Fatty aldehyde dehydrogenase is up-regulated by polyunsaturated fatty acid via peroxisome proliferator-activated receptor alpha and suppresses polyunsaturated fatty acid-induced endoplasmic reticulum stress.
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 alpha-oxidation pathway. FALDH-N, another splice isoform of FALDH, is induced by peroxisomal proliferator-activated receptor alpha 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 alpha 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 alpha. 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 alpha to activate the expression of FALDH-N, which then detoxifies polyunsaturated fatty acid-derived fatty aldehydes and protects cells from endoplasmic reticulum stress.
Department of Biochemistry, Meiji Pharmaceutical University, Kiyose, Tokyo, Japan.
Bunichiro
B
Ashibe
Kiyoto
K
Motojima
D000445:Aldehyde Oxidoreductases / Q000235:genetics* / Q000378:metabolism; D000818:Animals; D002478:Cells, Cultured; D004721:Endoplasmic Reticulum / Q000378:metabolism*; D005231:Fatty Acids, Unsaturated / Q000494:pharmacology*; D006801:Humans; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D018384:Oxidative Stress; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D014162:Transfection; D015854:Up-Regulation
D005231:Fatty Acids, Unsaturated; D047493:PPAR alpha; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase