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mRNA levels and structures of rs2234970 polymorphic SCD1 variants. (a) The mRNA level was measured in transiently transfected HEK293T cells. Samples were harvested and prepared as described in Section 4. qPCR was carried out using GAPDH, SCD1 and Glu-Glu tag sequence specific primers as indicated in Section 4. The diagram presented depicts the results of three independent measurements. Statistical analysis was performed with the Tukey-Kramer Multiple Comparisons Test. Data are shown as mean values ± S.D. *** p < 0.001. (b) The secondary MFE structures of +670A and +670C SCD1 were predicted by RNAfold server as indicated in Section 4. mRNA numbering begins at the first nucleotide of the start codon. The difference in the secondary structure of mRNAs is magnified in the left corner of the figure. (c) Mountain plot representation of MFE structure. The mountain plot represents a secondary structure in a plot of height vs. position, where the height is given by the number of base pairs enclosing the base at given position. Loops corresponding to plateaus, hairpin loops to peaks, and helices to slopes. The position of the polymorphic nucleotide change is indicated on horizontal axis. Red line: +670A; blue line: +670C. (d) HEK293T cells were transiently transfected with Glu-Glu tagged Met224 and Leu224 expressing constructs. 24 h after transfection cells were treated with actinomycin D (5 µg/mL) for 0, 1, 2, 4, 8, or 12 h. Samples were harvested and prepared as described in Section 4. qPCR was carried out using GAPDH and Glu-Glu tag sequence specific primers as indicated in Section 4. The diagram presents the average of three parallels. Statistical analysis was performed with the Tukey-Kramer Multiple Comparisons Test. Data are shown as mean values ± S.D. * p < 0.05; ** p < 0.01; *** p < 0.001.
Source publication
Disturbances in lipid metabolism related to excessive food intake and sedentary lifestyle are among major risk of various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) has an essential role in these diseases, as it catalyzes the synthesis of unsaturated fatty acids, both supplying for fat storage and contributing to cellular defense against...
Contexts in source publication
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... primers designed for SCD1 amplification did not differentiate between endogenous and over-expressed untagged SCD1 mRNA in the quantitative assay, whereas the antisense oligo designed for the Glu-Glu tag sequence allowed a specific detection of the mRNA derived from the recombinant expression construct. In either case, however, the C (Leu224) version yielded significantly, 1.889-fold (untagged) and 1.972-fold (tagged) higher mRNA levels (Figure 2a). ...
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... 23, x FOR PEER REVIEW 4 of 20 detection of the mRNA derived from the recombinant expression construct. In either case, however, the C (Leu224) version yielded significantly, 1.889-fold (untagged) and 1.972-fold (tagged) higher mRNA levels ( Figure 2a). Since the mRNA molecules of A (Met224) and C (Leu224) desaturase are otherwise identical (i.e., they possess the same 5′ UTR, 3′ UTR regions, and polyA tail) in vivo as Figure 2. mRNA levels and structures of rs2234970 polymorphic SCD1 variants. ...
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... either case, however, the C (Leu224) version yielded significantly, 1.889-fold (untagged) and 1.972-fold (tagged) higher mRNA levels ( Figure 2a). Since the mRNA molecules of A (Met224) and C (Leu224) desaturase are otherwise identical (i.e., they possess the same 5′ UTR, 3′ UTR regions, and polyA tail) in vivo as Figure 2. mRNA levels and structures of rs2234970 polymorphic SCD1 variants. ...
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... minimum free energy (MFE) structure obtained by this in silico analysis revealed a significant rearrangement in the central segment adjacent to the SNP, i.e., an extra hairpin loop was formed in case of the variant C (Figure 2b). The mountain plot representation of the MFE structure also confirmed that an extra structural element may appear in the flanking region of the polymorphic site, which may contribute to the enhanced stability and more efficient translation of C allele containing mRNA (Figure 2c) [21]. ...
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... minimum free energy (MFE) structure obtained by this in silico analysis revealed a significant rearrangement in the central segment adjacent to the SNP, i.e., an extra hairpin loop was formed in case of the variant C (Figure 2b). The mountain plot representation of the MFE structure also confirmed that an extra structural element may appear in the flanking region of the polymorphic site, which may contribute to the enhanced stability and more efficient translation of C allele containing mRNA (Figure 2c) [21]. ...
