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

Published

Journal Article

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.

Full Text

Duke Authors

Cited Authors

  • Soni, MS; Rabaglia, ME; Bhatnagar, S; Shang, J; Ilkayeva, O; Mynatt, R; Zhou, Y-P; Schadt, EE; Thornberry, NA; Muoio, DM; Keller, MP; Attie, AD

Published Date

  • November 2014

Published In

Volume / Issue

  • 63 / 11

Start / End Page

  • 3805 - 3814

PubMed ID

  • 24969106

Pubmed Central ID

  • 24969106

Electronic International Standard Serial Number (EISSN)

  • 1939-327X

International Standard Serial Number (ISSN)

  • 0012-1797

Digital Object Identifier (DOI)

  • 10.2337/db13-1677

Language

  • eng