Proper regulation of lipid metabolism is central to human health. Disruption of lipid metabolic pathways can lead to a variety of diseases including diabetes and obesity, which represent a substantial public health burden, especially in the last few decades. microRNAs (miRNAs) are small, non-coding RNAs that have emerged as potent and abundant regulators of cholesterol and energy metabolism. Furthermore, dysfunction in miRNA pathways has been implicated in the etiology of a variety of metabolic disorders. Recently, we demonstrated that hepatic miR-29 is aberrantly elevated in animal models of dyslipidemia and diabetes and also showed that miR-29 regulates lipid metabolic pathways in vitro. Subsequent studies in vivo revealed that miR-29 inhibition leads to the suppression of cholesterol and fatty acid synthesis pathways and a dramatic reduction in plasma cholesterol and triglycerides. We confirmed in human hepatoma cells in vitro that inhibition of miR-29 suppresses de novo cholesterol and fatty acid synthesis. Upon further analysis, we showed that miR-29 inhibition in vivo up-regulates hepatic protein levels of the transcription factors (TFs) Ah and Foxo3, both of which are involved in the suppression of lipid synthesis. We also demonstrated that Ahr is likely a direct target of miR-29. Among the known Ahr target genes that were significantly upregulated by miR- 29 inhibition is Fgf21, an important endocrine regulator of lipid homeostasis. We also observed that miR-29 inhibition leads to >10-fold down-regulation of miR-200a, which has been linked previously to metabolic control. Ahr was reported recently as a negative regulator of miR-200a, and our bioinformatic analysis identified a candidate Ahr binding site in the miR-200a promoter. Based on these and related preliminary data, we hypothesize that miR-29 control of lipid homeostasis is mediated in large part by a regulatory cascade driven by Ahr, Foxo3, and miR-200a. In this proposal, we will test this hypothesis with a blend of genomic and molecular strategies, using miR-29 loss- and gain-of-function animal models. Successful completion of these aims will uncover the molecular and biological functions of miR-29 in lipid homeostasis. These findings will lay a strong foundation for future studies focused on the design of miR-29-based research tools and novel therapeutic strategies for metabolic disease.
We have recently discovered miR-29 as a robust regulator of hepatic and plasma cholesterol and triglyceride levels in vivo, but the underlying mechanisms are unknown. In this proposal, we aim to define the regulatory cascades through which miR-29 controls lipid homeostasis. We focus our investigation on the roles of two transcription factors, Ahr and Foxo3, as well as another miRNA, miR-200a, in mediating the lipid metabolism-related functions of miR-29.
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