Effect of chronic hypoxia and role of stearoyl-CoA desaturase 1 (SCD1) on the inflammatory response of human primary macrophages
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ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE286526 | GEO | 2025/07/01
REPOSITORIES: GEO
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Project description:Stearoyl-coenzyme A desaturase 1 (SCD1) catalyzes the rate-limiting step of de novo lipogenesis and modulates lipid homeostasis. Although numerous SCD1 inhibitors have been tested in treating metabolic disorders both in preclinical and clinic studies, the tissue-specific role of SCD1 in modulating obesity-associated metabolic disorders remains unclear. Here a novel role for intestinal SCD1 in obesity-associated metabolic disorders was uncovered. Intestinal SCD1 was found to be induced during obesity progression both in humans and mice. Intestine-specific, but not liver-specific, SCD1 deficiency reduced obesity and hepatic steatosis. A939572, a SCD1-specific inhibitor, ameliorated obesity and hepatic steatosis dependent on intestinal, but not hepatic, SCD1. Mechanistically, intestinal SCD1 deficiency impeded obesity-induced oxidative stress through its novel function of inducing metallothionein 1 (MT1) in intestinal epithelial cells. These results suggest that intestinal SCD1 could be a viable target that underlies the pharmacological effect of chemical SCD1 inhibition in the treatment of obesity-associated metabolic disorders.
2025-04-09 | GSE272268 | GEO
Project description:Stearoyl-CoA desaturase 1-deficient (SCD1-/-) mice have impaired monounsaturated fatty acid (MUFA) synthesis. When maintained on a very low-fat, high-carbohydrate (VLF-HC) diet, SCD1-/- mice develop severe hypercholesterolemia characterized by an increase in apolipoprotein B-containing lipoproteins and the appearance of lipoprotein-X. Additionally, high-density lipoprotein cholesterol is dramatically reduced in VLF-HC SCD1-/- mice. The concomitant presence of elevated plasma bile acids, bilirubin and aminotransferases in the VLF-HC SCD1-/- mouse are indicative of hepatic dysfunction. Supplementation of the VLF-HC diet with unsaturated fat (canola oil), but not saturated fat (coconut oil), prevents these plasma phenotypes. However, dietary oleate was not as effective as canola oil in reducing low-density lipoprotein cholesterol, signifying an additional role for dietary polyunsaturated fatty acid deficiency in the development of this phenotype. These results indicate that lack of SCD1 results in an increased requirement for dietary unsaturated fat to compensate for impaired MUFA synthesis and to prevent hypercholesterolemia and hepatic dysfunction. Experiment Overall Design: We used Affymetrix Mouse430v2.0 microarray chips to search for gene expression changes unique to the VLF-HC SCD1-/- group. These chips contain 45,101 probe sets representing over 39,000 transcripts and variants from over 34,000 mouse genes. We studied SCD1+/+ and SCD1-/- mice on chow or the VLF-HC diet, analyzing five individual livers from each subgroup for a total of twenty microarrays.
2007-11-01 | E-GEOD-3889 | biostudies-arrayexpress
Project description:Stearoyl-CoA desaturase (SCD) is a central lipogenic enzyme catalyzing the synthesis of monounsaturated fatty acids, mainly oleate (C18:1) and palmitoleate (C16:1), which are components of membrane phospholipids, triglycerides, wax esters, and cholesterol esters. Several SCD isoforms (SCD1-3) exist in the mouse. Here we show that mice with a targeted disruption of the SCD1 isoform have reduced body adiposity, increased insulin sensitivity, and are resistant to diet-induced weight gain. The protection from obesity involves increased energy expenditure and increased oxygen consumption. Compared with the wild-type mice the SCD1-/- mice have increased levels of plasma ketone bodies but reduced levels of plasma insulin and leptin. In the SCD1-/- mice, the expression of several genes of lipid oxidation are up-regulated, whereas lipid synthesis genes are down-regulated. These observations suggest that a consequence of SCD1 deficiency is an activation of lipid oxidation in addition to reduced triglyceride synthesis and storage. Experiment Overall Design: RNA was isolated from livers of 10 individual 6-week-old female mice by using a standard method. Mouse genome U74A arrays were used to monitor the expression level of approximately 10,000 genes and expressed sequence tags (Affymetrix). Genes differentially expressed were identified by comparing expression levels in SCD1-/- and wild-type mice.
