Regulation of Sphingolipid Metabolism by Micrornas: a Potential Approach to Alleviate Atherosclerosis
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diseases Review Regulation of Sphingolipid Metabolism by MicroRNAs: A Potential Approach to Alleviate Atherosclerosis Zainab Jahangir 1, Ahmed Bakillah 2 and Jahangir Iqbal 2,* 1 John P. Stevens High School, North Edison, NJ 08820, USA; [email protected] 2 King Abdullah International Medical Research Center, Ministry of National Guard Health Affairs, Al Ahsa 31982, Saudi Arabia; [email protected] * Correspondence: [email protected]; Tel.: +966-56-433-6270; Fax: +966-13-533-9998 Received: 2 September 2018; Accepted: 17 September 2018; Published: 17 September 2018 Abstract: The rapidly expanding field of bioactive lipids is exemplified by the many sphingolipids, which are structurally and functionally diverse molecules with significant physiologic functions. These sphingolipids are main constituents of cellular membranes and have been found associated with plasma lipoproteins, and their concentrations are altered in several metabolic disorders such as atherosclerosis, obesity, and diabetes. Understanding the mechanisms that regulate their biosynthesis and secretion may provide novel information that might be amenable to therapeutic targeting in the treatment of these diseases. Several sphingolipid synthesis genes have been targeted as potential therapeutics for atherosclerosis. In recent years, significant progress has been made in studying the role of microRNAs (miRNAs) in lipid metabolism. However, little effort has been made to investigate their role in sphingolipid metabolism. Sphingolipid biosynthetic pathways involve various enzymes that lead to the formation of several key molecules implicated in atherosclerosis, and the identification of miRNAs that regulate these enzymes could help us to understand these complex pathways better and may prove beneficial in alleviating atherosclerosis. Keywords: atherosclerosis; ceramides; lipids; lipoproteins; miRNA; sphingolipids; sphingomyelin 1. Introduction High plasma lipid levels are major risk factors for several cardiovascular and metabolic disorders such as atherosclerosis, obesity, and diabetes. Some of the most important risk factors for atherosclerosis are the circulating levels of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) cholesterol [1,2]. Besides traditional risk factors, changes in sphingolipids may contribute to the pathogenesis of cardiovascular disease (CVD) [3,4]. Sphingolipids are a class of lipids that contain a sphingoid base, an aliphatic amino alcohol including sphingosine. Sphingoid bases such as dihydrosphingosine and sphingosine are the fundamental building blocks of all sphingolipids. Sphingolipids are biologically active cell components that regulate cellular processes and play an important role in signal transduction and cellular stress responses. The synthesis and degradation of sphingolipids, which serve as both structural lipids as well as signaling molecules, are regulated to maintain homeostasis [3]. Sphingolipids are either derived from other sphingolipids through catabolism via the salvage pathway or synthesized de novo in the endoplasmic reticulum [5]. Ceramide is a simple sphingolipid composed of sphingosine and a fatty acid. Ceramide constitutes the hydrophobic backbone and serves as the key precursor for the de novo synthesis of other biologically active complex sphingolipids (Figure1)[ 6]. It represents a nodal point in the sphingolipid de novo pathway. It can be glycosylated or acquire a polar head group to form glycosphingolipids Diseases 2018, 6, 82; doi:10.3390/diseases6030082 www.mdpi.com/journal/diseases Diseases 2018, 6, 82 2 of 9 Diseases 2018, 6, x 2 of 8 glycosphingolipidsor sphingomyelin (SM), or sphingomyelin respectively [3 ].(SM), It can respectively also be reversibly [3]. It degradedcan also be to reversibly form sphingosine degraded which to formin turn sphingosine can be phosphorylated which in turn by can sphingosine be phosphorylated kinase (SPK) by to sphingosine form sphingosine-1-phospate kinase (SPK) to form (S1P). sphingosine-1-phospateOnce synthesized, sphingolipids (S1P). On cance besynthesized, transported sphingolipids to plasma lipoproteins can be transported [7] or remain to associated plasma lipoproteinswith cellular [7] membranes. or remain Anassociated imbalance with of cellular sphingolipid membranes. levels in An plasma imbalance and tissue of sphingolipid is associated levels with inseveral plasma metabolic and tissue diseases is associated including with atherosclerosis several metabolic [4]. diseases including atherosclerosis [4]. FigureFigure 1. 