Leucine metabolism in partially hepatectomized rats

Holeček, Milan; Tilšer, I; Skopec, F; Šprongl, Luděk

doi:10.1016/s0168-8278(97)80124-9

Cited by 4 publications

(4 citation statements)

References 28 publications

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“…Under conditions of starvation, the circulating levels of BCAAs have been shown to increase along with a significant decrease in BCAA oxidation . Enhanced rates of BCAA oxidation have been observed in whole body and skeletal muscle during sepsis, trauma, and after endotoxin or tumour necrosis factor treatment . It should be noted that each of these conditions is associated with cachexia.…”

Section: Discussionmentioning

confidence: 99%

“…31 Enhanced rates of BCAA oxidation have been observed in whole body and skeletal muscle during sepsis, trauma, and after endotoxin or tumour necrosis factor treatment. [32][33][34] It should be noted that each of these conditions is associated with cachexia. Interestingly, the F group had little change in circulating BCAA levels, but some of that may be due to the smaller extent of weight loss in that group.…”

Section: Discussionmentioning

confidence: 99%

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Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism

Barreto

Couch

et al. 2019

J cachexia sarcopenia muscle

176

223

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Background Cancer cachexia is a metabolic disorder involving perturbed energy balance and altered mitochondrial function. Chemotherapy is a primary treatment option for many types of cancer, but there is substantial evidence that some chemotherapeutic agents can also lead to the development and progression of cachexia. In this study, we apply a comprehensive and systems level metabolomics approach to characterize the metabolic perturbations in murine models of cancer‐induced and chemotherapy‐induced cachexia. Knowledge of the unique pathways through which cancer and chemotherapy drive cachexia is necessary in order to develop effective treatments. Methods The murine Colon26 (C26) adenocarcinoma xenograft model was used to study the metabolic derangements associated with cancer‐induced cachexia. In vivo administration of Folfiri (5‐fluorouracil, irinotecan, and leucovorin) was used to model chemotherapy‐induced cachexia. Comprehensive metabolic profiling was carried out using both nuclear magnetic resonance‐based and mass spectrometry‐based platforms. Analyses included plasma, muscle, and liver tissue to provide a systems level profiling. Results The study involved four groups of CD2F1 male mice ( n = 4–5), including vehicle treated (V), C26 tumour hosts (CC), Folfiri treated (F), and C26 tumour hosts treated with Folfiri (CCF). Significant weight loss including skeletal muscle was observed for each of the experimental groups with the tumour hosts showing the most dramatic change (−3.74 g vs. initial body weight in the CC group). Skeletal muscle loss was evident in all experimental groups compared with V, with the CCF combination resulting in the most severe depletion of quadriceps mass (−38% vs. V; P < 0.001). All experimental groups were characterized by an increased systemic glucose demand as evidenced by decreased levels of circulating glucose (−47% in CC vs. V; P < 0.001) and depletion of liver glucose (−51% in CC vs. V; P < 0.001) and glycogen (−74% in CC vs. V; P < 0.001). The cancer‐induced and chemotherapy‐induced cachexia models displayed unique alterations in flux through the tricarboxylic acid cycle and β‐oxidation pathways. Cancer‐induced cachexia was uniquely characterized by a dramatic elevation in low‐density lipoprotein particles (+6.9‐fold vs. V; P < 0.001) and a significant increase in the inflammatory marker, GlycA (+33% vs. V; P < 0.001). Conclusions The results of this study demonstrated for the first time that cancer‐induced and chemotherapy‐induced cachexia is characterized by a number of distinct metabolic derangements. Effective therapeutic interventions for cancer‐induced and chemotherapy‐induced cachexia must take into account the specific metabolic de...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism

Barreto

Couch

et al. 2019

J cachexia sarcopenia muscle

176

223

View full text Add to dashboard Cite

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“…As shown in the present study, L-Leucine and Leucylproline concentrations are higher in plasma from patients affected by NAFLD-cirrhosis and decreased after TIPS treatment. Under cirrhotic conditions, there is an increase in oxidised leucine, decreasing protein synthesis 55 . Pathophysiological leucine levels are antagonistic to insulin, promoting glucose uptake via the myostatin-AMP-activated protein kinase pathway leading to hepatic cell triglyceride accumulation 56 .…”

