Hepatocyte nuclear factor 4-mediated lipotoxicity provokes mitochondrial damage in peroxisome-deficient pex19 mutants

Peroxisomes are important metabolic organelles involved in the catabolism of several lipid classes, e.g. very-long-chain fatty acids. Malfunction or absence of peroxisomes leads to accumulation of educts for peroxisomal {beta}-oxidation and mitochondrial damage, resulting in fatal perturbation of metabolism. The impact of peroxisome deficiency on mitochondria is not elucidated yet. Here we present a model of Hepatocyte nuclear factor 4 (Hnf4)-induced lipotoxicity and accumulation of non-esterified fatty acids (NEFA) as the cause for mitochondrial damage in consequence of peroxisome loss in a Peroxin19 (pex19) mutant. Hyperactive Hnf4 signaling leads to upregulation of lipase 3 and enzymes fo