Downregulation of carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion.
Journal Article (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
- PMC4207388
Electronic International Standard Serial Number (EISSN)
- 1939-327X
Digital Object Identifier (DOI)
- 10.2337/db13-1677
Language
- eng
Conference Location
- United States