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... stable transcript of GAPDH served as endogenous control. A significant difference between polymorphic variants A and C was revealed as soon as 1 h after transcription arrest ( Figure 2d). The SCD1 transcript harboring allele A was reduced by 38% of the initial amount, while the decrement in variant C was only 14.5%. ...
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... difference widened further to only 34% of the A allele mRNA and more than 80% of the C allele transcript present at 4 h after transcription arrest in the cells. This difference was essentially maintained until the end of the experiment (Figure 2d). ...
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... most significant effects were observed for palmitoleate, linoleate, and stearate, resulting in as large as 3-fold, 4-fold, and 6-fold increase in Leu224 SCD1 levels, respectively, compared to the untreated control (Figure 4c). Since none of the FAs altered the mRNA levels of either the A or the C SCD1 variant during this short-term treatment ( Figure S2), this effect can be attributed clearly to translational or post-translational events. Other FAs did not affect the intracellular amount of this major variant (Figure 4a,c). ...
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... most significant effects were observed for palmitoleate, linoleate, and stearate, resulting in as large as 3-fold, 4-fold, and 6-fold increase in Leu224 SCD1 levels, respectively, compared to the untreated control ( Figure 4c). Since none of the FAs altered the mRNA levels of either the A or the C SCD1 variant during this short-term treatment ( Figure S2), this effect can be attributed clearly to translational or post-translational events. ...
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... general, polymorphisms in the 3'UTR as well as other variants (e.g., length, regulation by miRNAs, etc.) affect mRNA degradation [45], and there is also evidence in the literature that common variants of the coding region, even synonymous SNPs, may also alter mRNA stability [46]. Our assumption is substantiated by an extra hairpin loop predicted in the flanking region of the polymorphic site in the minor variant in silico (Figure 2b,c) and confirmed by a hindered mRNA degradation seen after actinomycin D treatment in vitro (Figure 2d). ...
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... general, polymorphisms in the 3'UTR as well as other variants (e.g., length, regulation by miRNAs, etc.) affect mRNA degradation [45], and there is also evidence in the literature that common variants of the coding region, even synonymous SNPs, may also alter mRNA stability [46]. Our assumption is substantiated by an extra hairpin loop predicted in the flanking region of the polymorphic site in the minor variant in silico (Figure 2b,c) and confirmed by a hindered mRNA degradation seen after actinomycin D treatment in vitro (Figure 2d). ...
Citations
... Stearoyl-CoA desaturase 1 (SCD1) is the rate-limiting enzyme converting saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs), which are major substrates for the biosynthesis of triacylglycerols and other lipids. Since dysregulated lipid metabolism has been implicated in the pathogenesis of type 2 diabetes, SCD1 has received attention for its role in diabetes treatment [18,19]. Although global knockout of Scd1 in lean mice improves insulin sensitivity, Scd1 deletion in obese mice with leptin-deficiency leads to glucose intolerance and insufficient insulin secretion [20]. ...
Aims/hypothesis
The key pancreatic beta cell transcription factor v-maf musculoaponeurotic fibrosarcoma oncogene homologue A (MafA) is critical for the maintenance of mature beta cell function and phenotype. The expression levels and/or activities of MafA are reduced when beta cells are chronically exposed to diabetogenic stress, such as hyperglycaemia (i.e. glucotoxicity). Interventional targets and adjuvant therapies to abate MafA loss in beta cells may provide evidence to support the effective treatment of diabetes. In this study, we aimed to investigate the function of stearoyl-CoA desaturase 1 (SCD1) in the stabilisation of MafA expression and activity in order to maintain functional beta cell mass, with a view to suppressing the development of type 2 diabetes.
Methods
SCD1 expression levels were analysed in islets obtained from humans with type 2 diabetes, hyperglycaemic db/db mice, and a high-fat diet (HFD)-induced mouse model of diabetes. Pancreatic beta cell-specific Scd1 knockin (βSCD1KI) mice were generated to study the role of SCD1 in beta cell function and identity. The protein-to-protein interactions between SCD1 and MafA were detected in MIN6 and HEK293A cells. We used experiments including chromatin immunoprecipitation, cell-based ubiquitination assay and fatty acid composition analysis to investigate the specific molecular mechanism underlying the effect of SCD1 on the restoration of MafA and beta cell function under glucotoxic conditions.
