Non-coding RNAs and Metabolism.pdf

CRNDELincRNA-p21GLUTMCT4UCA1miR-155miR-124miR-133bmiR-122miR-378/378*miR-370AdipocytesPERIPHERALMETABOLICTISSUEHEPATOCYTEFatty acidelongationInsulinsecretionmiR-33a/bGLYCOLYSISmiR-33amiR-375VDCCmiR-7miR-143miR-103/107miR-33a/bGlucagonreleaseLeptin RGLP1RInsRInsRInsInsRIGF1RmiR-141/200DLK1-MEG3miRNAsApoptosisLipidraftsLnc-HCmiR-122ABCA1miR-122miR-103miR-107miR-181amiR-183Fatty acidsynthesismiR-34a/cmiR-369-3pmiR-374amiR-4524a/bNRCPlet-7let-7let-7IVIVIIIIILincRNA-p21miR-124Lin28a/bmiR-199amiR-143MCT1miR-93miR-133miR-223miR-195-5pmiR-144PCGEM1Pentose phosphatepathwayInsulin signalingNucleotidebiosynthesisNBR2NBR2miR-181cmiR-210miR-23a/bNucleotidebiosynthesisUCA1CCAT2Glucose metabolismLipid metabolismInsulin and glucacon metabolismAc-CoACitrateIsocitrateSuccinyl-CoASuccinateFumarateMalateOxaloacetateTCAcycleInsInsInsInsInsInsLEGENDHK2PKM2LDHPDHIDHGLSGLS2IDHmutPDK1FACSCPT1FASACCHMGCRAKTPI3KORPB8AKTAKTp53TP53INP1IRSsIRSsR5PPEPPyruvatePyruvatePyruvateGlutamineGlutamate2HGFatty acidsFatty acyl-CoAPalmitateAcyl carnitineAc-CoAHMG-CoAMalonyl-CoATGTGGLP-1LactateTCAcycleIGF-1LLLLCCLLLLGPGGGGAc-CoAPEPPyruvateGPGCa+Ca+Ca+Ca+Ca+Ca+LactateGlucoseTriglyceridesCholesterolInsulinCalciumGlutamine metabolism and TCA cycleDirect inhibitionIndirect inhibitionDirect activationIndirect activationDYNLRB2-2AMPKAMPKSee online version forlegend and references.220 Cell Metabolism 25,January 10,2017 2017 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.cmet.2016.12.012SnapShot:Non-coding RNAs and MetabolismRoxana Simona Redis1,2 and George Adrian Calin11Departments of Experimental Therapeutics and Leukemia and the Center for RNA Interference and Non-coding RNA,University of Texas M.D.Anderson Cancer Center,Houston,TX 77030,USA;2ProQR Therapeutics N.V.,2333 CK Leiden,the Netherlands220.e1 Cell Metabolism 25,January 10,2017 2017 Elsevier Inc.DOI http:/dx.doi.org/10.1016/j.cmet.2016.12.012SnapShot:Non-coding RNAs and MetabolismRoxana Simona Redis1,2 and George Adrian Calin11Departments of Experimental Therapeutics and Leukemia and the Center for RNA Interference and Non-coding RNA,University of Texas M.D.Anderson Cancer Center,Houston,TX 77030,USA;2ProQR Therapeutics N.V.,2333 CK Leiden,the NetherlandsMetabolic abnormalities represent one of the oldest recognized defects in cancer and other diseases(e.g.,obesity,diabetes,or cardiovascular diseases),and while the con-sequences of the metabolic changes are deeply investigated,the causes underlying these abnormalities are poorly understood.The deeper understandings of the interplay between non-coding RNAs(ncRNAs)and metabolism not only render a better knowledge of the intimate mechanisms that alter the metabolisms of glucose,glutamine,lipids,or hormones and other proteins,but also offer a strong basis for the development of new therapeutics based on the fi ne-tuning of metabolic pathways by short microRNAs(miRNAs)and long ncRNAs(lncRNAs).Glucose MetabolismAbnormal glucose metabolism is one of the main features of metabolically related diseases.miRNAs target the messenger RNA(mRNA)of metabolic enzymes either directly(e.g.,miR-34a/c and miR-374a targeting LDH)or indirectly via intermediary loops(e.g.,miR-155 targets CEBP,a transcription factor for miR-143,which targets and inhibi ts HK2).A miRNA has multiple metabolic targets;for instance,miR-124 regulates both PKM2 and genes involved in the pentose phosphate pathway(PPP).lncRNAs,on the other hand,exert their regulation indirectly through RNA-binding protein partners or interactor miRNAs.For example,UCA1 activates mTOR that in return induces STAT3 protein and blocks miR-143,leading to upregulation of HK2 messenger and protein and implicitly glycolysis.Similarly,by modulating MYC and AR proteins,PCGEM1 pro-motes glucose uptake for aerobic glycolysis,coupled with the PPP to facilitate biosynthesis of nucleotides and lipids,thereby generating NADPH for redox homeostasis.The majority of the ncRNAs modulate either the initial or the last reactions of the glycolysis corresponding to the rate-limiting steps in glucose metabolism.Glutamine Metabolism and TCA CycleGlutamine is another key nutrient fueling cellular metabolism,especially in cancer cells.Glutamine is converted into glutamate by glutaminase(encoded by two genes:kidney type,GLS,and liver type,GLS2).Two paradigms of GLS modulation have emerged:the fi rst is the concurrent regulation by miR-23a/b and the lncRNA CCAT2,and the second is the allele-specifi c reprogramming of glutamine metabolism by CCAT2.The latter suggests that the structure of the lncRNA directly refl ects its function,highlighting a need for understanding the tertiary structures of these transcripts to