title: Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.
abstract: We previously demonstrated that micro-RNAs (miRNAs) 132 and 212 are differentially upregulated in response to obesity in two mouse strains that differ in their susceptibility to obesity-induced diabetes. Here we show the overexpression of miRNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including nonfuel stimuli. We determined that carnitine acyl-carnitine translocase (CACT; Slc25a20) is a direct target of these miRNAs. CACT is responsible for transporting long-chain acyl-carnitines into the mitochondria for β-oxidation. Small interfering RNA-mediated knockdown of CACT in β-cells led to the accumulation of fatty acyl-carnitines and enhanced IS. The addition of long-chain fatty acyl-carnitines promoted IS from rat insulinoma β-cells (INS-1) as well as primary mouse islets. The effect on INS-1 cells was augmented in response to suppression of CACT. A nonhydrolyzable ether analog of palmitoyl-carnitine stimulated IS, showing that β-oxidation of palmitoyl-carnitine is not required for its stimulation of IS. These studies establish a link between miRNA-dependent regulation of CACT and fatty acyl-carnitine-mediated regulation of IS.
authors: Department of Biochemistry, University of Wisconsin, Madison, WI.
authors: Mufaddal S
authors: MS
authors: Soni
authors: Department of Biochemistry, University of Wisconsin, Madison, WI.
authors: Mary E
authors: ME
authors: Rabaglia
authors: Department of Biochemistry, University of Wisconsin, Madison, WI.
authors: Sushant
authors: S
authors: Bhatnagar
authors: Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ.
authors: Jin
authors: J
authors: Shang
authors: Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC.
authors: Olga
authors: O
authors: Ilkayeva
authors: Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA.
authors: Randall
authors: R
authors: Mynatt
authors: Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ.
authors: Yun-Ping
authors: YP
authors: Zhou
authors: Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY.
authors: Eric E
authors: EE
authors: Schadt
authors: Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ.
authors: Nancy A
authors: NA
authors: Thornberry
authors: Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC Departments of Medicine and Pharmacology and Cancer Biology, Duke University, Durham, NC.
authors: Deborah M
authors: DM
authors: Muoio
authors: Department of Biochemistry, University of Wisconsin, Madison, WI.
authors: Mark P
authors: MP
authors: Keller
authors: Department of Biochemistry, University of Wisconsin, Madison, WI adattie@wisc.edu.
authors: Alan D
authors: AD
authors: Attie
mesh_terms: D000818:Animals; D002333:Carnitine Acyltransferases / Q000235:genetics / Q000378:metabolism*; D002460:Cell Line; D015536:Down-Regulation / Q000187:drug effects; D005947:Glucose / Q000494:pharmacology*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D051379:Mice; D035683:MicroRNAs / Q000235:genetics*; D051381:Rats
chemical_list: D007328:Insulin; D035683:MicroRNAs; D002333:Carnitine Acyltransferases; D005947:Glucose