Results
SCD1 expression was reduced in beta cells of humans with type 2 diabetes and in HFD-fed and db/db mice compared with healthy controls, which was attributed to glucotoxicity-induced Scd1 promoter histone deacetylation. Gain-of-function of SCD1 in beta cells improved insulin deficiency, glucose intolerance and beta cell dedifferentiation/transdifferentiation in the HFD-induced mouse model of diabetes. Mechanistically, SCD1 directly bound to the E3 ubiquitin ligase HMG-CoA reductase degradation 1 (HRD1) and stabilised nuclear MafA through interrupting MafA–HRD1 interactions in mouse islets and MIN6 cells, which inhibited the ubiquitination-mediated degradation of MafA. Moreover, the products of SCD enzyme reactions (mainly oleic acid) also alleviated glucotoxicity-mediated oxidative stress in MIN6 cells.
Conclusions/interpretation
Our findings indicate that SCD1 stabilises beta cell MafA both in desaturase-dependent and -independent manners, thus improving glucose homeostasis under metabolic stress. This provides a potential novel target for precision medicine for the treatment of diabetes.
Graphical Abstract
... In this study, the n-6/n-3 PUFA ratio in serum phospholipids, reflecting their medium-term dietary intake, and both desaturation indices, showing endogenous biosynthesis of MUFAs from SFAs, were predictors of LI above the median. Previous studies have demonstrated that increased activity and/or overexpression of SCD1 (EC 1.14.19.1), a highly conserved member of the ferrous Δ-9 desaturases family, are relevant contributing factors for T2D [35]. Moreover, higher desaturation indices were associated with IR, T2D, obesity and metabolic syndrome [36]. ...
Background
Little is known about the mechanisms underlying the association of the serum phospholipid lipophilic index (LI) with atherosclerotic cardiovascular disease (ASCVD) in patients with type 2 diabetes (T2D). Therefore, we investigated whether the LI is associated with glucometabolic control, meta-inflammation, thrombin generation, fibrin clot properties, endothelial function and platelet activation in T2D patients with angiographically documented ASCVD.
Methods
We studied 74 T2D patients with ASCVD, aged 65.6 ± 6.8 years, with a median diabetes duration of 10 years and median HbA1c of 7.0%. Serum phospholipid fatty acids (FAs) were measured by gas chromatography. The serum phospholipid LI was calculated as the sum of the products of the proportion (% of total FAs) with the melting points (°C) of each individual FA, divided by the sum of the proportions of all FAs. Levels of HbA1c, insulin, leptin, adiponectin, lipid profiles, inflammatory markers (hsCRP, interleukin-6, TNF-α), Lp-PLA2 (a biomarker of vascular inflammation), endothelial function (sICAM-1, sVCAM-1, FMD, NMD), thrombin generation, fibrin clot properties and platelet activation, measured by light transmission aggregometry with arachidonic acid [AA] and adenosine diphosphate [ADP], were assessed.
Results
Patients with LI > 16.9 °C (median) had higher HbA1c concentrations by 5.9% compared to the remaining subjects (p = 0.035). In this group, HbA1c levels ≥ 7.0% were found more often than in individuals with LI ≤ 16.9 °C (62.2 vs. 35.1%; p = 0.020). Subjects with LI > 16.9 °C had higher levels of TCh by 17.1% (p = 0.012), LDL-Ch by 29.4% (p = 0.003), interleukin-6 by 22.2% (p = 0.031) and Lp-PLA2 by 32.4% (p = 0.040), compared to the remaining patients. Moreover, they had increased maximal platelet aggregation induced by AA (p = 0.045), but not by ADP. Serum phospholipid LI correlated with HbA1c (r = 0.24; p = 0.037), TCh (r = 0.36; p = 0.002), LDL-Ch (r = 0.38; p < 0.001), interleukin-6 (r = 0.27; p = 0.020) and Lp-PLA2 (r = 0.26; p = 0.026). There were no intergroup differences in endothelial function, thrombin generation and fibrin clot properties. Regression analysis showed that HbA1c ≥ 7.0% and serum levels of LDL-Ch, interleukin-6 and Lp-PLA2 were predictors of LI > 16.9 °C in adjusted models.
