104 Chapter 4 into the peroxisome via PTS1, which then binds to PEX5. Nonetheless, PEX5 is clearly upregulated in the amino-acid deprived conditions, which does not go in line with the decrease in both catalase and ACOX1. This might indicate a compensatory mechanism in order to promote peroxisomal import in conditions with lower number of peroxisomes. Different therapeutics, including peroxisomal and mitochondrial biogenesis activators as well as autophagy regulators, have been tested in order to prevent peroxisomal and mitochondrial loss and hepatic dysfunction in the context of malnutrition. Activation of PPAR-α activates peroxisomal and mitochondrial biogenesis as well as genes encoding enzymes involved in peroxisomal and mitochondrial fatty acid oxidation22,44,45. In order to prevent peroxisomal and mitochondrial loss in the context of malnutrition, PPAR-α agonist fenofibrate has been previously tested both in vitro and in vivo1,5. Fenofibrate supplementation recovered the levels of peroxisomal protein marker PMP70 and lowered hepatic triglycerides while increasing the levels of ATP in a LPD rat model1. Fibrates have been widely used for the treatment of dyslipidemia and to induce the biogenesis of peroxisomes and mitochondria ameliorating the hepatic phenotype46. Fibrates however cause some side effects. When PPAR-α null mice were administered fenofibrate, the levels of serum triglycerides were decreased, but intrahepatic TGs were significantly increased47. These results suggest that these compounds might not be ideal candidates to treat malnourished children. In the case of malnourished children, treatment with dietary supplements is attractive as a simple and safe approach when compared to synthetic compounds such as fibrates. Conveniently, polyunsaturated fatty acids have also been reported to be potent PPAR activators48. These compounds can be found in foods and can be easily supplemented on ready-to-use foods (RTUF) already used in refeeding protocols for malnourished children. Docosahexaenoic acid is a potential candidate to prevent peroxisomal loss in in vivo conditions Docosahexaenoic acid is an ω-3 LCPUFA commonly found in seafood, seaweed and breast milk. It can also be synthesized from α-linolenic acid (ALA)49. DHA plays an important role in many metabolic processes, and can be found in the bloodstream, lipid stores and cell membranes. Adequate levels of DHA in infants have been linked with optimal development50. Moreover, low levels of DHA were found in breast milk from mothers from malnourished children and
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