Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.

Autor:	Soni MS; Department of Biochemistry, University of Wisconsin, Madison, WI., Rabaglia ME; Department of Biochemistry, University of Wisconsin, Madison, WI., Bhatnagar S; Department of Biochemistry, University of Wisconsin, Madison, WI., Shang J; Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ., Ilkayeva O; Sarah W. Stedman Nutrition and Metabolism Center, Department of Medicine, Duke University, Durham, NC., Mynatt R; Pennington Biomedical Research Center, Louisiana State University, Baton Rouge, LA., Zhou YP; Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ., Schadt EE; Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, NY., Thornberry NA; Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, NJ., Muoio DM; 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., Keller MP; Department of Biochemistry, University of Wisconsin, Madison, WI., Attie AD; Department of Biochemistry, University of Wisconsin, Madison, WI adattie@wisc.edu.
Jazyk:	angličtina
Zdroj:	Diabetes [Diabetes] 2014 Nov; Vol. 63 (11), pp. 3805-14. Date of Electronic Publication: 2014 Jun 26.
DOI:	10.2337/db13-1677
Abstrakt:	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. (© 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.)
Databáze:	MEDLINE
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