2007-08-31 | E-GEOD-2926 | biostudies-arrayexpress
Project description:Niche for stem cells can profoundly influence the position and fate of stem cells in tissue homeostasis and associated disorders, however, the mechanisms underlying the maintenance of stem cell niche remain poorly understood. Here we report that fatty acid desaturation catabolized by stearoyl-coenzyme A desaturase 1 (SCD1) regulates the activity of hair follicle stem cells (HFSCs) via blocking the formation of the bulge, a niche for HFSCs. We further unraveled that the abnormal hair growth in mice with SCD1 deletion is due to its function in K14+ basal keratinocytes rather than directly affecting HFSCs. Mechanistically, SCD1 deficiency impaired the expression of integrin α6 and the formation of hemidesmosomes (HDs), and thus allowed the activation of FAK in K14+ keratinocytes. Activated FAK subsequently stimulated PI3K and promoted the differentiation and proliferation of these keratinocytes, resulting in downward extension of the outer root sheath (ORS) and the disruption of bulge formation. Interestingly, inhibition of PI3K signaling restored bulge formation and normalized HFSCs and hair growth. Supplementation of oleic acid, the product of SCD1, to SCD1-/- mice also enhanced HD numbers, normalized the niche of HFSCs, and promoted hair growth in SCD1-/- mice. Taken together, SCD1 is indispensable for hair growth through stabilizing the number of HDs and thus sustaining bulge formation for HFSC residence and periodic activity.
2023-02-08 | GSE184346 | GEO
Project description:To help elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin pathology in mice lacking Scd1, we performed microarray analysis of skin gene expression in male skin Scd1 knockout (SKO) and Scd1 flox/flox control (Lox) mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebocyte atrophy, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXR?. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin pathology. We analyzed dorsal skin gene expression in non-fasted 8-9 week old male skin Scd1 knockout (SKO) mice (n=3) and Scd1flox/flox (Lox) control mice (n=3)on a C57BL/6J background using Affymetrix 430 2.0 microarrays.
2011-05-09 | E-GEOD-24243 | biostudies-arrayexpress
Project description:To help elucidate the metabolic changes in the skin that contribute to the obesity resistance and skin pathology in mice lacking Scd1, we performed microarray analysis of skin gene expression in male skin Scd1 knockout (SKO) and Scd1 flox/flox control (Lox) mice fed a standard rodent diet. We identified an extraordinary number of differentially expressed genes that support the previously documented histological observations of sebocyte atrophy, inflammation and epidermal hyperplasia in SKO mice. Additionally, transcript levels were reduced in skin of SKO mice for genes involved in fatty acid synthesis, elongation and desaturation, which may be attributed to decreased abundance of key transcription factors including SREBP1c, ChREBP and LXRα. Conversely, genes involved in cholesterol synthesis were increased, suggesting an imbalance between skin fatty acid and cholesterol synthesis. Unexpectedly, we observed a robust elevation in skin retinol, retinoic acid and retinoic acid-induced genes in SKO mice. These results highlight the importance of monounsaturated fatty acid synthesis for maintaining retinol homeostasis and point to disturbed retinol metabolism as a novel contributor to the Scd1 deficiency-induced skin pathology.
2011-05-09 | GSE24243 | GEO
Project description:BackgroundBuffalo milk is considered as a highly nutritious food owing to its higher contents of fatty acids (FA) and rich nutrient profile. Higher fat contents of buffalo milk make it suitable for processing to develop various healthy and nutritious products. Moreover, buffalo milk contains more unsaturated FAs (UFA) such as oleic and linolenic acid, which are important from the human health point of view owing to their desirable physiological effects. However, inadequate information is available about the chemical composition and mechanism of FA synthesis in buffalo milk. In this study, we hypothesized that expression of SCD1 gene could alter the biosynthesis of FA in epithelial cells of mammary gland and subsequently affect the FA contents in buffalo milk. We investigated the transcriptional and biological role of Stearoyl-CoA Desaturase 1 (SCD1) in the buffalo mammary epithelial cells (BMECs) during FA and triacylglycerol (TAG) synthesis.ResultsResults revealed that unsaturated fatty acid contents were much higher in concentration in buffalo milk as compared to Holstein cow. Significant increase in the expression level of FAS, ACACA, SREBP1, PPARG, GPAT, and AGPAT genes was observed in response to altered expression of SCD1 in buffalo milk. Moreover, change in SCD1 gene in BMECs also mediated the expression of genes related to FA biosynthesis subsequently leading to alter the FA composition. Overexpression of SCD1 significantly increased the expression of genes associated with FA and TAG synthesis leading to enhance FA and unsaturated FA contents in BMECs. However, down-regulation of SCD1 exhibited opposite consequences.ConclusionOur study provides mechanistic insights on transcriptional regulation of SCD1 to alter FA and TAG synthesis through directly or indirectly mediating biosynthesis and metabolic pathways in BMECs. We provide preliminary findings regarding engineering of FA contents in buffalo milk through SCD1 signaling.