Conclusions
In well-controlled T2D patients with ASCVD, the higher serum phospholipid LI is associated with worse glucometabolic control, enhanced vascular inflammation and higher platelet reactivity during aspirin treatment at cyclooxygenase-1-selective doses.
... The expression of wild-type SCD1 alone resulted in a nearly twofold increase in palmitoleate levels compared to both the untreated control and the empty vector transfected samples. The amount of palmitoleate detected in the presence of p.M224L was slightly elevated above that found in the wild type, in accordance with previously published results [23], and p.A333T showed a 33% lower level, although these differences were not significant. The palmitoleate content of cells expressing p.H125P or p.R253AfsTer7 was significantly reduced to the level of the controls, i.e., approximately half of the wild type, which is not unexpected given the structural predictions (Figure 2, Supplementary Figure S1). ...
... The amount of the tagged proteins exhibited a similar pattern to that of the corresponding untagged versions ( Figure 4A,B). Consistent with our earlier studies, significantly higher intracellular protein levels were observed for the p.M224L polymorphic variant compared to the wild-type protein, which served as a positive control [23]. In accordance with the lower desaturase capacity (Figure 3) and the predicted structural anomalies (Figure 2), transfection with p.H125P led to a significant decrease in the cellular SCD1 levels, whether untagged (60%, Figure 4A) or tagged (40%, Figure 4B). ...
... Consistent with our earlier studies, significantly higher intracellular protein levels were observed for the p.M224L polymorphic variant compared to the wild-type protein, which served as a positive control [23]. In accordance with the lower desaturase capacity ( Figure 3) and the predicted structural anomalies (Figure 2), transfection with p.H125P led to a significant decrease in the cellular SCD1 levels, whether untagged (60%, Figure 4A) or tagged (40%, Figure 4B). ...
Background: A considerable proportion of the symptoms associated with excessive dietary intake can be attributed to systemic imbalances in lipid metabolism. The prominent toxicity of saturated fatty acids has been repeatedly demonstrated and sheds light on the protective role of stearoyl-CoA desaturase-1 (SCD1), the key enzyme for fatty acid desaturation. SCD1 protein expression is regulated at the levels of transcription, translation, and degradation. However, the modulating effect of the variability of the human genome must also be taken into account. Therefore, we aimed to ascertain whether natural missense or frameshift mutations in SCD1 (p.H125P, p.M224L, p.A333T, p.R253AfsTer7) could influence the expression, degradation, or function of the enzyme. Methods: In silico and in vitro experiments were conducted to comprehensively evaluate the consequences associated with each genetic variation, with the objective of using the results to propose a risk or severity ranking of SCD1 variants. Results: As anticipated, the p.R253AfsTer7 variant was identified as the most deleterious in structural, functional, and quantitative terms. The p.H125P variant also reduced the desaturation capacity of the enzyme in accordance with the predicted structural alterations and augmented degradation resulting from folding complications. This was aggravated by increased mRNA instability and accompanied by mild endoplasmic reticulum stress induction. The p.A333T protein exhibited an intermediate phenotype, whereas p.M224L showed no deleterious effects and even increased the amount of SCD1. Conclusions: In conclusion, the large-scale identification of genetic variations needs to be supplemented with comprehensive functional characterization of these variations to facilitate adequate personalized prevention and treatment of lipid metabolism-related conditions.
... SCD1-catalyzed MUFAs effectively suppress ferroptosis by substituting polyunsaturated fatty acids in the lipid membrane, thereby reducing the accumulation of lipid ROS (58). SCD1 has been extensively studied for a number of years in the context of metabolic diseases, such as diabetes and obesity (59,60). However, to the best of our knowledge, the exact role of SCD1 in the development of cancer remains unclear. ...
