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The Mechanisms of Action Beyond Stearoyl-Coa Desaturase Inhibition and Therapeutic Opportunities in Human Diseases

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The Mechanisms of Action Beyond Stearoyl-Coa Desaturase Inhibition and Therapeutic Opportunities in Human Diseases cells Review Sterculic Acid: The Mechanisms of Action beyond Stearoyl-CoA Desaturase Inhibition and Therapeutic Opportunities in Human Diseases Rafael Peláez y , Ana Pariente y, Álvaro Pérez-Sala and Ignacio M. Larráyoz * Biomarkers and Molecular Signaling Group, Neurodegeneration Area, Center for Biomedical Research of La Rioja (CIBIR), Piqueras 98, 26006 Logroño, Spain; [email protected] (R.P.); [email protected] (A.P.); [email protected] (Á.P.-S.) * Correspondence: [email protected]; Tel.: +34-941278770 These authors contributed equally to this work. y Received: 19 December 2019; Accepted: 5 January 2020; Published: 7 January 2020 Abstract: In many tissues, stearoyl-CoA desaturase 1 (SCD1) catalyzes the biosynthesis of monounsaturated fatty acids (MUFAS), (i.e., palmitoleate and oleate) from their saturated fatty acid (SFA) precursors (i.e., palmitate and stearate), influencing cellular membrane physiology and signaling, leading to broad effects on human physiology. In addition to its predominant role in lipid metabolism and body weight control, SCD1 has emerged recently as a potential new target for the treatment for various diseases, such as nonalcoholic steatohepatitis, Alzheimer’s disease, cancer, and skin disorders. Sterculic acid (SA) is a cyclopropene fatty acid originally found in the seeds of the plant Sterculia foetida with numerous biological activities. On the one hand, its ability to inhibit stearoyl-CoA desaturase (SCD) allows its use as a coadjuvant of several pathologies where this enzyme has been associated. On the other hand, additional effects independently of its SCD inhibitory properties, involve anti-inflammatory and protective roles in retinal diseases such as age-related macular degeneration (AMD). This review aims to summarize the mechanisms by which SA exerts its actions and to highlight the emerging areas where this natural compound may be of help for the development of new therapies for human diseases. Keywords: sterculic acid; inflammation; cell death; macular degeneration; metabolism 1. Introduction Under normal conditions, lipogenesis and lipolysis coexist in dynamic equilibrium. Signals coming from the central nervous system as well as peripheral tissues determine the balance of synthesis and breakdown of triglycerides. Fat is mainly accumulated in adipose tissue, especially white adipose tissue, which is the principal energy storage organ [1,2]. There are two different sources of lipogenesis, de novo lipogenesis and circulating triglycerides. In tissues with high metabolic rate, such as the liver, or in adipose tissue, de novo lipogenesis is more active, although every single cell is able to perform lipogenesis [2]. In particular, human adipose tissue seems to be the principal tissue where de novo lipogenesis is carried out [3]. This type of lipogenesis is characterized by the transformation of carbohydrates into fatty acids, which are then esterified and stored as triglycerides if there is no demand of energy in the body. This process starts with the glycolysis of dietary carbohydrates in order to obtain acetyl-CoA. The enzyme acetyl-CoA carboxylase 1 (ACC1) converts acetyl-CoA into malonyl-CoA, which is next transformed to palmitate by the fatty acid synthase (FASN) [2]. Finally, the last step of de novo lipogenesis is carried out by stearoyl-CoA desaturase (SCD), the first rate-limiting enzyme involved in SFA desaturation [4]. SCD introduces a single double bound in Cells 2020, 9, 140; doi:10.3390/cells9010140 www.mdpi.com/journal/cells Cells 2020, 9, 140 2 of 20 palmitoyl-CoACells 2020, 9, tox transform it into palmitoleoyl-CoA, in a reaction in which reduced nicotinamide2 of 20 β adenine[4]. dinucleotide SCD introduces (NADH), a single flavoprotein double bound cytochrome in palmitoyl-CoA5 reductase, to transform as wellit into as palmitoleoyl-CoA, the electron acceptor cytochromein a βreaction5 are also in involvedwhich reduced [5]. In additionnicotinamide topalmitic adenine acid,dinucleotide stearic acid(NADH), is also flavoprotein one of the main substratescytochrome of SCD, β which5 reductase, is desaturated as well as andthe electron converted acceptor into oleiccytochrome acid [ 6β].5 Toare aalso lesser involved extent, [5]. SCD In also catalyzesaddition the conversion to palmitic acid, of myristic stearic acid acid is into also myristoleicone of the main acid substrates [7]. of SCD, which is desaturated Deand novo converted lipogenesis into oleic is stimulated acid [6]. To when a lesser glucose extent, and SCD insulin also catalyzes blood levelsthe conversion are elevated of myristic [2] as they induceacid the into activation myristoleic of ChREBP acid [7]. (carbohydrate response element binding protein), SREBP-1c (sterol De novo lipogenesis is stimulated when glucose and insulin blood levels are elevated [2] as they regulatory element binding protein 1c), and LXR (liver X receptor), specific transcriptional factors induce the activation of ChREBP (carbohydrate response element binding protein), SREBP-1c (sterol whose activationregulatory element promotes binding lipogenesis protein [ 41c),,8] (Figureand LXR1 ).