Malnutrition-associated hepatic steatosis and ATP depletion is caused by peroxisomal and mitochondrial dysfunction and rescued by fenofibrate

Severe malnutrition in young children is associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, but its etiology is unknown. To investigate the underlying mechanisms of hepatic dysfunction we used a rat model of malnutrition by placing weanling rats on a low protein or control diet (5% or 20% of calories from protein, respectively) for four weeks. Low protein diet-fed rats developed hypoalbuminemia and severe hepatic steatosis, consistent with the human phenotype. Hepatic peroxisome content was decreased and metabolomic analysis indicated impaired peroxisomal function. Loss of peroxisomes was followed by accumulation of dysfunctional mitochondria and decreased hepatic ATP levels. Fenofibrate supplementation restored hepatic peroxisome abundance and increased mitochondrial fatty acid -oxidation capacity, resulting in reduced steatosis and normalization of ATP and plasma albumin levels. These findings provide important insight into the metabolic

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van Zutphen T, Ciapaite J, Bloks VW, Ackereley C, Gerding A, Jurdzinski A, de Moraes RA, Zhang L, Wolters JC, Bischoff R, Wanders RJ, Houten SM, Bronte-Tinkew D, Shatseva T, Lewis GF, Groen AK, Reijngoud DJ, Bakker BM, Jonker JW, Kim PK, Bandsma RH