Regulation of Stearoyl Coenzyme A Desaturase Expression in Human Retinal Pigment Epithelial Cells by Retinoic Acid

Abstract

Stearoyl-CoA desaturase (SCD) is a regulatory enzyme involved in the synthesis of the monounsaturated fatty acids palmitoleate and oleate. The regulation of SCD is of physiological importance because the ratio of saturated fatty acids to unsaturated fatty acids is thought to modulate membrane fluidity. Differential display analysis of retinal pigment epithelial (ARPE-19) cells identified SCD as a gene regulated by retinoic acid. Two SCD transcripts of 3.9 and 5.2 kilobases in size were found to be expressed in these cells by Northern blot analysis. All-trans-retinoic acid (all-trans-RA) increased SCD mRNA expression in a dose-and time-dependent manner; a ϳ7-fold increase was observed with 1 M all-trans-RA at 48 h. SCD mRNA expression was also increased by 9-cis-retinoic acid (9-cis-RA) as well as 4-(E-2-(5,6,7,8-tetrahydro-5,5,8,8-tetramethyl-2-naphthalenyl)-1-propenyl)benzoic acid (TT-NPB), a retinoic acid receptor (RAR)-specific agonist. AGN194301, a RAR␣-specific antagonist, suppressed the SCD expression induced by all-trans-RA, TTNPB, and 9-cis-RA. These results indicate the involvement of RAR␣ in the induction of SCD expression by retinoic acid. However, AGN194204, a RXR (retinoid X receptor) pan agonist, also increased SCD mRNA expression. This increase was not blocked by AGN194301, suggesting that an RARindependent mechanism may also be involved. Thus, SCD expression in retinal pigment epithelial cells is regulated by retinoic acid, and the regulation appears to be mediated through RAR and RXR.Stearoyl-CoA desaturase (SCD, EC 1.14.99.5), 1 a microsomal enzyme, catalyzes the initial desaturation of long chain saturated fatty acids into monounsaturated fatty acids. Palmitate and stearate are the preferred substrates for this enzyme. They are converted to palmitoleate and oleate, respectively (1, 2). This oxidative reaction also requires the participation of 0 2 , NADPH, cytochrome b 5 , and cytochrome b 5 reductase. Two SCD genes, SCD1 and SCD2, characterized from both rat and mouse, encode functionally active proteins that share Ͼ80% sequence homology (3, 4). SCD1 and SCD2 show different tissue-specific expression patterns, possibly because of marked differences in the promoter sequences of their genes (5). There are also two loci for SCD genes in the human genome, one on chromosome 10 and another on chromosome 17 (6). However, the gene on chromosome 17 appears to be a transcriptionally inactive pseudogene. The gene on chromosome 10 encodes the functionally active 359-amino acid SCD protein. This gene yields two transcripts, 5.2 and 3.9 kb in size, which differ in the length of the 3Ј-untranslated region.The regulation of SCD by dietary factors, hormones, and peroxisomal proliferators has been studied in mouse and rat (7-12). The regulation of SCD is of physiological importance because changes in this enzyme activity could lead to changes in cell membrane phospholipid composition (8). Palmitoleic and oleic acids are the predominant unsaturated fatty acids present in fat depots and membrane phospholipids (9...

Biochemical and physiological function of stearoyl-CoA desaturase

“…Humans do not have the Harderian gland, but because this structure is part of the retinal axis in mice, it is likely that this tissue has similar functions in the human retina. Consistent with this stipulation, high SCD expression has been reported in human retinal pigment epithelial cells (52), and its expression may play an important role in the pathophysiology of these cells.…”

“…Malonyl-CoA is known to inhibit the catabolism of fats, and one possibility is that somehow SCD-1 controls malonyl-CoA levels. In this mechanism the saturated fatty acyl-CoAs would allosterically inhibit ACC, thus reducing cellular levels of malonyl-CoA (52,53). Malonyl-CoA is required for fatty acid biosynthesis and also inhibits the mitochondrial CPT shuttle system, the rate-limiting step in the import and oxidation of fatty acids in mitochondria (54,55).…”

Retinoid X Receptor Agonists Increase Bcl2a1 Expression and Decrease Apoptosis of Naive T Lymphocytes

“…Several genes known to be directly regulated by RXR homo-or heterodimers were identified. For example, mRNA levels of the stearoyl-CoA desaturase 1 (Scd1) gene are increased by both RAR and RXR agonists (42). In this analysis, the mean fold-increases for Scd1 RNA was 17.1 (Table II).…”

Identification of Biomarkers Modulated by the Rexinoid LGD1069 (Bexarotene) in Human Breast Cells Using Oligonucleotide Arrays

“…Down-regulated genes included COX-2 (catalyzing enzyme for prostaglandin synthesis), EGR-3 (transcription factor), X-box binding protein, ODC (ornithine decarboxylase), uPAR (plasminogen activator, urokinase receptor), and v-maf-F (transcriptional inactivator). Several of these genes (IGFBP-6, SCD-1, COX-2, and ODC) are known retinoid-regulated genes (23)(24)(25)(26).…”