Malnutrition-associated liver steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction.
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.
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Tim
T
van Zutphen
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.
Jolita
J
Ciapaite
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Vincent W
VW
Bloks
Department of Paediatric Laboratory Medicine, The Hospital for Sick Children, Toronto, Canada.
Cameron
C
Ackereley
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Albert
A
Gerding
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Angelika
A
Jurdzinski
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Roberta Allgayer
RA
de Moraes
Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada.
Ling
L
Zhang
Systems Biology Centre for Energy Metabolism and Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands.
Justina C
JC
Wolters
Systems Biology Centre for Energy Metabolism and Ageing, University of Groningen, University Medical Centre Groningen, Groningen, The Netherlands; Department of Pharmacy, Analytical Biochemistry, University of Groningen, Groningen, The Netherlands.
Rainer
R
Bischoff
Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands (current address: Icahn Institute for Genomics and Multiscale Biology, New York, USA).
Ronald J
RJ
Wanders
Laboratory Genetic Metabolic Diseases, Departments of Pediatrics and Clinical Chemistry, Academic Medical Center, Amsterdam, The Netherlands (current address: Icahn Institute for Genomics and Multiscale Biology, New York, USA).
Sander M
SM
Houten
Program in Cell Biology, Hospital for Sick Children, Toronto, Canada.
Dana
D
Bronte-Tinkew
Program in Cell Biology, Hospital for Sick Children, Toronto, Canada.
Tatiana
T
Shatseva
The Division of Endocrinology and Metabolism, Department of Medicine and the Banting and Best Diabetes Centre, University of Toronto, Toronto, Canada.
Gary F
GF
Lewis
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Albert K
AK
Groen
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Dirk-Jan
DJ
Reijngoud
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.
Barbara M
BM
Bakker
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands.
Johan W
JW
Jonker
Program in Cell Biology, Hospital for Sick Children, Toronto, Canada; Department of Biochemistry, University of Toronto, Toronto, Canada. Electronic address: pkim@sickkids.ca.
Peter K
PK
Kim
Department of Pediatrics, Center for Liver, Digestive and Metabolic Diseases, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands; Physiology and Experimental Medicine Program, Research Institute, The Hospital for Sick Children, Toronto, Canada; Division of Gastroenterology, Hepatology and Nutrition, The Hospital for Sick Children, Toronto, Canada; Centre for Global Child Health, The Hospital for Sick Children, Toronto, Canada. Electronic address: robert.bandsma@sickkids.ca.
Robert H J
RH
Bandsma
D000255:Adenosine Triphosphate; D000818:Animals; D002648:Child; D005234:Fatty Liver; D006801:Humans; D008099:Liver; D044342:Malnutrition; D008928:Mitochondria; D010084:Oxidation-Reduction; D051381:Rats
D000255:Adenosine Triphosphate
Hepatic steatosis; Kwashiorkor; Malnutrition; Marasmus; Metabolism; Mitochondria; Peroxisomes; Targeted quantitative proteomics