predict their functional roles.In addition to GLS,other key enzymes involved in either glutamine metabo-lism or the TCA cycle are targeted by ncRNAs,such as IDH by miR-181a and miR-183,or PDK1 by let-7.Lipid MetabolismLipid metabolism is intimately related to the metabolism of carbohydrates,and in glucose-deprived conditions it can sustain cell survival via Ac-CoA production.Several miRNAs regulate lipid metabolism,including during adipocyte differentiation,HDL biogenesis,and cholesterol metabolism.miR-122,the most abundant liver miRNA,which accounts for almost 70%of all liver miRNAs,regulates cholesterol and fatty acid metabolism by controlling the expression of lipogenic and cholesterol synthesis genes in the liver(e.g.,SREBP-1,FASN,SCD1,ACC1,ACC2,and LDLR).miR-33a/b also play essential roles in cholesterol and lipid metabolism by targeting the ABCA1 transporter to control cellular cholesterol effl ux.Similarly,the lncRNA DYNLRB2-2 promotes ABCA1-mediated cholesterol effl ux in response to oxidized-LDL induction by upregulating the expression of GPR119 and ABCA1 through the GLP-1 receptor signaling pathway.The ABCA1 mRNA is destabilized by direct interaction with the hnRNPA2B1-lnc-HC com-plex.Additionally,miR-33a/b link lipid metabolism and the insulin signaling pathway in the liver as they target genes involved in both pathways(e.g.,CPT1 and IRS).Insulin and Glucagon MetabolismInsulin promotes glycogenesis in the liver and inhibits glucagon secretion from cells,resulting in gluconeogenesis inhibition.miRNAs regulate the insulin pathway mainly in the cells,where they target genes involved in insulin and growth hormone receptors(let-7)or insulin secretion(Cdr1as/miR-7).Inhibition of let-7 improves glucose uptake and insulin resistance in the myocardium of diabetic rats by consequential upregulation of InsR,GLUT4,and IGF-1R and confers cardioprotection against ischemia-reperfu-sion.Transgenic mice overexpressing miR-7 in cells develop diabetes due to reduced insulin secretion and impaired cell dedifferentiation.Another level of regulation is provided by the circular RNA Cdr1as,which acts as a sponge for miR-7 and improves cell function.A large number of genes regulated by miRNAs are involved in prolifera-tion and regulation of cell mass(miR-141/200 family,DLK1-MEG3 miRNA family and miR-375).Loss of miR-375 in mice decreases cell mass and promotes hyperglycemia,hepatic gluconeogenesis,and type 2 diabetes.Interestingly,the DLK1-MEG3 genomic region encompasses multiple maternally expressed ncRNAs,including one of the larg-est miRNA clusters in human genome,suggesting that miRNAs transcribed from this region contribute to the hereditary mechanisms of hormone regulation.Therapeutic ImplicationsBlocking dysfunctional metabolic pathways and/or restoring cellular homeostasis represent promising therapeutic windows.Similar to reprograming the immune system to attack malignant cells,altering cellular fuel may be an alternative or complementary therapeutic approach.ncRNAs are attractive candidates as they inhibit pathways at stra-tegic steps by targeting multiple key genes.ncRNA inhibitors or mimics may potentially act in tandem with compounds currently in clinical trials specifi cally designed to target metabolic enzymes,boosting the effi cacy of the treatment.ABBREVIATIONSGLUT,glucose transporters;LDH,lactate dehydrogenase;TCA,tricarboxylic cycle;IDH,isocitrate dehydrogenase;PDK,pyruvate dehydrogenase kinase;Ac-CoA,acetyl coenzyme A;HDL,high-density lipoprotein;ABCA1,ATP binding cassette subfamily member 1;GLP-1,glucagon-like peptide-1;DLK1-MEG3,delta-like homolog 1,maternally expressed gene 3;LincRNA,long intergenic non-coding RNA;CRNDE,colorectal neoplasia differentially expressed lncRNA.REFERENCESAltman,B.J.,Stine,Z.E.,and Dang,C.V.(2016).Nat.Rev.Cancer 16,619634.Beltrn-Anaya,F.O.,Cedro-Tanda,A.,Hidalgo-Miranda,A.,and Romero-Cordoba,S.L.(2016).Front.Physiol.7,342.Hartig,S.M.,Hamilton,M.P.,Bader,D.A.,and McGuire,S.E.(2015).Trends Endocrinol.Metab.26,733745.Lan,X.,Yan,J.,Ren,J.,Zhong,B.,Li,J.,Li,Y.,Liu,L.,Yi,J.,Sun,Q.,Yang,X.,et al.(2016).Hepatology 64,5872.Moore,K.J.,Rayner,K.J.,Surez,Y.,and Fernndez-Hernando,C.(2011).Annu.Rev.Nutr.31,4963.Qiu,Z.,Guo,W.,Wang,Q.,Chen,Z.,Huang,S.,Zhao,F.,Yao,M.,Zhao,Y.,and He,X.(2015).Gastroenterology 149,15871598.e11.Redis,R.S.,Vela,L.E.,Lu,W.,Ferreira de Oliveira,J.,Ivan,C.,Rodriguez-Aguayo,C.,Adamoski,D.,Pasculli,B.,Taguchi,A.,Chen,Y.,et al.(2016).Mol.Cell 61,520534.Sborov,D.W.,Haverkos,B.M.,and Harris,P.J.(2015).Expert Opin.Investig.Drugs 24,7994.Tomasetti,M.,Amati,M.,Santarelli,L.,and Neuzil,J.(2016).Int.J.Mol.Sci.17,E754.10.3390/ijms17050754.Vander Heiden,M.G.(2011).Nat.Rev.Drug Discov.10,671684.