Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing ␤ -oxidation in skeletal muscle

University of Dundee, Dundee, Scotland, United Kingdom
AJP Endocrinology and Metabolism (Impact Factor: 3.79). 04/2005; 288(3):E599-607. DOI: 10.1152/ajpendo.00439.2004
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Stearoyl-CoA desaturase (SCD) has recently been shown to be a critical control point of lipid partitioning and body weight regulation. Lack of SCD1 function significantly increases insulin sensitivity in skeletal muscles and corrects the hypometabolic phenotype of leptin-deficient ob/ob mice, indicating the direct antilipotoxic action of SCD1 deficiency. The mechanism underlying the metabolic effects of SCD1 mutation is currently unknown. Here we show that SCD1 deficiency reduced the total ceramide content in oxidative skeletal muscles (soleus and red gastrocnemius) by approximately 40%. The mRNA levels and activity of serine palmitoyltransferase (SPT), a key enzyme in ceramide synthesis, as well as the incorporation of [14C]palmitate into ceramide were decreased by approximately 50% in red muscles of SCD1-/- mice. The content of fatty acyl-CoAs, which contribute to de novo ceramide synthesis, was also reduced. The activity and mRNA levels of carnitine palmitoyltransferase I (CPT I) and the rate of beta-oxidation were increased in oxidative muscles of SCD1-/- mice. Furthermore, SCD1 deficiency increased phosphorylation of AMP-activated protein kinase (AMPK), suggesting that AMPK activation may be partially responsible for the increased fatty acid oxidation and decreased ceramide synthesis in red muscles of SCD1-/- mice. SCD1 deficiency also reduced SPT activity and ceramide content and increased AMPK phosphorylation and CPT I activity in muscles of ob/ob mice. Taken together, these results indicate that SCD1 deficiency reduces ceramide synthesis by decreasing SPT expression and increasing the rate of beta-oxidation in oxidative muscles.

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Available from: Makoto Miyazaki, Sep 15, 2014
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    • "Study has shown that SCD1 deficiency increases the rate of β-oxidation in soleus and red gastrocnemius muscles by activating of the AMP-activated protein kinase (AMPK) pathway [34,35]. AMPK leads to phosphorylation and inactivation of acetyl-CoA carboxylase resulting in decreased malonyl-CoA content [36]. "
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    ABSTRACT: Bone marrow mesenchymal stem cells (BM-MSCs) are capable of differentiating into endothelial cells in vitro and acquire major characteristics of mature endothelial-like expression of vWF and CD31. SFAs and lipid oxidation products have been linked with postprandial endothelial dysfunction. Consumption of SFAs impairs arterial endothelial function, while a Mediterranean-type MUFA-diet has a beneficial effect on endothelial function by producing a decrease in levels of vWF, TFPI and PAI-1. Stearoyl-CoA desaturase 1 (SCD1), which converts SFA to MUFA, is involved in the cellular biosynthesis of MUFAs from SFA substrates. High expression of SCD1 is corresponded with low rates of fatty acid oxidation, therefore it might reduce inflammatory responses and be beneficial for the growth of induced endothelial cells. Overexpression of SCD1 in BM-MSCs might increase the growth of induced endothelial cells. The goal of this research is to study the relationship between overexpression of SCD1 and the expression of induced endothelial cells in BM-MSCs in vitro. The gene SCD1 was integrated into a lentiviral vector, and then 293 T cells were transfected by the connected product to produce a packaged virus. BM-MSCs were infected by the packaged virus. Cell culture and endothelial induction were performed. Fluorescent quantitative PCR of CD31, vWF and VE-cad was performed after 1 week and 2 weeks to test the growth of induced endothelial cells. The mRNA amount of CD31, vWF and VE-cad of the SCD1 overexpressed group was statistically higher than that of the empty vector (EV) group and that of the normal group after 1 week and 2 weeks, respectively (p < 0.05). Immunocytochemical staining of CD31 or vWF was detected by visualizing red color. This study suggested that overexpression of SCD1 in BM-MSCs could increase the expression of induced endothelial cells in vitro.
    Lipids in Health and Disease 03/2014; 13(1):53. DOI:10.1186/1476-511X-13-53 · 2.22 Impact Factor
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    • "We recently described that knock-out mice for SCD-1, and non-transgenic mice treated with a SCD-1 inhibitor, present improved nerve regeneration after peripheral nerve injury (Hussain et al., 2013). Moreover, the products of SCD-1, the mono-unsaturated fatty acids, favor cytotoxic SOD-1 aggregation (Kim et al., 2005), and the accumulation of toxic lipid species such as ceramide (Dobrzyn et al., 2005), suggesting that loss of SCD-1 activity could lower cytotoxicity in ALS. Further work is needed to understand the link between loss of SCD-1 activity and benefits for the motor units, especially in ALS. "
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    ABSTRACT: Motor neuron diseases (MNDs) are characterized by selective death of motor neurons and include mainly adult-onset amyotrophic lateral sclerosis (ALS) and spinal muscular atrophy (SMA). Neurodegeneration is not the single pathogenic event occurring during disease progression. There are multiple lines of evidence for the existence of defects in lipid metabolism at peripheral level. For instance, hypermetabolism is well characterized in ALS, and dyslipidemia correlates with better prognosis in patients. Lipid metabolism plays also a role in other MNDs. In SMA, misuse of lipids as energetic nutrients is described in patients and in related animal models. The composition of structural lipids in the central nervous system is modified, with repercussion on membrane fluidity and on cell signaling mediated by bioactive lipids. Here, we review the main epidemiologic and mechanistic findings that link alterations of lipid metabolism and motor neuron degeneration, and we discuss the rationale of targeting these modifications for therapeutic management of MNDs.
    Frontiers in Cellular Neuroscience 02/2014; 8:25. DOI:10.3389/fncel.2014.00025 · 4.29 Impact Factor
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    • "SCD1 is a key enzyme involved in hepatic MUFA synthesis and its expression is regulated by multiple transcription factors, including sterol regulatory element binding protein (SREBP1), carbohydrate response element binding protein (ChREBP), liver X receptor (LXR), and peroxisome proliferator activated receptor γ2 (PPARγ2) [33]. Furthermore, regulation of SCD1 has been linked to SPTLC activity and has been implicated in sphingomyelin synthesis [34]. We previously reported the effects of a high-fat high-cholesterol diet and addition of C20-22 n-3 PUFA on SREBP1 and ChREBP nuclear abundance [17]. "
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    PLoS ONE 12/2013; 8(12):e83756. DOI:10.1371/journal.pone.0083756 · 3.23 Impact Factor
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