| S-EPMC7053061 | biostudies-literature
Project description:Presently, there is a deficiency of effective therapies designed to target clear cell renal cell carcinoma (ccRCC), with poor prognosis resulting in patients with advanced disease. Additionally, there is a lack of molecular factors which can be remedially targeted resulting in tumor specific inhibition, and therefore current therapeutic approaches often produce adverse side effects in patients. We identified that Stearoyl-CoA desaturase 1 (SCD1) was consistently overexpressed in patient ccRCC samples, and further investigation of SCD1 as a potential molecular target for ccRCC intervention utilizing a SCD1 inhibitor (A939572) resulted in tumor specific growth inhibition and induction of cell death. In order to understand the mechanism by which the SCD1 inhibitor mediated its anti-tumor effects, we performed gene array analysis and compared expression patterns between treated and untreated samples. Four established ccRCC cell lines purchased from ATCC were treated with DMSO control versus A939572 over a 24 hour time period. RNA from each group was isolated and sent of for gene array anaylsis. Gene expression data from each individual treatment group was normalized to its respective DMSO contol, and resulting expression patterns associated with drug exposure was compared between the four cell lines.
2012-10-11 | E-GEOD-41485 | biostudies-arrayexpress
Project description:Presently, there is a deficiency of effective therapies designed to target clear cell renal cell carcinoma (ccRCC), with poor prognosis resulting in patients with advanced disease. Additionally, there is a lack of molecular factors which can be remedially targeted resulting in tumor specific inhibition, and therefore current therapeutic approaches often produce adverse side effects in patients. We identified that Stearoyl-CoA desaturase 1 (SCD1) was consistently overexpressed in patient ccRCC samples, and further investigation of SCD1 as a potential molecular target for ccRCC intervention utilizing a SCD1 inhibitor (A939572) resulted in tumor specific growth inhibition and induction of cell death. In order to understand the mechanism by which the SCD1 inhibitor mediated its anti-tumor effects, we performed gene array analysis and compared expression patterns between treated and untreated samples.
2012-10-11 | GSE41485 | GEO
Project description:Gene expression studies in humans and animals have shown that elevated stearoyl-CoA desaturase (SCD1) activity is associated with increased fat accumulation and monounsaturation of saturated fatty acids in skeletal muscle. However, results of the two reported association studies in humans are inconsistent. In the present study, we annotated the bovine SCD1 gene and identified 3 single nucleotide polymorphisms (SNPs) in its 3'untranslated region (UTR). Genotyping these SNPs on a Wagyu x Limousin reference population revealed that the SCD1 gene was significantly associated with six fat deposition and fatty acid composition traits in skeletal muscle, but not with subcutaneous fat depth and percent kidney-pelvic-heart fat. In particular, we confirmed that the high stearoyl-CoA desaturase activities/alleles were positively correlated with beef marbling score, amount of monounsaturated fatty acids and conjugated linoleic acid content, but negatively with amount of saturated fatty acids. The inconsistent associations between human studies might be caused by using different sets of markers because we observed that most associated markers are located near the end of 3'UTR. We found that the proximity of the polyadenylation signal site is highly conserved among human, cattle and pig, indicating that the region might contain functional elements involved in posttranscriptional control of SCD1 activity. In conclusion, our cross species study provided solid evidence to support SCD1 gene as a critical player in skeletal muscle fat metabolism.
| S-EPMC2556050 | biostudies-literature