Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Systems Biology Centre for Energy Metabolism and Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands.
J Hepatol. 2016 Dec;65(6):1198-1208. doi: 10.1016/j.jhep.2016.05.046. Epub 2016 Jun 14.
BACKGROUND & AIMS: Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. Peroxisomes and mitochondria play key roles in various hepatic metabolic functions including lipid metabolism and energy production. To investigate the involvement of these organelles in the mechanisms underlying malnutrition-induced hepatic dysfunction we developed a rat model of malnutrition.
Weanling rats were placed on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Peroxisomal and mitochondrial structural features were characterized using immunofluorescence and electron microscopy. Mitochondrial function was assessed using high-resolution respirometry. A novel targeted quantitative proteomics method was applied to analyze 47 mitochondrial proteins involved in oxidative phosphorylation, tricarboxylic acid cycle and fatty acid β-oxidation pathways.
Low protein diet-fed rats developed hypoalbuminemia and hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated peroxisomal dysfunction. This was followed by changes in mitochondrial ultrastructure and increased mitochondrial content. Mitochondrial function was impaired due to multiple defects affecting respiratory chain complex I and IV, pyruvate uptake and several β-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial β-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels.
Malnutrition leads to severe impairments in hepatic peroxisomal and mitochondrial function, and hepatic metabolic dysfunction. We discuss the potential future implications of our findings for the clinical management of malnourished children.
Severe malnutrition in children is associated with metabolic disturbances that are poorly understood. In order to study this further, we developed a malnutrition animal model and found that severe malnutrition leads to an impaired function of liver mitochondria which are essential for energy production and a loss of peroxisomes, which are important for normal liver metabolic function.
幼儿严重营养不良与肝功能障碍的迹象有关，如脂肪变性和低白蛋白血症，但病因不明。过氧化物酶体和线粒体在各种肝代谢功能中发挥关键作用，包括脂质代谢和能量产生。为了研究这些细胞器在营养不良引起的肝功能障碍机制中的作用，我们建立了一种营养不良的大鼠模型。
我们将断乳大鼠置于低蛋白或对照饮食（分别为 5%或 20%的热量来自蛋白质）4 周。使用免疫荧光和电子显微镜观察过氧化物酶体和线粒体的结构特征。使用高分辨率呼吸测定法评估线粒体功能。应用一种新的靶向定量蛋白质组学方法分析涉及氧化磷酸化、三羧酸循环和脂肪酸β-氧化途径的 47 种线粒体蛋白。
低蛋白饮食喂养的大鼠出现低白蛋白血症和肝脂肪变性，与人类表型一致。肝过氧化物酶体含量减少，代谢组学分析表明过氧化物酶体功能障碍。随后，线粒体超微结构发生变化，线粒体含量增加。由于影响呼吸链复合物 I 和 IV、丙酮酸摄取和几种β-氧化酶的多种缺陷，导致肝 ATP 水平显著降低，线粒体功能受损。非诺贝特补充恢复了肝过氧化物酶体的丰度，并增加了线粒体β-氧化能力，从而减少了脂肪变性并使肝 ATP 和血浆白蛋白水平正常化。
营养不良导致肝过氧化物酶体和线粒体功能以及肝代谢功能严重受损。我们讨论了我们的发现对营养不良儿童临床管理的潜在未来意义。
儿童严重营养不良与代谢紊乱有关，但目前对此了解甚少。为了进一步研究，我们建立了一种营养不良动物模型，发现严重营养不良导致肝脏线粒体功能受损，这对于能量产生至关重要，同时还导致过氧化物酶体丧失，而过氧化物酶体对于正常的肝脏代谢功能也很重要。
