Department of Exercise Science and Health Promotion, Florida Atlantic University, Boca Raton, Florida.
Institute for Human Health & Disease Intervention, Florida Atlantic University, Jupiter, Florida.
Physiol Genomics. 2020 May 1;52(5):203-216. doi: 10.1152/physiolgenomics.00124.2019. Epub 2020 Mar 9.
Cachexia is a life-threatening complication of cancer traditionally characterized by weight loss and muscle dysfunction. Cachexia, however, is a systemic disease that also involves remodeling of nonmuscle organs. The liver exerts major control over systemic metabolism, yet its role in cancer cachexia is not well understood. To advance the understanding of how the liver contributes to cancer cachexia, we used quantitative proteomics and bioinformatics to identify hepatic pathways and cellular processes dysregulated in mice with moderate and severe colon-26 tumor-induced cachexia; ~300 differentially expressed proteins identified during the induction of moderate cachexia were also differentially regulated in the transition to severe cachexia. KEGG pathway enrichment revealed representation by oxidative phosphorylation, indicating altered hepatic mitochondrial function as a common feature across cachexia severity. Glycogen catabolism was also observed in cachexic livers along with decreased pyruvate dehydrogenase protein X component (Pdhx), increased lactate dehydrogenase A chain (Ldha), and increased lactate transporter Mct1. Together this suggests altered lactate metabolism and transport in cachexic livers, which may contribute to energetically inefficient interorgan lactate cycling. Acyl-CoA synthetase-1 (ACSL1), known for activating long-chain fatty acids, was decreased in moderate and severe cachexia based on LC-MS/MS analysis and immunoblotting. ACSL1 showed strong linear relationships with percent body weight change and muscle fiber size (R = 0.73-0.76, < 0.01). Mitochondrial coupling efficiency, which is compromised in cachexic livers to potentially increase energy expenditure and weight loss, also showed a linear relationship with ACSL1. Findings suggest altered mitochondrial and substrate metabolism of the liver in cancer cachexia, and possible hepatic targets for intervention.
恶病质是一种危及生命的癌症并发症，传统上以体重减轻和肌肉功能障碍为特征。然而，恶病质是一种全身性疾病，还涉及非肌肉器官的重塑。肝脏对全身代谢起着主要的控制作用，但它在癌症恶病质中的作用尚未得到很好的理解。为了深入了解肝脏如何导致癌症恶病质，我们使用定量蛋白质组学和生物信息学方法来鉴定中度和重度结肠-26 肿瘤诱导恶病质的小鼠中失调的肝途径和细胞过程；在中度恶病质诱导过程中鉴定的约 300 个差异表达蛋白在向严重恶病质的转变过程中也受到差异调节。KEGG 途径富集显示氧化磷酸化的代表性，表明肝脏线粒体功能改变是恶病质严重程度的共同特征。在恶病质肝脏中还观察到糖原分解，同时丙酮酸脱氢酶蛋白 X 成分（Pdhx）减少，乳酸脱氢酶 A 链（Ldha）增加，以及乳酸转运蛋白 Mct1 增加。这表明在恶病质肝脏中存在改变的乳酸代谢和转运，这可能有助于能量效率低下的器官间乳酸循环。酰基辅酶 A 合成酶-1（ACSL1），已知可激活长链脂肪酸，根据 LC-MS/MS 分析和免疫印迹显示在中度和重度恶病质中减少。ACSL1 与体重百分比变化和肌肉纤维大小呈强线性关系（R = 0.73-0.76， < 0.01）。在恶病质肝脏中受损的线粒体偶联效率可能会增加能量消耗和体重减轻，与 ACSL1 也呈线性关系。研究结果表明，在癌症恶病质中肝脏的线粒体和底物代谢发生改变，可能成为干预的潜在靶点。
