Downregulation of Carnitine acyl-carnitine translocase by miRNAs 132 and 212 amplifies glucose-stimulated insulin secretion
- Mufaddal S. Soni1,
- Mary E. Rabaglia1,
- Sushant Bhatnagar1,
- Jin Shang2,
- Olga Ilkayeva3,
- Randall Mynatt4,
- Yun-Ping Zhou2,
- Eric E. Schadt6,
- Nancy A. Thornberry2,
- Deborah M. Muoio5,
- Mark P. Keller1 and
- Alan D. Attie1⇑
- From the 1Department of Biochemistry, University of Wisconsin, Madison, Wisconsin
- 2Department of Metabolic Disorders-Diabetes, Merck Research Laboratories, Rahway, New Jersey
- 3Sarah W. Stedman Nutrition and Metabolism Center, Duke Institute of Molecular Physiology
- 5Departments of Medicine and Pharmacology and Cancer Biology, Durham, North Carolina
- 4Pennington Biomedical Research Center, Louisiana State University system, Baton Rouge, Louisiana
- 6Institute for Genomics and Multiscale Biology, Mount Sinai School of Medicine, New York, New York.
- Corresponding Author: Alan D. Attie, E-mail: .
We previously demonstrated that micro-RNAs 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 micro-RNAs 132 and 212 enhances insulin secretion (IS) in response to glucose and other secretagogues including non-fuel 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. SiRNA 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 INS-1 β-cells as well as primary mouse islets. The effect in INS-1 cells was augmented in response to suppression of CACT. A non-hydrolyzable 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.
- Received October 31, 2013.
- Accepted June 19, 2014.
- © 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. See http://creativecommons.org/licenses/by-nc-nd/3.0/ for details.