(liv Thus,er X receptor), SCD-1 hepatic specific expression transcriptional is induced factors after a carbohydrate-richwhose activation intake promotes through lipoge a SREBP-1c-dependentnesis [4,8] (Figure 1). Thus, mechanism SCD-1 hepatic that involves expression the bindingis induced of LXR to a LXR-responseafter a carbohydrate-rich in the SCD-1 intake promoter through element a SREBP-1c-dependent through the activation mechanism of SREBP-1c that involves transcription, the but alsobinding through of aLXR SREBP-1c-independent to a LXR-response in pathwaythe SCD- [18 –promoter12]. element through the activation of SterculicSREBP-1c acid transcription, (SA) is abut cyclopropene also through a fattySREBP-1c-independent acid with numerous pathway biological [8–12]. activities. In this review weSterculic describe acid how (SA) its is ability a cyclopropene to inhibit fatty stearoyl-CoA acid with numerous desaturase biological (SCD) activities. directly, In can this be of interestreview as a coadjuvant we describe for how the its treatment ability to forinhibit various stearoyl-CoA diseases, desaturase such as, nonalcoholic(SCD) directly, steatohepatitis, can be of interest as a coadjuvant for the treatment for various diseases, such as, nonalcoholic steatohepatitis, Alzheimer’s disease, cancer, and retinal disorders. In addition, it displays anti-inflammatory properties, Alzheimer’s disease, cancer, and retinal disorders. In addition, it displays anti-inflammatory independentlyproperties, of independently SCD inhibition, of SCD which inhibition, can be which useful can to be treat useful other to treat pathologies other pathologies such as such age-related as macularage-related degeneration macular (AMD). degeneration (AMD). FigureFigure 1. Genetic 1. Genetic control control of theof the stearoyl-CoA stearoyl-CoAdesaturase desaturase (SCD) (SCD) family family and and other other lipogenic lipogenic gene gene expression.expression. Promoter Promoter regions regions of of SCD SCD genes genes present many many transcription transcription factor factor binding binding sites, such sites, as such sterol regulatory element binding protein 1 (SREBP1), carbohydrate response element binding as sterol regulatory element binding protein 1 (SREBP1), carbohydrate response element binding protein (ChREBP), CCAAT/enhancer-binding protein (C/EBP), liver X receptor (LXR), or peroxisome proteinproliferator-activated (ChREBP), CCAAT receptor/enhancer-binding (PPAR). Black protein arrows (C represent/EBP), liver inductive X receptor signals (LXR), while or red peroxisome lines proliferator-activatedrepresent repressive receptor signals (PPAR). that negatively Black arrows modulate represent SCD inductive genes expression. signals while Glucose red linesuptake represent or repressiveinsulin signals signaling, that negatively but also lipid modulate uptake, SCD hormones genes, expression.or growth factors Glucose binding uptake to ortheir insulin receptors, signaling, but alsosignaling lipid uptake, pathways hormones, such as phosphatidylinositol or growth factors binding 3-kinase to (PI3K), their receptors,mitogen-activated signaling protein pathways kinase such as phosphatidylinositol(MAPK), mammalian 3-kinase target (PI3K),of rapamycin mitogen-activated (mTOR), or endoplasmic protein kinase reticulum (MAPK), (ER) stress, mammalian promote target of rapamycindirect or (mTOR), indirect transcription or endoplasmic factorreticulum binding to (ER)SCDs stress,promoters promote to modulate direct SCD or indirect gene expression. transcription factor bindingSome microRNAs to SCDs promoters(mirRNA121, to modulate221, 222, and SCD 600) gene ha expression.ve been reported Some to microRNAs downregulate (mirRNA121, SCDs 221, 222, and 600) have been reported to downregulate SCDs expression. Activator protein 1 (AP-1) is a transcription factor that reduces SCD1 expression after leptin stimulation. C/EBP induction can also downregulate SCD1 expression after bacterial infection. Cells 2020, 9, 140 3 of 20 2. Stearoyl-CoA Desaturase (SCD) Stearoyl-CoA desaturase (SCD) is an enzyme which is known to be active in the conversion of saturated fats into (MUFAs). While mouse genome presents 4 isoforms (SCD1-4), human genome only has two isoforms (SCD1 and SCD5). In humans, both enzymes have the same catalytic activity and generate the same products, but they present different locations and effects
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