Fatty aldehyde dehydrogenase is up-regulated by polyunsaturated fatty acid via peroxisome proliferator-activated receptor α and suppresses polyunsaturated fatty acid-induced endoplasmic reticulum stress

Abstract

Fatty aldehyde dehydrogenase (FALDH; also known as ALDH3A2 or ALDH10) oxidizes medium- or long-chain aliphatic aldehydes. FALDH deficiency in humans is known to be the cause of Sjögren-Larsson syndrome, in which individuals display neurological symptoms and cutaneous abnormality. FALDH-V, a splice isoform of FALDH, is localized in the peroxisome and contributes to the oxidization of pristanal, an intermediate of the α-oxidation pathway. FALDH-N, another splice isoform of FALDH, is induced by peroxisomal proliferator-activated receptor α ligands, although its activation mechanism has not been clarified. In the present study, we show that transcriptional activation of FALDH is directly regulated by peroxisomal proliferator-activated receptor α through a direct repeat-1 site located in the FALDH promoter. In addition, FALDH is efficiently induced by linoleic acid in rat hepatoma Fao cells through transcriptional activation by peroxisomal proliferator-activated receptor α. Furthermore, ectopic expression of endoplasmic reticulum-localizing FALDH-N, but not peroxisome-localizing FALDH-V, suppresses endoplasmic reticulum stress caused by linoleic acid in HEK293 cells. These results suggest the autocatalytic nature of the FALDH-N system against endoplasmic reticulum stress that is induced by polyunsaturated fatty acid; polyunsaturated fatty acid binds to peroxisomal proliferator-activated receptor α to activate the expression of FALDH-N, which then detoxifies polyunsaturated fatty acid-derived fatty aldehydes and protects cells from endoplasmic reticulum stress. © 2009 FEBS.