Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism

Aljohani, Ahmed; Syed, Deeba N.; Ntambi, James M.

doi:10.1016/j.tem.2017.10.003

Cited by 190 publications

(120 citation statements)

References 67 publications

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“…Stearoyl‐coenzyme A desaturase‐1 (SCD1), an integral protein anchored in the endoplasmic reticulum membrane (ER), catalyses the synthesis of primarily oleate, palmitoleate and monounsaturated fatty acids (MUFAs), from palmitate, stearate and saturated fatty acids (SFAs) respectively . SCD1 is involved in regulating diverse cellular processes and functions including inflammation, hormonal signalling, thermogenesis and lipid synthesis and oxidation . Previous studies have shown that SCD1 deficiency attenuated hypertriglyceridemia, hepatic steatosis and insulin resistance in several mouse models of obesity .…”

Section: Introductionmentioning

confidence: 99%

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

Wang

Liu

et al. 2019

J Cellular Molecular Medi

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The formation of fat‐laden foam cells, which contributes to the fatty streaks in the plaques of atheromas, is an important process in atherosclerosis. Vascular smooth muscle cells (VSMCs) are a critical origin of foam cells. However, the mechanisms that underlie VSMC foam cell formation are not yet completely understood. Here, we demonstrated that oxidized low‐density lipoprotein (oxLDL) inhibited lipophagy by suppressing lipid droplet (LD)‐lysosome fusion and increased VSMC foam cell formation. Moreover, although oxLDL treatment inhibited lysosomal biogenesis, it had no significant effect on lysosomal proteolysis and lysosomal pH. Notably, through TMT‐based quantitative proteomic analysis and database searching, 94 differentially expressed proteins were identified, of which 54 were increased and 40 were decreased in the oxLDL group compared with those in the control group. Subsequently, SCD1, a protein of interest, was further investigated. SCD1 levels in the VSMCs were down‐regulated by exposure to oxLDL in a time‐dependent manner and the interaction between SCD1 and LDs was also disrupted by oxLDL. Importantly, SCD1 overexpression enhanced LD‐lysosome fusion, increased lysosomal biogenesis and inhibited VSMC foam cell formation by activating TFEB nuclear translocation and its reporter activity. Modulation of the SCD1/TFEB‐mediated lipophagy machinery may offer novel therapeutic approaches for the treatment of atherosclerosis.

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Section: Introductionmentioning

confidence: 99%

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

Wang

Liu

et al. 2019

J Cellular Molecular Medi

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“…Interestingly, oleate and palmitoleate, the major products of SCD1 activity, have different metabolic functions. The oleate, but not palmitoleate, normalized the excess ER stress in SCD1 liver-specific deficient mice (11). Thus, SCD expression in T FH cells may contribute cellular homeostasis through maintenance of balance between SFAs and MUFAs.…”

Section: Discussionmentioning

confidence: 99%

“…Interestingly, it has been reported that obese humans have higher levels of SCD1 expression and MUFA contents compared to lean objects (31). SCD1 has been associated with obesity-related abnormal metabolic diseases such as hyperlipidemia, nonalcoholic liver disease and type 2 diabetes in animal model and human exhibiting increased MUFA levels (11). These reports suggest that T cell lipid metabolism, particularly SCD pathway, may represent a promising target to dampen autoimmunity, especially in those obesity associated autoimmunity (32).…”

Section: Discussionmentioning

confidence: 99%

“…Stearoyl-CoA desaturase (SCD) is an endoplasmic reticulum (ER) protein that catalyzes the synthesis of monounsaturated fatty acids (MUFAs) from saturated fatty acids (SFAs). Besides the needs of MUFAs for the synthesis of complex lipids such as diacyglycerols (DG), triglycerides (TGs) and cholesterol esters, MUFAs also have important functions in cell signaling and membrane fluidity (11). Therefore, SCD is a highly regulated and conserved enzyme that plays important roles in regulating obesity, insulin resistance, inflammation and cancer progression (12,13).…”

Section: Introductionmentioning

confidence: 99%

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Inhibition of Stearoyl-CoA desaturase suppresses follicular help T and germinal center B cell responses