Ferroptosis, characterized by iron-mediated non-apoptotic cell death and alterations in lipid redox metabolism, has emerged as a critical process implicated in various cellular functions, including cancer. Aurantio-obtusin (AO), a bioactive compound derived from Cassiae semen (the dried mature seeds of Cassie obtusifolia L. or Cassia toral L.), has anti-hyperlipidemic and antioxidant properties; however, to the best of our knowledge, the effect of AO on liver cancer cells remains unclear. The Cell Counting Kit-8, EdU staining and migration assays were employed to assess the anti-liver cancer activity of AO. Intracellular levels of glutathione peroxidase 4 protein and lipid peroxidation were measured as indicators of ferroptotic status. Immunohistochemical analyses, bioinformatics analyses and western blotting were conducted to evaluate the potential of stearoyl-CoA desaturase 1 (SCD1) in combination with ferroptosis inducers for the personalized treatment of liver cancer. The present study revealed that AO significantly inhibited the proliferation of liver cancer cells in vitro and in vivo. Mechanistically, AO inhibited AKT/mammalian target of rapamycin (mTOR) signaling, suppressed sterol regulatory element-binding protein 1 (SREBP1) expression, and downregulated fatty acid synthase expression, thereby inhibiting de novo fatty acid synthesis. Further investigations demonstrated that AO suppressed glutathione peroxidase 4 protein expression through the nuclear factor erythroid 2-related factor 2/heme oxygenase-1 pathway, induced ferroptosis in liver cancer cells, and simultaneously inhibited lipogenesis by suppressing SCD1 expression through the AKT/mTOR/SREBP1 pathway. Consequently, this increased the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. Additionally, the enhanced effects of AO and RSL3, which resulted in significant tumor suppression, were confirmed in a xenograft mouse model. In conclusion, the present study demonstrated that AO induced ferroptosis, downregulated the expression of SCD1 and enhanced the sensitivity of liver cancer cells to the ferroptosis inducer RSL3. The synergistic use of AO and a ferroptosis inducer may have promising therapeutic effects in liver cancer cells.
... Stearyl CoA desaturase-1 (SCD1) is an essential enzyme that regulates the transformation of saturated fatty acids (SFA) into monounsaturated fatty acids (MUFA), and plays a crucial role in controlling fatty acid metabolism and the balance between SFA and MUFA (Balatskyi & Dobrzyn, 2023). Activated SCD1 promotes MUFA biosynthesis, fat accumulation, and the development of T2DM (Igal & Sinner, 2021;Tibori et al., 2022Tibori et al., , 2024. Recently, multiple studies have demonstrated that reducing the expression levels of sbp-1, fat-5, fat-6, and fat-7 significantly decreases intestinal fat accumulation in C. elegans (Bai et al., 2021;Nomura et al., 2010). ...
Sweet pepper, a globally commercialized horticultural crop, has been demonstrated to impede fat accumulation, but its mechanism remains incompletely understood. This study was designed to explore the potential mechanism of sweet pepper in reducing fat accumulation in Caenorhabditis elegans through RNA‐seq and metabolome analysis. A total of 22 metabolites were identified from sweet pepper by UHPLC‐ESI‐TOF‐MS analysis. In vivo, sweet pepper significantly inhibited α‐glucosidase activity and reduced the levels of glucose, triglycerides (TG), total cholesterol (TC), and the area stained with oil red O. Additionally, it increased body length and the number of head swings in C. elegans compared to the control group. The KEGG enrichment analysis revealed significant enrichment of the biosynthesis of unsaturated fatty acids signaling pathway among the differentially expressed genes and metabolites. Furthermore, the mRNA levels of sterol regulatory element‐binding proteins (SREBPs) ortholog SBP‐1, as well as the stearyl CoA desaturase‐1 (SCD1), including fat‐5, fat‐6, and fat‐7, were significantly decreased after treatment with sweet pepper. Collectively, sweet pepper effectively reduces fat accumulation, which is probably related to downregulating the SREBP‐SCD axis, offering new insights for future functional food development.
... As SNPs in the upstream regulatory region of SCD1 have not yet been functionally investigated, and only the rs670213 polymorphism has been analyzed and found to be unrelated to metabolic risk 52,53 , in the present study, we tested the promoter polymorphisms in vitro in a luciferase reporter system both in the absence (Fig. 4) and presence (Fig. 5, Supplementary Fig. S1) of various dietary FAs. The observed allele-specific inducing properties of the FAs are not without precedent, as the elevated expression of the only common missense SCD1 variant (rs2234970) is also attributed partly to a FA-mediated and sequence-dependent protein stabilization 24 . Although the rs1054411 SNP, which was found to be functional in the presence of FAs (Fig. 5), did not show significant association with T2DM in our study (Table 2), its role in the development of metabolic conditions cannot be ruled out completely. ...
