Fatty aldehyde dehydrogenase (FALDH, ALDH3A2) is thought to be involved in the degradation of phytanic acid, a saturated branched chain fatty acid derived from chlorophyll. However, the identity, subcellular distribution, and physiological roles of FALDH are unclear because several variants produced by alternative splicing are present in varying amounts at different subcellular locations. Subcellular fractionation experiments do not provide a clear-cut conclusion because of the incomplete separation of organelles. We established human cell lines heterologously expressing mouse FALDH from each cDNA without tagging under the control of an inducible promoter and detected the variant FALDH proteins using a mouse FALDHspecific antibody. One variant, FALDH-V, was exclusively detected in peroxisomal membranes. Human FALDH-V with an amino-terminal Myc sequence also localized to peroxisomes. The most dominant form, FALDH-N, and other variants examined, however, were distributed in the endoplasmic reticulum. A gas chromatography-mass spectrometry-based analysis of metabolites in FALDH-expressing cells incubated with phytol or phytanic acid showed that FALDH-V, not FALDH-N, is the key aldehyde dehydrogenase in the degradation pathway and that it protects peroxisomes from oxidative stress. In contrast, both FALDHs had a protective effect against oxidative stress induced by a model aldehyde for lipid peroxidation, dodecanal. These results suggest that FALDH variants are produced by alternative splicing and share an important role in protecting against oxidative stress in an organelle-specific manner.Plants produce a variety of secondary metabolites, and some of these are potentially toxic to animals (1). Herbivora have developed behavioral and physiological strategies to avoid specific plants and to detoxify any toxins ingested. Detoxification can occur in the mouth and the gut rumen with or without the help of microbes (2). The absorbed toxins must be detoxified in the intestine and liver, but studies on these mechanisms are limited because to date most animal experiments have been carried out using laboratory diets. Recently we found that a nuclear receptor, peroxisome proliferator-activated receptor ␣ (PPAR␣), 2 is involved in the detoxification by using plant seeds as a diet for mice (3).PPAR␣ is activated by fatty acid ligands and is an important regulator of lipid metabolism in animals (4). Despite the claimed essential role of this receptor in the liver, the PPAR␣-null mouse shows little phenotypic change when fed a normal laboratory diet (5, 6). We have examined its extrahepatic roles and found that PPAR␣ induces the expression of 17␤-hydroxysteroid dehydrogenase type 11 in the intestine (7). Recent studies on the substrates of 17␤-hydroxysteroid dehydrogenase type 11 showed that they include not only glucocorticoids and sex steroids but also bile acids, fatty acids, and branched amino acids (8, 9). So we examined the possibility that PPAR␣ plays a vital role in inducing enzymes for metabolizing secondary metabolites...

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.

The peroxisome proliferator-activated receptor (PPAR) subtype specificity of GW501516, a well-known PPARδ-specific agonist, was studied by examining its effects on the expression of endogenous genes in primary hepatocytes and the liver of wild-type and PPARα-null mice. GW501516, like the PPARα-specific agonist Wy14,643, induced the expression of several PPAR target genes in a dose-dependent manner but this action was mostly absent in the cells and liver of PPARα-null mice. Results indicated that GW501516 acts as an efficient PPARα activator in the mouse liver.

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