MicroRNA-29 fine-tunes the expression of key FOXA2-activated lipid metabolism genes and is dysregulated in animal models of insulin resistance and diabetes.
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 upregulated 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.
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
C Lisa
CL
Kurtz
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Bailey C E
BC
Peck
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Emily E
EE
Fannin
KineMed, Inc., Emeryville, CA.
Carine
C
Beysen
Department of Pediatrics, Boston Children's Hospital, Boston, MA.
Ji
J
Miao
Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN.
Stuart R
SR
Landstreet
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Shengli
S
Ding
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC.
Vandana
V
Turaga
Department of Nutrition, University of North Carolina at Chapel Hill, Chapel Hill, NC.
P Kay
PK
Lund
KineMed, Inc., Emeryville, CA.
Scott
S
Turner
Department of Pediatrics, Boston Children's Hospital, Boston, MA.
Sudha B
SB
Biddinger
Department of Medicine, School of Medicine, Vanderbilt University, Nashville, TN.
Kasey C
KC
Vickers
Department of Genetics, School of Medicine, University of North Carolina at Chapel Hill, Chapel Hill, NC Genetics and Molecular Biology Curriculum, University of North Carolina at Chapel Hill, Chapel Hill, NC praveen_sethupathy@med.unc.edu.
Praveen
P
Sethupathy
D000818:Animals; D045744:Cell Line, Tumor; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy / Q000235:genetics; D005260:Female; D051542:Hepatocyte Nuclear Factor 3-beta / Q000235:genetics / Q000502:physiology; D006801:Humans; D007333:Insulin Resistance / Q000235:genetics*; D051379:Mice; D035683:MicroRNAs / Q000502:physiology*; D023421:Models, Animal; D000077205:Pioglitazone; D051381:Rats; D011924:Rats, Zucker; D045162:Thiazolidinediones / Q000627:therapeutic use; D015854:Up-Regulation
C496504:Foxa2 protein, rat; C547014:MIRN29 microRNA, mouse; C526366:MIRN29 microRNA, rat; C532045:MIRN29a microRNA, human; D035683:MicroRNAs; D045162:Thiazolidinediones; D051542:Hepatocyte Nuclear Factor 3-beta; D000077205:Pioglitazone