title: Fatty aldehyde dehydrogenase: potential role in oxidative stress protection and regulation of its gene expression by insulin.
abstract: Phosphatidylinositol 3-kinase signaling regulates the expression of several genes involved in lipid and glucose homeostasis; deregulation of these genes may contribute to insulin resistance and progression toward type 2 diabetes. By employing RNA arbitrarily primed-PCR to search for novel phosphatidylinositol 3-kinase-regulated genes in response to insulin in isolated rat adipocytes, we identified fatty aldehyde dehydrogenase (FALDH), a key component of the detoxification pathway of aldehydes arising from lipid peroxidation events. Among these latter events are oxidative stresses associated with insulin resistance and diabetes. Upon insulin injection, FALDH mRNA expression increased in rat liver and white adipose tissue and was impaired in two models of insulin-resistant mice, db/db and high fat diet mice. FALDH mRNA levels were 4-fold decreased in streptozotocin-treated rats, suggesting that FALDH deregulation occurs both in hyperinsulinemic insulin-resistant state and hypoinsulinemic type 1 diabetes models. Moreover, insulin treatment increases FALDH activity in hepatocytes, and expression of FALDH was augmented during adipocyte differentiation. Considering the detoxifying role of FALDH, its deregulation in insulin-resistant and type 1 diabetic models may contribute to the lipid-derived oxidative stress. To assess the role of FALDH in the detoxification of oxidized lipid species, we evaluated the production of reactive oxygen species in normal versus FALDH-overexpressing adipocytes. Ectopic expression of FALDH significantly decreased reactive oxygen species production in cells treated by 4-hydroxynonenal, the major lipid peroxidation product, suggesting that FALDH protects against oxidative stress associated with lipid peroxidation. Taken together, our observations illustrate the importance of FALDH in insulin action and its deregulation in states associated with altered insulin signaling.
authors.affiliation: INSERM U145, IFR 50, Faculté de Médecine, Avenue de Valombrose, 06107 Nice Cedex 2, France.
authors.forename: Damien
authors.initials: D
authors.lastname: Demozay
authors.forename: Stéphane
authors.initials: S
authors.lastname: Rocchi
authors.forename: Jean-Christophe
authors.initials: JC
authors.lastname: Mas
authors.forename: Sophie
authors.initials: S
authors.lastname: Grillo
authors.forename: Luciano
authors.initials: L
authors.lastname: Pirola
authors.forename: Carine
authors.initials: C
authors.lastname: Chavey
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Van Obberghen
mesh_terms: D000256:Adenoviridae / Q000235:genetics; D017667:Adipocytes / Q000378:metabolism; D000273:Adipose Tissue / Q000378:metabolism; D000445:Aldehyde Oxidoreductases / Q000737:chemistry / Q000502:physiology*; D000447:Aldehydes / Q000494:pharmacology; D000818:Animals; D015152:Blotting, Northern; D015153:Blotting, Western; D002454:Cell Differentiation; D046508:Culture Techniques; D015853:Cysteine Proteinase Inhibitors / Q000494:pharmacology; D003921:Diabetes Mellitus, Experimental / Q000201:enzymology; D015971:Gene Expression Regulation, Enzymologic; D022781:Hepatocytes / Q000378:metabolism; D006801:Humans; D007328:Insulin / Q000378:metabolism*; D007333:Insulin Resistance; D050356:Lipid Metabolism; D015227:Lipid Peroxidation; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008954:Models, Biological; D018384:Oxidative Stress; D010100:Oxygen / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016133:Polymerase Chain Reaction; D012313:RNA / Q000737:chemistry; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D017382:Reactive Oxygen Species; D015398:Signal Transduction; D013311:Streptozocin / Q000494:pharmacology; D014018:Tissue Distribution
chemical_list: D000447:Aldehydes; D015853:Cysteine Proteinase Inhibitors; D007328:Insulin; D012333:RNA, Messenger; D017382:Reactive Oxygen Species; D013311:Streptozocin; D012313:RNA; D000445:Aldehyde Oxidoreductases; C038828:long-chain-aldehyde dehydrogenase; D019869:Phosphatidylinositol 3-Kinases; C027576:4-hydroxy-2-nonenal; D010100:Oxygen