microRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes
- C. Lisa Kurtz1,ϕ,
- Bailey C. E. Peck1,2,ϕ,
- Emily E. Fannin1,
- Carine Beysen3,
- Ji Miao4,
- Stuart R. Landstreet5,
- Shengli Ding6,
- Vandana Turaga1,
- P. Kay Lund6,
- Scott Turner3,
- Sudha B. Biddinger4,
- Kasey C. Vickers5 and
- Praveen Sethupathy1,2,*
- 1Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 2Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- 3KineMed, Inc., Emeryville, CA, USA
- 4Department of Pediatrics, Boston Children’s Hospital, Boston, MA, USA
- 5Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN, USA
- 6Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA
- *Corresponding Author: Praveen Sethupathy, E-mail:
microRNAs (miRNAs) have emerged as biomarkers of metabolic status, etiological factors in complex disease, and promising drug targets. Recent reports suggest that miRNAs are critical regulators of pathways underlying the pathophysiology of type 2 diabetes. In this study, we demonstrate by deep sequencing and real time quantitative PCR that hepatic levels of Foxa2 mRNA and miR-29 are elevated in a mouse model of diet-induced insulin resistance. We also show that Foxa2 and miR-29 are significantly up-regulated in the livers of Zucker Diabetic Fatty (fa/fa) rats and that the levels of both returned to normal upon treatment with the insulin-sensitizing agent Pioglitazone. We present evidence that miR-29 expression in human hepatoma cells is controlled in part by FOXA2, which is known to play a critical role in hepatic energy homeostasis. Moreover, we demonstrate that miR-29 fine-tunes FOXA2-mediated activation of key lipid metabolism genes, including PPARGC1A, HMGCS2, and ABHD5. These results suggest that miR-29 is an important regulatory factor in normal metabolism and may represent a novel therapeutic target in type 2 diabetes and related metabolic syndromes.
ϕ These authors contributed equally to this work.
- Received June 28, 2013.
- Accepted April 4, 2014.
- © 2014 by the American Diabetes Association.
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