MicroRNA 33 Regulates Glucose Metabolism

Abstract

Metabolic diseases are characterized by the failure of regulatory genes or proteins to effectively orchestrate specific pathways involved in the control of many biological processes. In addition to the classical regulators, recent discoveries have shown the remarkable role of small noncoding RNAs (microRNAs [miRNAs]) in the posttranscriptional regulation of gene expression. In this regard, we have recently demonstrated that miR-33a and miR33b, intronic miRNAs located within the sterol regulatory element-binding protein (SREBP) genes, regulate lipid metabolism in concert with their host genes. Here, we show that miR-33b also cooperates with SREBP1 in regulating glucose metabolism by targeting phosphoenolpyruvate carboxykinase (PCK1) and glucose-6-phosphatase (G6PC), key regulatory enzymes of hepatic gluconeogenesis. Overexpression of miR-33b in human hepatic cells inhibits PCK1 and G6PC expression, leading to a significant reduction of glucose production. Importantly, hepatic SREBP1c/miR-33b levels correlate inversely with the expression of PCK1 and G6PC upon glucose infusion in rhesus monkeys. Taken together, these results suggest that miR-33b works in concert with its host gene to ensure a fine-tuned regulation of lipid and glucose homeostasis, highlighting the clinical potential of miR-33a/b as novel therapeutic targets for a range of metabolic diseases.

ACKNOWLEDGMENTS

This work was supported by the National Institutes of Health (grants R01HL107953 and R01HL106063 to C.F.-H., R01HL105945 to Y.S., and 1F31AG043318-01 to L.G.), the American Heart Association (grant 12POST9780016 to C.M.R.), the Deutsche Forschungsgemeinschaft (to D.C.-S.), and the Ministerio de Educación (Programa Nacional de Movilidad de Recursos Humanos del Plan Nacional de I-D+i 2008-2011 [to N.R.]). R.D.C. was supported by the Intramural Research Program of the NIH National Institute on Aging.