105 4 Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model it was suggested that DHA levels in malnourished children highly depend on the DHA intake from breast milk51. The effects of DHA supplementation have been previously tested in the context of malnutrition. For instance, supplementation in malnourished rats led to a decrease in the production of malondialdehyde (MDA) in blood, a lipid peroxidation marker that reports oxidative stress. It also increased the levels of superoxide dismutase52, together suggesting that DHA supplementation may reduce oxidative stress. A clinical study in malnourished Malawian children showed that RUTF supplemented with DHA led to an increase in the Malawi Developmental Assessment Tool (MDAT) score. This could be attributed to its clear cognitive benefit and increase in levels of in 1-palmitoyl2-eicosapentaenoyl-sn-glycero-3-phosphocholine, an ω3 fatty acid that is important for regulation of cognition53. In line with this, breast-milk LCPUFA levels were linked to neural maturation of breastfed infants54,55. These reports in combination emphasize the potential of DHA as a beneficial supplement for the treatment of malnourished children. To the best of our knowledge, there are no reports on the effect of DHA on the peroxisomal and mitochondrial content in the liver of malnourished children. Moreover, the fact that WY-14463 and LA showed no effect on peroxisomal recovery suggests that the effects of DHA might not be PPAR-α related. In fibroblasts from patients carrying defects in peroxisomal β-oxidation, DHA supplementation induced peroxisomal elongation via oligomerization of PEX11β and peroxisomal division via DLP1, thus boosting peroxisomal content 56. This mechanism might potentially explain the higher levels of peroxisomal proteins in DHA treated organoids in our study. It needs to be investigated whether DHA prevents peroxisomal loss in vivo during exposure to an LPD. When combining all information, both the effect of LDP and of DHA seem context dependent. The LPD induced autophagy in a short-term experiment1. DHA blocked autophagy activation in Huh7 cells, had no effect on autophagy in amino-acid deprived hepatic organoids (this study), and was previously reported to activate autophagy in the presence of amino acids, via mTORC 57. One study reported that DHA inhibited oxidative stressed-induced autophagy via the AMPK-dependent signaling pathway42, while another showed a decrease in autophagy markers in TNF-α-induced autophagy41. This suggests that DHA may act via multiple routes in a context dependent manner. That PPAR-α activators (WY-14463 and LA) had no effect on the Huh7 (Supplementary Figure 3), may be explained by the generally low effect of PPAR- α activators on human cells in contrast to rodent cells58.
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