15 1 General Introduction number of autophagic structures in the cells, they do not quantify the actual autophagic flux73. Very few papers have been published on the role of autophagy in the intestine of LPD-fed rodents. Only one study has reported that 2 weeks of low protein diet led to a decreased autophagy in the intestine of rodents, which was thought to be the cause of the observed accumulation of dysfunctional mitochondria60. Peroxisomal biogenesis and PPAR-α activation To date, no clear link between amino-acid restriction and decreased peroxisomal biogenesis has been made. One in vivo studied in malnourished rats showed no clear effect of LPD on the expression of different peroxins56. Peroxisome proliferator-activated receptor (PPAR)-α is a transcriptional factor belonging to the family of nuclear receptors. It is an important regulator of energy homeostasis74 and it controls the expression of genes involved in β-oxidation of fatty acids75,76. Moreover, PPAR- α activation is known to induce proliferation of peroxisomes77. Traditionally, PPAR-α activators, such as fibrates, have been used to treat dyslipidemia as well as to induce biogenesis of peroxisomes and mitochondria78. While no clear effect of malnutrition on peroxisomal and mitochondrial biogenesis has been described, the effect of these compounds has been previously studied in the context of malnutrition56,79. It is important to mention that some of these compounds have also been reported to cause side effects. For example, fenofibrate was able to reduce plasma triglycerides in PPAR-α null mice, as expected, but it also increased the levels of intrahepatic triglycerides80. Different natural ligands, such as eicosanoid derivatives and long chain polyunsaturated fatty acids (LCPUFA) have been reported to activate PPARα76,81,82. The ability of these natural compounds to activate PPAR-α, and thereby peroxisomal and mitochondrial biogenesis, opens the door to potential new therapies for malnutrition based on natural food supplements. In this line, several studies have already been published on the positive effects of the LCPUFA docosahexaenoic acid (DHA) on different aspects of malnutrition, such as antioxidants metabolism in rodents83 and regulation of cognition in malnourished infants84. Both of these studies highlighted the benefits of DHA supplementation in severe malnutrition.
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