1. SchematicSchematic representation representation of of miRNAs miRNAs implicated implicated in in the the synthesis synthesis of of some some key key sphingolipid sphingolipid molecules.molecules. The The figure figure is isrepresentative representative of of some some key key enzymatic enzymatic steps steps involved involved in in sphingolipid sphingolipid biosyntheticbiosynthetic pathways pathways that that are are known known to to be be re regulatedgulated by by various various miRNAs miRNAs (dotted (dotted rectangles). rectangles). EnzymesEnzymes with with asterisks asterisks (dotted (dotted ovals) ovals) may may be be pote potentialntial targets targets for for other other miRNAs miRNAs that that need need to to be be identified.identified. Increased Increased levels levels of of ceramides, ceramides, sphi sphingomyelinngomyelin and and glucosylceramide glucosylceramide (red (red arrows) arrows) and and decreaseddecreased levels levels of of sphingosine-1- sphingosine-1-phosphatephosphate (green (green arrow) arrow) have have been been implicated implicated in in atherosclerosis. atherosclerosis. TheThe identification identification of of novel novel miRNAs miRNAs that that regulate regulate sphingolipid sphingolipid metabolism metabolism may may be be a a potential potential therapeutictherapeutic target target to to treat treat atherosclerosis. atherosclerosis. Abbrevia Abbreviations:tions: SPT, SPT, serine serine palmitoyl palmitoyl transferase; transferase; CDase, CDase, ceramidase;ceramidase; CS, CS, ceramide ceramide synthase; synthase; SPK, SPK, sphi sphingosinengosine kinase; kinase; S1PP, S1PP, sphingosine-1-phosphate sphingosine-1-phosphate phosphatase;phosphatase; SMS, SMS, sphingomyelin sphingomyelin synthase; synthase; SMas SMase,e, sphingomyelinase; sphingomyelinase; GCS, GCS, glucosylceramide glucosylceramide synthase;synthase; GCDase, GCDase, glucosylceramidase. glucosylceramidase. AnAn increased increased plasma plasma SM SM level level has has been been proposed proposed as as an an independent independent risk risk factor factor for for coronary coronary heartheart disease disease and and has has been been shown shown to tobe be associated associated with with increased increased atherosclerosis atherosclerosis in humans in humans [8]. [A8]. reductionA reduction in inSM SM levels levels in insphingomyelin sphingomyelin synthase synthase (SMS) (SMS) knockout knockout mice mice is is known known to to decrease decrease atherosclerosisatherosclerosis [9,10]. [9,10]. Like Like SM, SM, increased increased plasma plasma an andd aortic aortic ceramide ceramide levels levels are are also also associated associated with with anan increased increased risk risk of of CVD CVD [11]. [11]. Genetic Genetic deficiency deficiency or or the the inhibition inhibition of of type type 2-neutral 2-neutral sphingomyelinase sphingomyelinase (nSMase2),(nSMase2), a a key key enzyme enzyme in in sphingolipid sphingolipid metabolis metabolism,m, has has been been shown shown to to decrease decrease atherosclerosis atherosclerosis in in ApoEApoE knockout knockout mice mice by by reducing reducing inflammatory inflammatory responses responses due due to to aa dec decreaserease in in ceramide ceramide levels levels [12]. [12]. Furthermore,Furthermore, plasma plasma glycosphingolipid concentrationsconcentrationshave have been been reported reported to to be be elevated elevated in in patients patients at atincreased increased risk risk of of atherosclerosis atherosclerosis [13 [13].]. The The pharmacological pharmacological inhibition inhibition of glucosylceramideof glucosylceramide synthase synthase that thatis responsible is responsible for the for synthesis the synthesis of glucosylceramides of glucosylceramides has been reported has been to ameliorate reported atherosclerosis to ameliorate in atherosclerosisApoE knockout in mice ApoE and knockout rabbits mice [14]. and In contrast rabbits to[14]. ceramide, In contrast glycosphingolipid, to ceramide, glycosphingolipid, and SM, plasma andS1P isSM, believed plasma to beS1P cardioprotective is believed to [3be]. Regulationcardioprotective of the interconvertible[3]. Regulation sphingolipidof the interconvertible metabolites, sphingolipidceramide and metabolites, S1P, and their ceramide opposing and signalingS1P, and th pathwayseir opposing may signaling determine pathways the net biologicalmay determine effect, thea concept net biological referred effect, to as thea concept “sphingolipid referred rheostat”. to as the Plasma“sphingolipid S1P levels rheostat”. significantly Plasma decrease S1P levels after significantlymyocardial infarctiondecrease [after15] and myocardial increase ininfarction patients after[15] and percutaneous increase in coronary patients intervention after percutaneous [16]. It is coronarybelieved thatintervention S1P bound [16]. to It HDL is believed may predict that S1P the severitybound to of HDL coronary may heartpredict disease the severity [17]. Recently, of