplasms
STAT3 Transcription Factor
Phosphoenolpyruvate
protein synthesis
Iron-Regulatory Proteins
glycogen
Glycogen
Immunoglobulins
Proteins
Enzymes
Neoplasms

All Science Journal Classification (ASJC) codes

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

Cite this

Narsale, A. A., Enos, R. T., Puppa, M. J., Chatterjee, S., Murphy, E. A., Fayad, R., ... Carson, J. A. (2015). Liver inflammation and metabolic signaling in ApcMin/+ mice: The role of cachexia progression. PloS one, 10(3), [e0119888]. https://doi.org/10.1371/journal.pone.0119888

Liver inflammation and metabolic signaling in ApcMin/+ mice : The role of cachexia progression. / Narsale, Aditi A.; Enos, Reilly T.; Puppa, Melissa J.; Chatterjee, Saurabh; Murphy, E. Angela; Fayad, Raja; Pena, Majorette O.; Durstine, J. Larry; Carson, James A.

In: PloS one, Vol. 10, No. 3, e0119888, 19.03.2015.

Research output: Contribution to journalArticle

Narsale, AA, Enos, RT, Puppa, MJ, Chatterjee, S, Murphy, EA, Fayad, R, Pena, MO, Durstine, JL & Carson, JA 2015, 'Liver inflammation and metabolic signaling in ApcMin/+ mice: The role of cachexia progression', PloS one, vol. 10, no. 3, e0119888. https://doi.org/10.1371/journal.pone.0119888
Narsale AA, Enos RT, Puppa MJ, Chatterjee S, Murphy EA, Fayad R et al. Liver inflammation and metabolic signaling in ApcMin/+ mice: The role of cachexia progression. PloS one. 2015 Mar 19;10(3). e0119888. https://doi.org/10.1371/journal.pone.0119888
Narsale, Aditi A. ; Enos, Reilly T. ; Puppa, Melissa J. ; Chatterjee, Saurabh ; Murphy, E. Angela ; Fayad, Raja ; Pena, Majorette O. ; Durstine, J. Larry ; Carson, James A. / Liver inflammation and metabolic signaling in ApcMin/+ mice : The role of cachexia progression. In: PloS one. 2015 ; Vol. 10, No. 3.
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