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

Abstract

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.

The Peroxisome-Mitochondria Connection: How and Why?

“…Interestingly, one of these studies found that severe malnutrition in young children, a condition associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, resulted in an almost complete disappearance of hepatic peroxisomes [173]. Recently, this finding was confirmed and extended by others, who developed a rat model of malnutrition and demonstrated that (i) prolonged dietary protein restriction decreases mitochondrial fitness in hepatocytes from weanling rats; (ii) this decrease in mitochondrial fitness is caused by enhanced peroxisome degradation; and (iii) fenofibrate supplementation, a condition enhancing hepatic peroxisome abundance (see Section 2.1), recovers hepatic mitochondrial function, thereby reducing steatosis and restoring plasma albumin levels [116]. Taken together, these studies once again underline the importance of functional peroxisomes for maintenance of mitochondrial fitness.…”

“…In the case where peroxisome biogenesis is completely blocked, such treatment also results in other mitochondrial perturbations, including structural alterations of the inner mitochondrial membrane [57,58,59], a reduction in the activities of multiple respiratory chain complexes [57,58,59], reduced mitochondrial DNA abundance [57], and an increase in mitochondrial volume [57,59]. On the other hand, an increase in catalase activity [109,114], peroxisomal β-oxidation [115] or peroxisome number [116] has been reported to ameliorate mitochondrial fitness and protect these organelles against oxidative insults. In reverse, to the best of our knowledge, there are no published studies that have addressed how specific defects in mitochondrial functions affect the redox state of peroxisomes, and this issue remains an unresolved open question.…”

“…Growing evidence suggests that changes in peroxisome turnover rates can affect human physiology and pathology [116,173,174,175]. Interestingly, one of these studies found that severe malnutrition in young children, a condition associated with signs of hepatic dysfunction such as steatosis and hypoalbuminemia, resulted in an almost complete disappearance of hepatic peroxisomes [173].…”

Metabolic Profiling Analysis of the Alleviation Effect of Treatment with Baicalin on Cinnabar Induced Toxicity in Rats Urine and Serum

“…It is important to note that peroxisomes and mitochondria play key roles in various hepatic metabolic functions, including lipid metabolism and energy production, and dysfunction in these organelles is linked to various disorders that affect the liver (van Zutphen et al, 2016). In agreement with the results, we observed high urinary alanine and lactate levels in the cinnabar group; alanine and lactate are intermediates of anaerobic metabolism.…”

Aggressive non-alcoholic steatohepatitis following rapid weight loss and/or malnutrition

“…18,31,32 Malnutrition also depresses hepatic antioxidant reserves and impairs overall metabolic function of mitochondria. 33,34 Similarly, primary graft dysfunction, which can occur in association with markedly steatotic liver allografts, corresponds to an impaired ability to recover from ischemia reperfusion. 35 It seems plausible that sustained delivery of enough free fatty acid (and perhaps associated endotoxin/cytokines), to an already compromised fatty liver, may underlie development of aggressive non-alcoholic steatohepatitis, 18,31 but mechanistic studies are needed to further investigate this hypothesis and to consider a potential role for antioxidants to protect the liver during rapid weight loss/malnutrition.…”