Phytosphingosine degradation pathway includes fatty acid α-oxidation reactions in the endoplasmic reticulum

Significance Although the synthetic pathway of phytosphingosine is already known, its degradation pathway has remained unclear. In the present study, we reveal the entire phytosphingosine degradation pathway, where fatty acid α-oxidation is involved. We show that the Sjögren–Larsson syndrome-causative gene ALDH3A2 and HACL2 (2-hydroxyacyl-CoA lyase 2) are involved in the fatty acid α-oxidation reactions as an aldehyde dehydrogenase and a 2-hydroxy acyl-CoA lyase, respectively. Our findings are important for understanding the molecular mechanism of phytosphingosine/sphingolipid homeostasis. HACL2 is localized in the endoplasmic reticulum, indicating that fatty acid α-oxidation occurs in the endoplasmic reticulum in mammals, in addition to the α-oxidation already known to occur in peroxisomes.