Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction

JOURNAL OF HEPATOLOGY

卷:65

Article

van Zutphen, Tim¹  Ciapaite, Jolita^1,2  Bloks, Vincent W.¹  Ackereley, Cameron³  Gerding, Albert¹  Jurdzinski, Angelika¹  de Moraes, Roberta Allgayer¹  Zhang, Ling⁴  Wolters, Justina C.^2,5  Bischoff', Rainer^2,5  Wanders, Ronald J.^6,7,8  Houten, Sander M.^6,7,8  Bronte-Tinkew, Dana⁹  Shatseva, Tatiana⁹  Lewis, Gary F.^10,11  Groen, Albert K.¹  Reijngoud, Dirk-Jan¹  Bakker, Barbara M.^1,2  Jonker, Johan W.¹  Kim, Peter K.^9,13  Bandsma, Robert H. J.^1,4,12,14 

[1] Univ Groningen, Univ Med Ctr Groningen, Ctr Liver Digest & Metab Dis, Dept Pediat, Groningen, Netherlands

[2] Univ Groningen, Univ Med Ctr Groningen, Syst Biol Ctr Energy Metab & Ageing, Groningen, Netherlands

[3] Hosp Sick Children, Dept Paediat Lab Med, Toronto, ON, Canada

[4] Hosp Sick Children, Res Inst, Physiol & Expt Med Program, Toronto, ON, Canada

[5] Univ Groningen, Analyt Biochem, Dept Pharm, Groningen, Netherlands

[6] Acad Med Ctr, Lab Genet Metab Dis, Dept Pediat, Amsterdam, Netherlands

[7] Acad Med Ctr, Lab Genet Metab Dis, Dept Clin Chem, Amsterdam, Netherlands

[8] Icahn Inst Genom & Multiscale Biol, New York, NY USA

[9] Hosp Sick Children, Program Cell Biol, Toronto, ON, Canada

[10] Univ Toronto, Dept Med, Div Endocrinol & Metab, Toronto, ON, Canada

[11] Univ Toronto, Banting & Best Diabet Ctr, Toronto, ON, Canada

[12] Hosp Sick Children, Div Gastroenterol Hepatol & Nutr, Toronto, ON, Canada

[13] Univ Toronto, Dept Biochem, Toronto, ON, Canada

[14] Hosp Sick Children, Ctr Global Child Hlth, Toronto, ON, Canada

关键词: Malnutrition;    Kwashiorkor;    Marasmus;    Metabolism;    Hepatic steatosis;    Peroxisomes;    Mitochondria;    Targeted quantitative proteomics;   

DOI  :  10.1016/j.jhep.2016.05.046

来源: Elsevier

【 摘 要 】

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. Methods: 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 beta-oxidation pathways. Results: 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 13-oxidation enzymes, leading to strongly reduced hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial beta-oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. Conclusions: 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. Lay summary: 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. (C) 2016 European Association for the Study of the Liver. Published by Elsevier B.V.

【 授权许可】

Free