title: MicroRNAs in metabolism and metabolic diseases.
abstract: Aberrant cholesterol/lipid homeostasis is linked to a number of diseases prevalent in the developed world, including metabolic syndrome, type II diabetes, and cardiovascular disease. We have previously uncovered gene regulatory mechanisms of the sterol regulatory element-binding protein (SREBP) family of transcription factors, which control the expression of genes involved in cholesterol and lipid biosynthesis and uptake. Intriguingly, we recently discovered conserved microRNAs (miR-33a/b) embedded within intronic sequences of the human SREBF genes that act in a concerted manner with their host gene products to regulate cholesterol/lipid homeostasis. Indeed, miR-33a/b control the levels of ATP-binding cassette (ABC) transporter ABCA1, a cholesterol efflux pump critical for high-density lipoprotein (HDL) synthesis and reverse cholesterol transport from peripheral tissues. Importantly, antisense inhibition of miR-33 in mice results in elevated HDL and decreased atherosclerosis. Interestingly, miR-33a/b also act in the fatty acid/lipid homeostasis pathway by controlling the fatty acid β-oxidation genes carnitine O-octanoyltransferase (CROT), hydroxyacyl-coenzyme A-dehydrogenase (HADHB), and carnitine palmitoyltransferase 1A (CPT1A), as well as the energy sensor AMP-activated protein kinase (AMPKα1), the NAD(+)-dependent sirtuin SIRT6, and the insulin signaling intermediate IRS2, key regulators of glucose and lipid metabolism. These results have revealed a highly integrated microRNA (miRNA)-host gene circuit governing cholesterol/lipid metabolism and energy homeostasis in mammals that may have important therapeutic implications for the treatment of cardiometabolic disorders.
authors.affiliation: Massachusetts General Hospital Cancer Center, Charlestown, Massachusetts 02129, USA.
authors.forename: V
authors.initials: V
authors.lastname: Rottiers
authors.forename: S H
authors.initials: SH
authors.lastname: Najafi-Shoushtari
authors.forename: F
authors.initials: F
authors.lastname: Kristo
authors.forename: S
authors.initials: S
authors.lastname: Gurumurthy
authors.forename: L
authors.initials: L
authors.lastname: Zhong
authors.forename: Y
authors.initials: Y
authors.lastname: Li
authors.forename: D E
authors.initials: DE
authors.lastname: Cohen
authors.forename: R E
authors.initials: RE
authors.lastname: Gerszten
authors.forename: N
authors.initials: N
authors.lastname: Bardeesy
authors.forename: R
authors.initials: R
authors.lastname: Mostoslavsky
authors.forename: A M
authors.initials: AM
authors.lastname: Näär
mesh_terms: D055372:AMP-Activated Protein Kinases / Q000378:metabolism; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters / Q000378:metabolism; D000818:Animals; D001483:Base Sequence; D001692:Biological Transport / Q000235:genetics; D002784:Cholesterol / Q000378:metabolism; D017124:Conserved Sequence / Q000235:genetics; D004734:Energy Metabolism / Q000235:genetics; D005227:Fatty Acids / Q000378:metabolism; D005947:Glucose / Q000378:metabolism; D006706:Homeostasis / Q000235:genetics; D006801:Humans; D055504:Insulin Receptor Substrate Proteins / Q000378:metabolism; D007438:Introns / Q000235:genetics; D008659:Metabolic Diseases / Q000235:genetics*; D008660:Metabolism / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008954:Models, Biological; D008969:Molecular Sequence Data; D010084:Oxidation-Reduction; D037761:Sirtuins / Q000378:metabolism; D051779:Sterol Regulatory Element Binding Proteins / Q000235:genetics / Q000378:metabolism
chemical_list: C577836:ABCA1 protein, human; D064286:ATP Binding Cassette Transporter 1; D018528:ATP-Binding Cassette Transporters; D005227:Fatty Acids; D055504:Insulin Receptor Substrate Proteins; D035683:MicroRNAs; D051779:Sterol Regulatory Element Binding Proteins; D002784:Cholesterol; D055372:AMP-Activated Protein Kinases; D037761:Sirtuins; D005947:Glucose