Aberrant regulation of cholesterol and lipid homeostasis leads to metabolic syndrome and cardiovascular diseases. microRNAs (miRNA) are short non-coding RNAs that control gene expression predominantly through post-transcriptional repression. They are implicated in the control of multiple physiological and pathological processes. However the specific roles of miRNAs in regulating cholesterol and lipoprotein metabolism are just beginning to be explored. Our previous work has shown that hsa-miR- 33a/b and its mouse homologue mmu-miR-33 (herein after referred to as miR-33), intronic miRNAs located within the sterol-regulatory element-binding protein (SREBP) 2 and 1 genes, respectively, in humans;regulate cholesterol homeostasis in concert with the SREBP host gene. MiR-33 inhibits the expression of the ATP-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apoA1 and high-density lipoprotein (HDL) biogenesis. Conversely, silencing of miR-33 in vivo increased hepatic ABCA1 and plasma HDL. In addition, our recent preliminary data suggest that miR-33 also coordinates genes regulating fatty acid metabolism and insulin signaling. For example, miR-33 targets carnitine O- octaniltransferase (CROT), Carnitine palmitoyltransferase 1A (CPT1a) and hydroxyacyl-CoA- dehydrogenase (HADHB), key enzymes involved in the regulation of fatty acid oxidation, and insulin receptor substrate 2 (IRS2), which regulates insulin signaling. Thus, we hypothesize that inhibition of miR-33 may represent a therapeutic target for ameliorating cardiometabolic disease, including atherosclerosis and metabolic syndrome. The objective of this proposal is to determine the molecular mechanism underlying the miR-33-mediated responses in cardiometabolic disease. We propose the following specific Aims:
Aim 1. To delineate the role of miR-33 in regulating cholesterol metabolism, - oxidation of fatty acid and insulin signaling in vivo and Aim 2. To define the role of miR-33 in lipid metabolism, insulin signaling, and atherosclerosis in vivo.
Aberrant regulation of cholesterol and lipid homeostasis leads to metabolic syndrome and cardiovascular diseases. Our recent data suggest that microRNA (miRNA) is important regulators in the control of lipoprotein metabolism and insulin signaling. MiR-33 inhibits the expression of the ATP-binding cassette (ABC) transporter, ABCA1, thereby attenuating cholesterol efflux to apoA1 and high-density lipoprotein (HDL) biogenesis. The proposal main goal is to investigate the mechanism by which miR-33 regulates lipid metabolism and cardiovascular related disorders. This work will provide critical insight into fundamental regulatory mechanism and may identify potential therapeutic strategies for the regulation of lipoprotein metabolism and insulin signaling, two hallmarks of the metabolic syndrome. ]
| Willeit, Peter; Skroblin, Philipp; Moschen, Alexander R et al. (2017) Circulating MicroRNA-122 Is Associated With the Risk of New-Onset Metabolic Syndrome and Type 2 Diabetes. Diabetes 66:347-357 |
| Price, Nathan L; Rotllan, Noemi; Canfrán-Duque, Alberto et al. (2017) Genetic Dissection of the Impact of miR-33a and miR-33b during the Progression of Atherosclerosis. Cell Rep 21:1317-1330 |
| Zhang, Xinbo; Fernández-Hernando, Carlos (2017) miR-33 Regulation of Adaptive Fibrotic Response in Cardiac Remodeling. Circ Res 120:753-755 |
| Canfrán-Duque, Alberto; Rotllan, Noemi; Zhang, Xinbo et al. (2017) Macrophage deficiency of miR-21 promotes apoptosis, plaque necrosis, and vascular inflammation during atherogenesis. EMBO Mol Med 9:1244-1262 |
| Araldi, Elisa; Fernández-Fuertes, Marta; Canfrán-Duque, Alberto et al. (2017) Lanosterol Modulates TLR4-Mediated Innate Immune Responses in Macrophages. Cell Rep 19:2743-2755 |
| Aryal, Binod; Rotllan, Noemi; Araldi, Elisa et al. (2016) ANGPTL4 deficiency in haematopoietic cells promotes monocyte expansion and atherosclerosis progression. Nat Commun 7:12313 |
| Price, Nathan L; Holtrup, Brandon; Kwei, Stephanie L et al. (2016) SREBP-1c/MicroRNA 33b Genomic Loci Control Adipocyte Differentiation. Mol Cell Biol 36:1180-93 |
| Goedeke, Leigh; Wagschal, Alexandre; Fernández-Hernando, Carlos et al. (2016) miRNA regulation of LDL-cholesterol metabolism. Biochim Biophys Acta 1861:2047-2052 |
| Ulrich, Victoria; Rotllan, Noemi; Araldi, Elisa et al. (2016) Chronic miR-29 antagonism promotes favorable plaque remodeling in atherosclerotic mice. EMBO Mol Med 8:643-53 |
| Price, Nathan L; Fernández-Hernando, Carlos (2016) miRNA regulation of white and brown adipose tissue differentiation and function. Biochim Biophys Acta 1861:2104-2110 |
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