Alterations in the control of cholesterol homeostasis can lead to pathological processes, including atherosclerosis, the most common cause of mortality in Western societies. Epidemiological studies have identified many environmental and genetic factors that contribute to atherogenesis. In particular, high levels of low-density lipoprotein cholesterol (LDL-C) and low levels of high-density lipoprotein cholesterol (HDL-C) are associated with increased cardiovascular disease (CVD) risk. In addition to protein coding genes, non- coding RNAs including microRNAs (miRNAs) have recently shown to play a key role in regulating gene expression. Alteration in miRNAs expression has been associated to numerous diseases including CVD. Our previous work has demonstrated the importance of miRNAs in regulating HDL-C and LDL-C. In particular, work from our group and others identified miR-33a/b and miR-148a as key regulators of cellular cholesterol efflux and uptake, HDL biogenesis and LDL clearance. While these studies highlight the therapeutic potential of manipulating miRNAs to control circulating HDL-C and LDL-C, the effect of both miRNAs in controlling lipid and glucose metabolism remains poorly understood. To investigate in depth the molecular mechanism by which miR-33a/b and miR-148a regulate glucose and lipid metabolism, we have recently developed a number of unique mouse models that will allow us to define the contribution of miR-33 and miR-148a in controlling lipid metabolism and atherogenesis in vivo. Using cutting-edge techniques, we will identify the regulatory network through which miR-33a/b and miR-148a regulate lipid metabolism both in vitro and in vivo, and assess the potential therapeutic value of anti-miR- 33a/b and antimiR-148a therapy for treating cardiometabolic diseases including atherosclerosis and metabolic syndrome. Additionally, we will continue our efforts to identify and characterize novel non-coding RNAs, including long non-coding RNAs (lncRNAs) that regulate lipid metabolism and other processes that influence the development of CVD. In another different topic, we will also study the molecular mechanisms that regulate the initial steps of atherogenesis. We hypothesize that Cav-1/caveolae expression is regulated by flow and mediates LDL infiltration and retention in atheroprone areas leading to the progression of atherosclerosis. Using unique animal models and innovative electron microscopy technics we aim to characterize how this process is regulated.

Public Health Relevance

Complications from atherosclerosis represent a major cause of morbidity and mortality in Western society. High circulating levels of LDL-C and the accumulation of low-density lipoprotein (LDL)-derived cholesterol and inflammatory cells in the artery wall are the initiating events that cause atherosclerosis. However, the contribution of non-coding RNAs and the factors that underlie the initiation of atherosclerosis are still poorly understood. Our recent data suggest that a number of miRNAs including miR-33a/b and miR-148a regulates plasma lipid levels. Moreover, we found that the infiltration of lipoproteins and inflammation in atheroprone areas is regulated by Caveolin-1, an important structural component of caveolae. This proposal aims to investigate the molecular mechanisms by which non-coding RNAs regulate lipid metabolism and define how Caveolin-1/caveolae influence the initial steps of atherogenesis. This work will provide critical insight into the fundamental regulatory mechanisms that controls the progression of atherosclerosis and may identify potential therapeutic strategies to reduce circulating LDL-C and increase HDL-C levels and combat CVDs, such as atherosclerosis.

National Institute of Health (NIH)
National Heart, Lung, and Blood Institute (NHLBI)
Unknown (R35)
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Special Emphasis Panel (ZHL1)
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Hasan, Ahmed a K
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Yale University
Veterinary Sciences
Schools of Medicine
New Haven
United States
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Zhang, Xinbo; Price, Nathan L; Fernández-Hernando, Carlos (2018) Non-coding RNAs in lipid metabolism. Vascul Pharmacol :
Price, Nathan L; Singh, Abhishek K; Rotllan, Noemi et al. (2018) Genetic Ablation of miR-33 Increases Food Intake, Enhances Adipose Tissue Expansion, and Promotes Obesity and Insulin Resistance. Cell Rep 22:2133-2145
Aryal, Binod; Singh, Abhishek K; Zhang, Xinbo et al. (2018) Absence of ANGPTL4 in adipose tissue improves glucose tolerance and attenuates atherogenesis. JCI Insight 3:
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Aranda, Juan F; Rathjen, Stefan; Johannes, Ludger et al. (2018) MiR-199a-5p attenuates retrograde transport and protects against toxin-induced inhibition of protein biosynthesis. Mol Cell Biol :
Singh, Abhishek K; Aryal, Binod; Chaube, Balkrishna et al. (2018) Brown adipose tissue derived ANGPTL4 controls glucose and lipid metabolism and regulates thermogenesis. Mol Metab 11:59-69
Zhang, Xinbo; Sessa, William C; Fernández-Hernando, Carlos (2018) Endothelial Transcytosis of Lipoproteins in Atherosclerosis. Front Cardiovasc Med 5:130
Fernández-Hernando, Carlos; Suárez, Yajaira (2018) MicroRNAs in endothelial cell homeostasis and vascular disease. Curr Opin Hematol 25:227-236
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

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