Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis

Peroxisomes play an essential role in the ß-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ?-oxidation of fatty acids. The physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). We performed RNA-seq in WT and Ehhadh KO livers, treated with vehicle or L-aminocarnitine (L-AC), an inhibitor of mitochondrial fatty acid oxidation. We show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA ß-oxidation is a regulator of hepatic cholesterol biosynthesis. Overall design: 23 samples from mouse livers were analyzed distributed into 4 groups (WT+Veh; KO+Veh; WT+L-AC; KO+L-AC)