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

Narsale AA, Enos RT, Puppa MJ, Chatterjee S, Murphy EA, Fayad R, Pena MO, Durstine JL, Carson JA - PLoS ONE (2015)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


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Changes in liver metabolic and anabolic markers with cachexia progression.A) Liver mRNA expression of metabolic genes PFK and PEPCK B) Protein expression liver anabolic signaling with cachexia progression. Values are expressed as Mean ± SE. * denotes significantly different from Non—cachectic ApcMin/+ $ denotes significant difference from the pre—cachectic ApcMin/+ mice as analyzed by One—Way ANOVA. Values are normalized either to the respective total protein for phosphoproteins and to GAPDH for non—phosphorylated proteins. (n = 5–6 per group, p < 0.05) Dotted line on the graph indicates levels of Non—cachectic ApcMin/+, while a dotted line on the Western blot indicates different regions of the same gel. Non = Non—Cachectic ApcMin/+ Sev = severely cachectic ApcMin/+.
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pone.0119888.g008: Changes in liver metabolic and anabolic markers with cachexia progression.A) Liver mRNA expression of metabolic genes PFK and PEPCK B) Protein expression liver anabolic signaling with cachexia progression. Values are expressed as Mean ± SE. * denotes significantly different from Non—cachectic ApcMin/+ $ denotes significant difference from the pre—cachectic ApcMin/+ mice as analyzed by One—Way ANOVA. Values are normalized either to the respective total protein for phosphoproteins and to GAPDH for non—phosphorylated proteins. (n = 5–6 per group, p < 0.05) Dotted line on the graph indicates levels of Non—cachectic ApcMin/+, while a dotted line on the Western blot indicates different regions of the same gel. Non = Non—Cachectic ApcMin/+ Sev = severely cachectic ApcMin/+.

Mentions: To examine the effect of cancer cachexia progression we examined non-cachectic, pre-cachectic, and severely cachectic ApcMin/+ mice. Cachexia progression suppressed Bip/GRP78 and p-IRE-1α expression, but there was no further effect on ATF6p50 expression. Expression of the apoptotic marker CHOP was induced in the severely cachectic mice, which coincided with Bip/GRP78 and IRE1α suppression (Fig. 6). Liver glycogen content was depleted in the severely cachectic ApcMin/+ mice as compared to the non—cachectic and the pre—cachectic mice (Fig. 7). The progression of cachexia induced liver PFK mRNA expression 11-fold and PEPCK mRNA expression 2-fold (Fig. 8A). No difference in either PFK or PEPCK gene expression was observed early in cachexia, as pre—cachectic mice were not different from non—cachectic mice. A significant inhibition of liver Akt and S6 phosphorylation was observed with cachexia progression. Interestingly, mTOR phosphorylation was increased both in the pre—cachectic and severely cachectic ApcMin/+ mice (Fig. 8C). SOCS3 expression did not change further with cachexia progression (Fig. 9a). Acute phase gene expression for haptoglobin was elevated ~3.5 fold, but SAA expression was not significantly different from the non—cachectic ApcMin/+ mice (Fig. 9A). Liver haptoglobin expression was increased in livers from severely cachectic mice, but not in pre—cachectic mice. Cachexia progression further increased STAT-3 phosphorylation, though there was no change in liver gp130 and albumin protein content with cachexia progression (Fig. 9B). Interestingly, cachexia progression suppressed NF-κB phosphorylation ~ 75% in the severely cachectic mice as compared to non—cachectic mice and ~65% as compared to pre—cachectic mice (Fig. 9A). Liver MMP-2 expression, an angiogenic and fibrotic marker, was suppressed 90% in the severely cachectic mice (Fig. 9B).


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

Narsale AA, Enos RT, Puppa MJ, Chatterjee S, Murphy EA, Fayad R, Pena MO, Durstine JL, Carson JA - PLoS ONE (2015)

Changes in liver metabolic and anabolic markers with cachexia progression.A) Liver mRNA expression of metabolic genes PFK and PEPCK B) Protein expression liver anabolic signaling with cachexia progression. Values are expressed as Mean ± SE. * denotes significantly different from Non—cachectic ApcMin/+ $ denotes significant difference from the pre—cachectic ApcMin/+ mice as analyzed by One—Way ANOVA. Values are normalized either to the respective total protein for phosphoproteins and to GAPDH for non—phosphorylated proteins. (n = 5–6 per group, p < 0.05) Dotted line on the graph indicates levels of Non—cachectic ApcMin/+, while a dotted line on the Western blot indicates different regions of the same gel. Non = Non—Cachectic ApcMin/+ Sev = severely cachectic ApcMin/+.
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pone.0119888.g008: Changes in liver metabolic and anabolic markers with cachexia progression.A) Liver mRNA expression of metabolic genes PFK and PEPCK B) Protein expression liver anabolic signaling with cachexia progression. Values are expressed as Mean ± SE. * denotes significantly different from Non—cachectic ApcMin/+ $ denotes significant difference from the pre—cachectic ApcMin/+ mice as analyzed by One—Way ANOVA. Values are normalized either to the respective total protein for phosphoproteins and to GAPDH for non—phosphorylated proteins. (n = 5–6 per group, p < 0.05) Dotted line on the graph indicates levels of Non—cachectic ApcMin/+, while a dotted line on the Western blot indicates different regions of the same gel. Non = Non—Cachectic ApcMin/+ Sev = severely cachectic ApcMin/+.
Mentions: To examine the effect of cancer cachexia progression we examined non-cachectic, pre-cachectic, and severely cachectic ApcMin/+ mice. Cachexia progression suppressed Bip/GRP78 and p-IRE-1α expression, but there was no further effect on ATF6p50 expression. Expression of the apoptotic marker CHOP was induced in the severely cachectic mice, which coincided with Bip/GRP78 and IRE1α suppression (Fig. 6). Liver glycogen content was depleted in the severely cachectic ApcMin/+ mice as compared to the non—cachectic and the pre—cachectic mice (Fig. 7). The progression of cachexia induced liver PFK mRNA expression 11-fold and PEPCK mRNA expression 2-fold (Fig. 8A). No difference in either PFK or PEPCK gene expression was observed early in cachexia, as pre—cachectic mice were not different from non—cachectic mice. A significant inhibition of liver Akt and S6 phosphorylation was observed with cachexia progression. Interestingly, mTOR phosphorylation was increased both in the pre—cachectic and severely cachectic ApcMin/+ mice (Fig. 8C). SOCS3 expression did not change further with cachexia progression (Fig. 9a). Acute phase gene expression for haptoglobin was elevated ~3.5 fold, but SAA expression was not significantly different from the non—cachectic ApcMin/+ mice (Fig. 9A). Liver haptoglobin expression was increased in livers from severely cachectic mice, but not in pre—cachectic mice. Cachexia progression further increased STAT-3 phosphorylation, though there was no change in liver gp130 and albumin protein content with cachexia progression (Fig. 9B). Interestingly, cachexia progression suppressed NF-κB phosphorylation ~ 75% in the severely cachectic mice as compared to non—cachectic mice and ~65% as compared to pre—cachectic mice (Fig. 9A). Liver MMP-2 expression, an angiogenic and fibrotic marker, was suppressed 90% in the severely cachectic mice (Fig. 9B).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: 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.

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.

No MeSH data available.


Related in: MedlinePlus