Son

Cheon

Goplen

et al. 2019

Preprint

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25Stearoyl-CoA desaturases (SCD) are endoplasmic reticulum (ER) associated enzymes that 26 catalyze the synthesis of the monounsaturated fatty acids (MUFAs). As such, SCD play important 27 roles in maintaining the intracellular balance between saturated fatty acid (SFAs) and MUFAs. 28 The roles of SCD in CD4 + T helper cell responses are currently unexplored. Here, we have found 29 that murine and human follicular helper T (T FH ) cells express higher levels of SCD1 compared to 30 non-T FH cells. Further, the expression of SCD1 in T FH cells is dependent on the T FH lineage-31 specification transcription factor BCL6. We found that the inhibition of SCD1 impaired T FH cell 32 maintenance and shifted the balance between T FH and follicular regulatory T (T FR ) cells in the 33 spleen. Consequently, SCD1 inhibition dampened germinal center B cell responses following 34 influenza immunization. Mechanistically, we found that SCD inhibition led to increased ER stress 35 and enhanced T FH cell apoptosis in vitro and in vivo. These results reveal a possible link between 36 fatty acid metabolism and cellular and humoral responses induced by immunization or potentially, 37 autoimmunity. 38 39 40 41 42 43 44 45 46 47 48formation of germinal centers (GCs) and the production of class-switched high-affinity 53 immunoglobulins (1). T FH cells are required for the generation of antibody-mediated protection 54 against microbes, but aberrant T FH responses may cause autoimmunity (2). Therefore, it is 55 important to understand the positive and/or negative regulators of T FH cell responses for the proper 56 induction during vaccination or the inhibition of T FH responses during autoimmunity. 57T FH differentiation in vivo is a multifactorial multistep process. The transcription factor BCL-6 is 58 considered the master regulator for the differentiation of T FH cells and subsequent germinal center 59 responses (3,4). Interestingly, recent evidence suggests that cell metabolic processes may play 60 important roles in modulating T FH development in vivo. BCL6 was shown to repress glycolysis 61 promoting BCL6 expression in activated CD4 T cells (5,6). Consistent with those observations, it 62 has been demonstrated that T FH cells exhibit diminished glycolysis and mitochondrial respiration 63 compared to Th1 cells. However, a recent study has also suggested mTOR kinase complex 1 64 (mTORC1) related glucose metabolism is required for the T FH generation in vivo (7). Therefore, 65 the roles of glucose metabolism in negative and positive regulation of T FH differentiation and/or 66 maintenance remain to be elucidated. 67Besides glucose metabolism, emerging evidence has suggested that lipid metabolism also plays 68 important roles in regulating T helper cell responses. The inhibition of acetyl-CoA carboxylase 1 69 (ACC1), a key substrate for fatty acid synthesis, reduces human and mouse Th17 cell development 70 in favor of regulatory T (Treg) cell differentiation (8). Simvastatin, the inhibitors for 3-hydroxy-71 3-methyglutaryl (HMG)...

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“…Stearoyl‐coenzyme A desaturase 1 (Scd1) is an endoplasmic reticulum‐bound protein catalyzing the synthesis of monounsaturated fatty acids (MUFAs), primarily oleate and palmitoleate, from saturated fatty acids（SFAs), palmitate and stearate, respectively . Since the MUFAs are major components of membrane phospholipids, Scd has been recognized as one of the important desaturases involved in modulating the fatty acid composition of membrane phospholipids and has been implicated in a variety of metabolic processes, such as lipid and glucose metabolism, energy expenditure, and signal transduction . Two scd duplication and one loss events that have resulted in one, two, or four isoforms are now found in teleost fish species.…”

Section: Introductionmentioning

confidence: 99%

Cadmium transcriptionally regulates Scd1 expression in silver pomfret

Shi

Meng

Liao

et al. 2019

Environmental Toxicology

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Cadmium (Cd) is one of the major contaminants in aquatic ecosystem. Stearoylcoenzyme A desaturase 1 (Scd1) has been implicated in adaptive responses to environmental stressors. The objectives of this study are (a) to characterize scd1 mRNA from silver pomfret (Pampus argenteus); (b) to investigate the expression and activity of Scd1 in silver pomfret exposed to Cd; and (c) to investigate how Cd modifies scd1 gene transcription in silver pomfret. Results indicated that Scd1 was generally conserved across fish species and scd1 mRNA level was higher by far in the brain and liver, followed by the kidney and intestine. Exposure to Cd led to significant changes of the expression and activity of Scd1 in in the liver and intestine. The liver mRNA abundance of scd1 was significantly lower in the Cd-treated groups than in the control group. The 10 days treatment with 1 mg/L Cd significantly upregulated the intestinal scd1 mRNA level, an approximately 9-fold higher in the 1 mg/L Cd-treated group as compared with the control group. Accordingly, Scd1 activity indices (18:1n-9/18:0) in the liver were significantly decreased in the 0.5 mg/L group compared with the control group, while Scd1 activity indices in the intestine were significantly increased in the 1 mg/L group compared with the control group. Moreover, overexpression of sterol regulatory element binding transcription factor 1 (Srebp1) and peroxisome proliferator-activated receptor γ (Pparγ )in HEK 293T cells produced a 2-fold increment in the activity of the scd1 promoter. Furthermore, srebp1 had a similar expression pattern to scd1 in the liver and intestine of silver pomfret exposed to Cd. These results indicated that Cd could regulate scd1 expression, possibly through the transcriptional factor Srebp1. K E Y W O R D Scadmium, Scd1, silver pomfret, transcriptional regulation

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Insights into Stearoyl-CoA Desaturase-1 Regulation of Systemic Metabolism

Cited by 190 publications

References 67 publications

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

SCD1 activation impedes foam cell formation by inducing lipophagy in oxLDL‐treated human vascular smooth muscle cells

Inhibition of Stearoyl-CoA desaturase suppresses follicular help T and germinal center B cell responses

Cadmium transcriptionally regulates Scd1 expression in silver pomfret

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