Section: Discussionmentioning

confidence: 99%

Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt

Bagarolo,

Bhargava,

Schierwagen

et al. 2024

Preprint

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Portal-hypertension develops in patients with advanced chronic liver diseases(CLD), especially cirrhosis and is associated with complications, such as gastrointestinal bleeding and ascites resulting in high mortality. The transjugular intrahepatic portosystemic shunt(TIPS) is a treatment option for portal-hypertension, aiming to decrease portal venous pressure by establishing an artificial passage for blood from the gastrointestinal tract to the liver vein. This study focuses on the differences in the molecular composition of plasma samples from patients with portal-hypertension before and after TIPS intervention to identify and characterise mediators influencing gut-liver cross-talk. The plasma of 23 patients suffering from advanced CLD with portal-hypertension was collected from peripheral veins before and after TIPS treatment and analysed using a well-established non-targeted chromatography-mass spectrometric(LC-MS) approach. Sialomucin core protein 24(CD164)(160–180), meckelin(99–118), Histone-lysine N-methyltransferase(MLL3)(3019–3045) and transient receptor potential cation channel subfamily V member 5(TRPV5)(614–630) were identified to be downregulated after the TIPS treatment. In addition, the metabolites 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid(CMPF), uric acid, Dopamine, homoarginine, leucylproline and 5-methyluridine were significantly decreased after TIPS, whereas one yet unidentified low molecular-weight metabolite showed an increase after the medical procedure. In conclusion, these substances are novel biomarkers for portal-hypertension in patients with CLD, with mechanistic clues of involvement in regulating pathological gut-liver cross-talk.

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“…All three of the BCAAs were found to be decreased prior to the observation of weight loss. The BCAAs are primarily catabolized in skeletal muscle and increased rates of BCAA oxidation have been observed in a range of conditions associated with cachexia, including sepsis, trauma, and treatment with endotoxin or tumor necrosis factor (TNF) (Holecek, 1996;Holecek et al, 1997Holecek et al, , 2001. This increased oxidation is consistent with the decreased serum levels.…”

Section: Discussionmentioning

confidence: 99%

Metabolic Biomarkers for the Early Detection of Cancer Cachexia

O’Connell

Golzarri‐Arroyo

et al. 2021

Front. Cell Dev. Biol.

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Background: Cancer cachexia is a severe metabolic disorder characterized by progressive weight loss along with a dramatic loss in skeletal muscle and adipose tissue. Like cancer, cachexia progresses in stages starting with pre-cachexia to cachexia and finally to refractory cachexia. In the refractory stage, patients are no longer responsive to therapy and management of weight loss is no longer possible. It is therefore critical to detect cachexia as early as possible. In this study we applied a metabolomics approach to search for early biomarkers of cachexia.Methods: Multi-platform metabolomics analyses were applied to the murine Colon-26 (C26) model of cachexia. Tumor bearing mice (n = 5) were sacrificed every other day over the 14-day time course and control mice (n = 5) were sacrificed every fourth day starting at day 2. Linear regression modeling of the data yielded metabolic trajectories that were compared with the trajectories of body weight and skeletal muscle loss to look for early biomarkers of cachexia.Results: Weight loss in the tumor-bearing mice became significant at day 9 as did the loss of tibialis muscle. The loss of muscle in the gastrocnemius and quadriceps was significant at day 7. Reductions in amino acids were among the earliest metabolic biomarkers of cachexia. The earliest change was in methionine at day 4. Significant alterations in acylcarnitines and lipoproteins were also detected several days prior to weight loss.Conclusion: The results of this study demonstrate that metabolic alterations appear well in advance of observable weight loss. The earliest and most significant alterations were found in amino acids and lipoproteins. Validation of these results in other models of cachexia and in clinical studies will pave the way for a clinical diagnostic panel for the early detection of cachexia. Such a panel would provide a tremendous advance in cachectic patient management and in the design of clinical trials for new therapeutic interventions.

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Leucine metabolism in partially hepatectomized rats

Cited by 4 publications

References 28 publications

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism

Cachexia induced by cancer and chemotherapy yield distinct perturbations to energy metabolism

Alterations of the peptidomic composition of peripheral plasma after portal hypertension correction by transjugular intrahepatic portosystemic shunt

Metabolic Biomarkers for the Early Detection of Cancer Cachexia

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