Article

Stearoyl-CoA desaturase-1 deficiency reduces ceramide synthesis by downregulating serine palmitoyltransferase and increasing β-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
Source: PubMed

ABSTRACT

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.

Download full-text

Full-text

Available from: Makoto Miyazaki, Sep 15, 2014
  • Source
    • "lated to lipid metabolism, the SCD1 gene is considered a potential factor influencing body weight and obesity (Dobrzyn et al., 2005;Biddinger et al., 2006). In cattle, the SCD1 gene was significantly associated with MUFA content of marbling fat (Taniguchi et al., 2004) and milk production traits (fat and protein content, milk yield) (Macciotta et al., 2008). "
    [Show abstract] [Hide abstract]
    ABSTRACT: Stearoyl-CoA desaturase 1 (SCD1) is a critical enzyme that catalyzes the synthesis of monounsaturated fatty acids and is involved in several signaling pathways related to lipid metabolism. The objective of the present study was to estimate the expression of the SCD1 gene in three different ovine tissues strongly associated with lipid homeostasis. The SCD1 gene expression measurement was performed on three tissues (liver, subcutaneous fat, perirenal fat) originated from 15 old-type Polish Merino sheep. The SCD1 transcript abundance was evaluated based on the two most stable endogenous controls (RPS2 – ribosomal protein S2; ATP5G2 – H(+)-transporting ATP synthase). The highest expression of the SCD1 gene was observed in ovine subcutaneous fat compared to perirenal fat and liver. Furthermore, the present research indicated the significant correlation between ovine SCD1 transcript abundance and several important production traits. The expression of the SCD1 gene in liver and perirenal fat highly positively correlated with the feed : gain ratio, test of daily gain and age of the animals at slaughter. Moreover, in both tissues, the SCD1mRNA level positively correlated with weight and content of perirenal fat and subcutaneous fat (R = 0.64, 0.8, 0.6, respectively) and negatively with assessment of external fat content with the use of the EUROP scale (R = −0.64). The SCD1 expression in subcutaneous fat also corresponds with back fat of blade chop and thickness of longissimus dorsi muscles evaluated using USG (ultrasonography) (R = −0.6 and 0.62, respectively). The significant correlation between SCD1 transcript abundance and fattening and slaughtering traits indicate the ability to improve important production traits in sheep via modification of expression of the SCD1 gene.
    Full-text · Dataset · Jan 2016
  • Source
    • "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]. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Mar 2014 · Lipids in Health and Disease
  • Source
    • "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. "
    [Show abstract] [Hide abstract]
    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.
    Full-text · Article · Feb 2014 · Frontiers in Cellular Neuroscience
Show more