The metabolism of cholesterol and fatty acids, essential components of many biochemical pathways, is tightly regulated at the cellular level. Insufficient or excess levels can be detrimental to cells and are associated with aging-related diseases such as atherosclerosis, type 2 diabetes, and metabolic syndrome. Many regulatory pathways exist to ensure that cholesterol and fatty acid levels are balanced. In particular, recent findings have revealed a crucial role for small non-coding RNAs (miRNAs) in the post-transcriptional control of cholesterol and lipoprotein-related genes. Of note is microRNA-33 (miR-33), an intronic miRNA located within the sterol regulatory element-binding protein (SREBP) gene, one of the master regulators of cholesterol and fatty acid metabolism. miR-33 regulates cholesterol efflux and high density lipoprotein (HDL) formation in concert with the SREBP host genes, suggesting an important role for miRNAs in the regulation of cholesterol metabolism. miR-33 has also recently been to shown to regulate fatty acid metabolism and insulin signaling. miR-33 binds and represses key enzymes involved in the regulation of fatty acid oxidation, including carnitine O-octaniltransferase (CROT), carnitine palmitoyltransferase 1A (CPT1a), and hydroxyacyl-CoA-dehydrogenase (HADHB). In addition, miR-33 also targets the insulin receptor substrate 2 (IRS2), an essential component of the insulin- signaling pathway. Overexpression of miR-33 reduces both fatty acid oxidation and insulin signaling in hepatic cell lines, whereas endogenous inhibition of miR-33 increases these two metabolic pathways. In this proposal, we hypothesize that miR-33 regulates pathways controlling three of the risk factors of metabolic syndrome, including levels of HDL, triglycerides, and insulin signaling and that miR-33 may be useful as a therapeutic target to treat this growing health concern.

Public Health Relevance

The research proposed has significant implications in the field of lipid biology and cardiology- both key issues in aging that impact mortality and quality of life This work is intended to characterize a novel regulator of cholesterol, lipid, and glucose metabolism in liver cells and in mice fed a chow and high-fat diet. This work will also address how this regulator may impact risk factors that increase the chance of developing heart disease, stroke, and type 2 diabetes- important diseases and consequences of aging.

Agency
National Institute of Health (NIH)
Institute
National Institute on Aging (NIA)
Type
Predoctoral Individual National Research Service Award (F31)
Project #
5F31AG043318-03
Application #
8664329
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Finkelstein, David B
Project Start
2012-07-02
Project End
2015-07-01
Budget Start
2014-07-02
Budget End
2015-07-01
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
New York University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
City
New York
State
NY
Country
United States
Zip Code
10016
Rotllan, Noemi; Price, Nathan; Pati, Paramita et al. (2016) microRNAs in lipoprotein metabolism and cardiometabolic disorders. Atherosclerosis 246:352-60
Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana et al. (2016) Akt-mediated foxo1 inhibition is required for liver regeneration. Hepatology 63:1660-74
Aranda, Juan F; Canfrán-Duque, Alberto; Goedeke, Leigh et al. (2015) The miR-199-dynamin regulatory axis controls receptor-mediated endocytosis. J Cell Sci 128:3197-209
Rotllan, Noemi; Chamorro-Jorganes, Aránzazu; Araldi, Elisa et al. (2015) Hematopoietic Akt2 deficiency attenuates the progression of atherosclerosis. FASEB J 29:597-610
Goedeke, Leigh; Rotllan, Noemi; Canfrán-Duque, Alberto et al. (2015) MicroRNA-148a regulates LDL receptor and ABCA1 expression to control circulating lipoprotein levels. Nat Med 21:1280-9
Goedeke, Leigh; Rotllan, Noemi; Ramírez, Cristina M et al. (2015) miR-27b inhibits LDLR and ABCA1 expression but does not influence plasma and hepatic lipid levels in mice. Atherosclerosis 243:499-509
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
Ramírez, Cristina M; Lin, Chin Sheng; Abdelmohsen, Kotb et al. (2014) RNA binding protein HuR regulates the expression of ABCA1. J Lipid Res 55:1066-76
Goedeke, Leigh; Vales-Lara, Frances M; Fenstermaker, Michael et al. (2013) A regulatory role for microRNA 33* in controlling lipid metabolism gene expression. Mol Cell Biol 33:2339-52
Ramírez, Cristina M; Goedeke, Leigh; Rotllan, Noemi et al. (2013) MicroRNA 33 regulates glucose metabolism. Mol Cell Biol 33:2891-902