Short title: Lipid droplet localization of ALDH3B2Summary statement: The mouse aldehyde dehydrogenases ALDH3B2 and ALDH3B3 exhibit similar substrate specificity but distinct intracellular localization (ALDH3B2, lipid droplets; ALDH3B3, plasma membrane). The C-terminal prenylation and two Trp residues are important for the lipid droplet localization of ALDH3B2.2 ABSTRACT Aldehyde dehydrogenases (ALDHs) catalyze the conversion of toxic aldehydes to non-toxic carboxylic acids. Of the 21 ALDHs in mice, it is the ALDH3 family members (ALDH3A1, ALDH3A2, ALDH3B1, ALDH3B2, and ALDH3B3) that are responsible for the removal of lipid-derived aldehydes. However, ALDH3B2 and ALDH3B3 have yet to be characterized.Here, we examined the enzyme activity, tissue distribution, and subcellular localization of ALDH3B2 and ALDH3B3. Both were found to exhibit broad substrate preferences from medium-chain to long-chain aldehydes, resembling ALDH3A2 and ALDH3B1. Although ALDH3B2 and ALDH3B3 share extremely high sequence similarity, their localizations differed, with ALDH3B2 found in lipid droplets and ALDH3B3 localized to the plasma membrane. Both ALDH3B2 and ALDH3B3 were modified by prenylation at their C-termini; this modification greatly influenced their membrane localization and enzymatic activity toward hexadecanal. We found that their C-terminal regions, particularly the two Trp residues (Trp462 and Trp469) of ALDH3B2 and the two Arg residues (Arg462 and Arg463) of ALDH3B3, were important for the determination of their specific localization. Abnormal quantity and perhaps quality of lipid droplets are implicated in several metabolic diseases. We speculate that ALDH3B2 acts to remove lipid-derived aldehydes in lipid droplets generated via oxidative stress as a quality control mechanism.
The fatty aldehyde dehydrogenase (FALDH) ALDH3A2 is the causative gene of Sjögren Larsson syndrome (SLS Sjögren-Larsson syndrome (SLS)2 is a hereditary neurocutaneous disorder caused by mutations in the fatty aldehyde dehydrogenase (FALDH) gene, ALDH3A2. The major symptoms of SLS are mental retardation, spastic di-or tetraplegia, and ichthyosis, with crystalline macular dystrophy sometimes comorbid (1). ALDH3A2 catalyzes the conversion of fatty aldehydes with medium-chain (MC) to very-long-chain fatty acids (FA) (MC, C5-C10; long-chain (LC), C11-C20; and very-longchain, ՆC21), with the most preferred substrates being C16 and C18 aldehydes (2, 3). To date, more than 70 mutations have been found in the ALDH3A2 gene of SLS patients, and most of them cause Ͼ90% reduction in enzyme activity (4). Because aldehyde molecules are reactive and toxic in general, it is considered that accumulated fatty aldehydes cause the SLS pathology by reacting with certain important proteins in the nervous system and epidermis and compromising their functions. Furthermore, the literature lacks a detailed description of the characteristics of Aldh3a2 knock-out mice.The skin symptom ichthyosis is characterized by dry, thickened, and scaly skin, often likened to fish scales, and is caused by a skin permeability barrier defect related to multilayered lipids (lipid lamellae) in the epidermis. The epidermis is composed of four cell layers, the stratum basale, stratum spinosum, stratum granulosum, and the stratum corneum, the last of which is the site of these lipid lamellae, and accordingly has the most important role in skin barrier formation (5, 6). Keratinocytes proliferate in the stratum basale and migrate outward, differentiating into cell layer-specific cell types. The major lipid components of lipid lamellae are ceramides, cholesterol, and FAs, with ceramides being the most abundant (5, 6). A variety of ceramide species exist in the epidermis. Among them, acylceramides are a class of epidermis-specific ceramides that play an essential role in skin barrier formation (7,8). Ceramides are normally composed of a long-chain base (LCB) and a FA (9). However, acylceramides contain an additional hydrophobic chain (linoleic acid), which is esterified with the hydroxylated -carbon of the FA. In the epidermis of SLS patients, some ceramide species, including the acylceramide EOS (a combination of an esterified -hydroxy FA and the LCB sphingosine), are greatly reduced (10).Several metabolic pathways generate the substrates of ALDH3A2, fatty aldehydes. These include metabolic pathways of leukotriene B 4 , diet-derived phytol, plasmalogens, and fatty alcohols (11)(12)(13)(14)(15). Furthermore, we recently revealed that metabolism of LCBs also generates fatty aldehydes, i.e. hexadecanal (C16:0 aldehyde) from dihydrosphingosine (DHS) and
Purpose: This study aimed to assess the validity of diagnoses of congenital malformations (CMs) recorded in claims of a university hospital in Japan.Methods: Congenital malformations were identified according to Code Q00-Q89 of the International Classification of Diseases, 10th revision. All the children who had been diagnosed with CMs based on their claims in 2015 and within 1 year from their birth month were selected for this study. The infants' medical records were considered as a gold standard. Positive predictive values (PPVs) for CMs were calculated.Results: This study included 227 infants who had a CM diagnosis in their claims.Based on the algorithms established by the Quebec Pregnancy Cohort study group, the PPV for any CM was 90.7% and that for major CMs (MCMs) was 91.5%.Concerning MCMs of specific organ systems, those of the circulatory system (PPV 85.1%) were the most frequent, followed by cleft lip and cleft palate (PPV 100.0%), and other CMs of the digestive system (PPV 96.4%). Based on the EUROCAT classification, the PPV for any MCM was 88.5%. Specific MCMs reported in ≥20 infants were ventricular septal defect (PPV 96.0%), patent ductus arteriosus (PPV 72.7%) and cleft lip with or without cleft palate (PPV 100.0%). Conclusions:The PPVs for CMs in the Japanese administrative data were high enough to suggest that these data could be utilized for perinatal pharmacoepidemiological evaluations. The results were from a single center, and further validation studies are needed.
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