91 4 Docosahexaenoic acid prevents peroxisomal and mitochondrial protein loss in a murine hepatic organoid model INTRODUCTION Recent studies have identified the loss of peroxisomes and mitochondrial dysfunction as key consequences of low protein diets in rodents1–3, leading to metabolic aberrations, similarly as was previously observed in malnourished children4. These results were recapitulated in vitro using hepatic organoids grown in a low amino acid environment5. Although these models have shed some light on the interplay of mitochondria and peroxisomes in malnutrition, little is known about the pathophysiology behind the loss of both organelles. Degradation of organelles in low amino acid concentrations has been previously linked to an increase in autophagic turnover6, which was also observed in malnourished rodents1. Organelles such as peroxisomes and mitochondria are frequently degraded via selective autophagy7,8. Autophagy helps to remove and degrade misfolded proteins or damaged organelles. Moreover, autophagy also helps maintaining adequate cellular levels of amino acids as precursors for biosynthesis or as fuels, when there is a shortage of these nutrients9. Prolonged autophagy and loss of peroxisomes and mitochondria, however, may affect their essential functions in lipid metabolism. Staple foods high in carbohydrates, lack of access to varied diets, and food insecurity are common in developing countries. These factors, and specifically low protein diets, often lead to severe malnutrition in young children10, characterized by an imbalance in energy and nutrient intake in relation to the body’s requirements. Malnutrition is regarded as one of the most severe deficiencies of macronutrients and it affects metabolic homeostasis, thus hampering healthy development of children. Severe acute malnutrition (SAM) is known as the most life-threatening type of malnutrition11. Children with severe malnutrition commonly develop symptoms of hepatic dysfunction including hypoglycaemia, hypoalbuminemia and hepatic steatosis12,13. Impaired lipid oxidation has also been observed in malnourished children, and is thought to be the main cause of hepatic steatosis14,15. Post-mortem electron microscopy images showed a decreased number of peroxisomes and compromised mitochondria in the liver of malnourished children4. In agreement with the key role of these organelles in lipid metabolism, this is accompanied by the development of hepatic steatosis and increased oxidative stress in malnourished children. Current management protocols often do not lead to rapid metabolic recovery16 and mortality remains high in acutely ill children with severe malnutrition17, which makes the need for new treatment approaches of high importance. Peroxisome proliferator-activated receptor (PPAR)-α is a transcriptional
RkJQdWJsaXNoZXIy MTk4NDMw