Deregulation of lipid metabolism is the basis of some of the most common medical disorders in western populations, such as cardiovascular disease, fatty liver diseases, hyperlipidemia, and diabetes. The long-term goal in our laboratory is to gain a better understanding of whole-body lipid homeostasis in response to physiological, pathological, and pharmacological stimuli. In the previous cycle, we studied the role of the statin-induced murine miR-33 on hepatic lipid metabolism, HDL and bile secretion, reverse cholesterol transport, and atherogenesis. The current proposal includes two large sets of studies: first, to continue our studies on miR-33; and second, to introduce additional statin-induced miRNAs and study their role on hepatic metabolic control. In the first half of this proposal, we will use a novel liver-humanized mouse to continue our currently funded studies on miR-33. These mice overcome the critical limitations of traditional murine models, restoring hepatic human miR-33a and miR-33b, human miR-33 target specificity, and human-like lipoprotein profiles. The proposed studies will provide critical data on the consequences of therapeutic silencing of miR-33 in a human, functional liver. On the other hand, we present evidence that statins induce changes in the murine hepatic RISCome (RNA-induced silencing complex-associated mRNAs) in vivo. Among these changes, we focus on the miR-183/96/182 cluster target TCF7L2, and present evidence that the SREBP2-miR-183/96/182-TCF7L2 pathway mediates statin-stimulated hepatic glucose production in vivo. The translational relevance of this new conserved pathway is enhanced by the recently described diabetogenic effect of statins. We will test these new ideas using a combination of biochemical, cell biology, and in vivo techniques. Specifically, Aim 1 will test the functional role of human hepatic miR-33a and miR-33b on hepatic lipid metabolism, lipoprotein secretion, and atherogenesis. Importantly, the unique liver-humanized mice will also allow us to test for the first time the contribution of miR-33b to diet-induced fatty liver and hepatic insulin resistance.
Aim 2 will define the functiona role of miR-183/96/182 on hepatic and whole-body glucose homeostasis, by determining the contribution of each miR to hepatic glucose production, defining the mechanism by which the miR cluster and TCF7L2 regulate gluconeogenesis, and studying whether the levels of miR-183/96/182 and their functional targets are altered in murine models of altered glycemic control. The insights from these studies will fill a current gap of knowledge in pathophysiological hepatic metabolic control, and may uncover novel pharmacological targets to manage liver diseases, diabetes, and cardiovascular risk.

Public Health Relevance

The proposed studies will provide us with a better understanding of the molecular mechanisms that control lipid metabolism in the liver in response to a variety of stimuli, including high-fat diets and cholesterol-lowering drugs. The results from these studies may lead to novel, improved ways to manage patients with lipid-related disorders such as fatty liver disease, diabetes, and cardiovascular disease.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL107794-08
Application #
9441045
Study Section
Atherosclerosis and Inflammation of the Cardiovascular System Study Section (AICS)
Program Officer
Hasan, Ahmed a K
Project Start
2011-05-01
Project End
2020-02-29
Budget Start
2018-03-01
Budget End
2019-02-28
Support Year
8
Fiscal Year
2018
Total Cost
Indirect Cost
Name
Saint Louis University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
050220722
City
Saint Louis
State
MO
Country
United States
Zip Code
63103
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
Rajamoorthi, Ananthi; Arias, Noemí; Basta, Jeannine et al. (2017) Amelioration of diet-induced steatohepatitis in mice following combined therapy with ASO-Fsp27 and fenofibrate. J Lipid Res 58:2127-2138
Langhi, Cédric; Arias, Noemí; Rajamoorthi, Ananthi et al. (2017) Therapeutic silencing of fat-specific protein 27 improves glycemic control in mouse models of obesity and insulin resistance. J Lipid Res 58:81-91
Palladino, Elisa N D; Wang, Wen-Yi; Albert, Carolyn J et al. (2017) Peroxisome proliferator-activated receptor-? accelerates ?-chlorofatty acid catabolism. J Lipid Res 58:317-324
de Aguiar Vallim, Thomas Q; Lee, Elinor; Merriott, David J et al. (2017) ABCG1 regulates pulmonary surfactant metabolism in mice and men. J Lipid Res 58:941-954
Pauta, Montse; Rotllan, Noemi; Fernández-Hernando, Ana et al. (2016) Akt-mediated foxo1 inhibition is required for liver regeneration. Hepatology 63:1660-74
Baldán, Ángel; Fernández-Hernando, Carlos (2016) Truths and controversies concerning the role of miRNAs in atherosclerosis and lipid metabolism. Curr Opin Lipidol 27:623-629
Langhi, Cédric; Baldán, Ángel (2015) CIDEC/FSP27 is regulated by peroxisome proliferator-activated receptor alpha and plays a critical role in fasting- and diet-induced hepatosteatosis. Hepatology 61:1227-38
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
Allen, Ryan M; Marquart, Tyler J; Jesse, Jordan J et al. (2014) Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33. Circ Res 115:10-22

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