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.

Public Health Relevance

Aberrant regulation of cholesterol and lipid homeostasis leads to metabolic syndrome and cardiovascular diseases. Our recent data suggest that microRNA (miRNA) are 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.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
3R01HL107953-04S1
Application #
8764259
Study Section
Integrative Nutrition and Metabolic Processes Study Section (INMP)
Program Officer
Hasan, Ahmed AK
Project Start
2013-12-01
Project End
2015-11-30
Budget Start
2013-12-01
Budget End
2015-11-30
Support Year
4
Fiscal Year
2014
Total Cost
$359,382
Indirect Cost
$143,537
Name
Yale University
Department
Veterinary Sciences
Type
Schools of Medicine
DUNS #
043207562
City
New Haven
State
CT
Country
United States
Zip Code
06520
Ramírez, Cristina M; Lin, Chin Sheng; Abdelmohsen, Kotb et al. (2014) RNA binding protein HuR regulates the expression of ABCA1. J Lipid Res 55:1066-1076
Goedeke, Leigh; Aranda, Juan F; Fernández-Hernando, Carlos (2014) microRNA regulation of lipoprotein metabolism. Curr Opin Lipidol 25:282-8
Fernández-Hernando, Carlos (2014) Antiatherogenic properties of high-density lipoprotein-enriched microRNAs. Arterioscler Thromb Vasc Biol 34:e13-4
Canfrán-Duque, Alberto; Ramírez, Cristina M; Goedeke, Leigh et al. (2014) microRNAs and HDL life cycle. Cardiovasc Res 103:414-22
Goedeke, Leigh; Salerno, Alessandro; Ramírez, Cristina M et al. (2014) Long-term therapeutic silencing of miR-33 increases circulating triglyceride levels and hepatic lipid accumulation in mice. EMBO Mol Med 6:1133-41
van Solingen, Coen; Araldi, Elisa; Chamorro-Jorganes, Aranzazu et al. (2014) Improved repair of dermal wounds in mice lacking microRNA-155. J Cell Mol Med 18:1104-12
Aryal, Binod; Rotllan, Noemi; Fernández-Hernando, Carlos (2014) Noncoding RNAs and atherosclerosis. Curr Atheroscler Rep 16:407
Goedeke, Leigh; Fernández-Hernando, Carlos (2014) MicroRNAs: a connection between cholesterol metabolism and neurodegeneration. Neurobiol Dis 72 Pt A:48-53
Sala, Federica; Aranda, Juan F; Rotllan, Noemi et al. (2014) MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice. Thromb Haemost 112:796-802
Price, Nathan L; Ramírez, Cristina M; Fernández-Hernando, Carlos (2014) Relevance of microRNA in metabolic diseases. Crit Rev Clin Lab Sci 51:305-20

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