Overnutrition and genetic predisposition are major risk factors for various metabolic disorders. Stearoyl-CoA desaturase-1 (SCD1) plays a key role in these conditions by synthesizing unsaturated fatty acids (FAs), thereby promoting fat storage and alleviating lipotoxicity. Expression of SCD1 is influenced by various saturated and cis-unsaturated FAs, but the possible role of dietary trans FAs (TFAs) and SCD1 promoter polymorphisms in its regulations has not been addressed. Therefore, we aimed to investigate the impact of the two main TFAs, vaccenate and elaidate, and four common promoter polymorphisms (rs1054411, rs670213, rs2275657, rs2275656) on SCD1 expression in HEK293T and HepG2 cell cultures using luciferase reporter assay, qPCR and immunoblotting. We found that SCD1 protein and mRNA levels as well as SCD1 promoter activity are markedly elevated by elaidate, but not altered by vaccenate. The promoter polymorphisms did not affect the basal transcriptional activity of SCD1. However, the minor allele of rs1054411 increased SCD1 expression in the presence of various FAs. Moreover, this variant was predicted in silico and verified in vitro to reduce the binding of ETS1 transcription factor to SCD1 promoter. Although we could not confirm an association with type 2 diabetes mellitus, the FA-dependent and ETS1-mediated effect of rs1054411 polymorphism deserves further investigation as it may modulate the development of lipid metabolism-related conditions.
... Furthermore, the formation of the two protein variants may also be influenced by their different C-termini. SCD1, the other human isoform, has a short half-life, in which the role of its N-terminal PEST domain has been well established [35][36][37][38]. Although the absence of the PEST sequence may provide a longer half-life for SCD5 than SCD1, the distinct C-termini of its two TVs may result in different C-degron-dependent degradation pathways, and thus significantly affect the intracellular ratio of SCD5A and SCD5B in vivo [39]. ...
Alternative splicing (AS) is a major means of post-transcriptional control of gene expression, and provides a dynamic versatility of protein isoforms. Cancer-related AS disorders have diagnostic, prognostic and therapeutic values. Changes in the expression and AS of human stearoyl-CoA desaturase-5 (SCD5) are promising specific tumor markers, although the transcript variants (TVs) of the gene have not yet been confirmed. Our in silico, in vitro and in vivo study focuses on the distribution of SCD5 TVs (A and B) in human tissues, the functionality of the relevant splice sites, and their modulation by certain single-nucleotide variations (SNVs). An order of magnitude higher SCD5A expression was found compared with SCD5B. This unequal splicing is attributed to a weaker recognition of the SCD5B-specific splicing acceptor site, based on predictions confirmed by an optimized minigene assay. The pronounced dominance of SCD5A was largely modified (rs1430176385_A, rs1011850309_A) or even inverted (rs1011850309_C) by natural SNVs at the TV-specific splice sites. Our results provide long missing data on the proportion of SCD5 TVs in human tissues and reveal mutation-driven changes in SCD5 AS, potentially affecting tumor-associated reprogramming of lipid metabolism, thus having prognostic significance, which may be utilized for novel and personalized therapeutic approaches.
... The molecular diagnosis is fundamental in rare forms to choose the appropriate treatment, to reduce the risk of consequences, and for genetic counselling. This Special Issue contains two reviews [1,2], three original papers [3][4][5], and one case report [6] that address genetic issues in diabetes mellitus. ...
... Several loci are involved in type 2 diabetes mechanisms. Tibori et al. [4] focused their attention on the effect of the missense rs2234970 single-nucleotide polymorphism (SNP) on stearoyl-CoA desaturase-1 activity. This enzyme plays an important role in the synthesis of unsaturated fatty acids. ...
Diabetes mellitus constitutes a heterogeneous group of disorders characterized by chronic hyperglycaemia [...]
... The association between SCD1 gene polymorphism and disease development depends on many factors, such as diet: oil intake in case of obesity [97] and PUFA intake in case of cancer death [98]. The relationship between SCD1 and disease development could be explained by the variation in SCD1 expression according to gene variant, which influences the fatty acid profile (unsaturated: saturated fatty acid ratio) [99]. Despite the great attention attributed to SCD1 isoform, few studies on SCD5 isoform have been conducted. ...
Circulating fatty acids (FA) have an endogenous or exogenous origin and are metabolized under the effect of many enzymes. They play crucial roles in many mechanisms: cell signaling, modulation of gene expression, etc., which leads to the hypothesis that their perturbation could be the cause of disease development. FA in erythrocytes and plasma rather than dietary FA could be used as a biomarker for many diseases. Cardiovascular disease was associated with elevated trans FA and decreased DHA and EPA. Increased arachidonic acid and decreased Docosahexaenoic Acids (DHA) were associated with Alzheimer’s disease. Low Arachidonic acid and DHA are associated with neonatal morbidities and mortality. Decreased saturated fatty acids (SFA), increased monounsaturated FA (MUFA) and polyunsaturated FA (PUFA) (C18:2 n-6 and C20:3 n-6) are associated with cancer. Additionally, genetic polymorphisms in genes coding for enzymes implicated in FA metabolism are associated with disease development. FA desaturase (FADS1 and FADS2) polymorphisms are associated with Alzheimer’s disease, Acute Coronary Syndrome, Autism spectrum disorder and obesity. Polymorphisms in FA elongase (ELOVL2) are associated with Alzheimer’s disease, Autism spectrum disorder and obesity. FA-binding protein polymorphism is associated with dyslipidemia, type 2 diabetes, metabolic syndrome, obesity, hypertension, non-alcoholic fatty liver disease, peripheral atherosclerosis combined with type 2 diabetes and polycystic ovary syndrome. Acetyl-coenzyme A carboxylase polymorphisms are associated with diabetes, obesity and diabetic nephropathy. FA profile and genetic variants of proteins implicated in FA metabolism could be considered as disease biomarkers and may help with the prevention and management of diseases.
... Numerous studies have demonstrated the inevitable importance of stearoyl-CoA desaturase-1 (SCD1) in the metabolic and signaling pathways, making its role unquestionable in several prevalent human diseases, including obesity, diabetes, fatty liver, and cardiovascular diseases [11][12][13][14][15]. Much is known about the lipid-sensitive expression [16][17][18][19][20][21], rapid protein degradation [22,23], and complex transcriptional regulation [24] of SCD1. ...
... It is known that the promoter activity of SCD1 is influenced positively by the SFAs, and it is negatively influenced by the MUFAs and PUFAs [16][17][18][19][20][21]24]; in addition, oleate also enhances the intracellular degradation of the SCD1 protein [29,43]. Furthermore, a common missense polymorphism in the SCD1 gene can stabilize the protein in an FA-dependent manner [23]. Although the two desaturases catalyze the same reaction, increasing evidence suggests that SCD5 may be less sensitive to the regulation by lipid factors in comparison to SCD1. ...
... The present work is the first to functionally examine the two promoter SNPs of human SCD5, and it revealed that the T allele of rs3811792 reduces the SCD5 promoter activity in the kidneyderived and neuronal cell lines. Interestingly, not only the SCD5, but also the human SCD1 polymorphisms have been quite neglected, and only a few variants have been characterized so far, and there is no promoter SNP among them, instead there is only the stabilizing effect of a missense variant [23] and the microRNA binding site-modifying role of a 3 untranslated region (3 UTR) polymorphism [44] have been described. ...
The combined prevalence of type 1 (T1DM) and type 2 (T2DM) diabetes mellitus is 10.5% worldwide and this is constantly increasing. The pathophysiology of the diseases include disturbances of the lipid metabolism, in which acyl-CoA desaturases play a central role as they synthesize unsaturated fatty acids, thereby providing protection against lipotoxicity. The stearoyl-CoA desaturase-5 (SCD5) isoform has received little scientific attention. We aimed to investigate the SCD5 promoter and its polymorphisms in vitro, in silico and in a case-control study. The SCD5 promoter region was determined by a luciferase reporter system in HepG2, HEK293T and SK-N-FI cells and it was proved to be cell type-specific, but it was insensitive to different fatty acids. The effect of the SCD5 promoter polymorphisms rs6841081 and rs3811792 was tested in the transfected cells. The T allele of rs3811792 single nucleotide polymorphism (SNP) significantly reduced the activity of the SCD5 promoter in vitro and modified several transcription factor binding sites in silico. A statistically significant association of rs3811792 SNP with T1DM and T2DM was also found, thus supporting the medical relevance of this variation and the complexity of the molecular mechanisms in the development of metabolic disorders. In conclusion, the minor allele of rs3811792 polymorphism might contribute to the development of diabetes by influencing the SCD5 promoter activity.