High plasma lipids are risk factors for various cardiovascular and metabolic disorders such as obesity, atherosclerosis and metabolic syndrome. Our long term goal is to find ways to lower plasma lipids by targeting lipoprotein assembly. Microsomal triglyceride transfer protein (MTP) is critical for lipoprotein assembly. We observed that miR-30c induces MTP mRNA degradation and reduces apoB secretion in hepatoma cells. Further, it lowers plasma lipids and hepatic lipoprotein production in mice. Hence, we hypothesize that miR- 30c targets MTP, reduces apoB secretion, lowers plasma lipids, and prevents atherosclerosis.
Aim 1 : We will evaluate the efficacy of miR-30c in reducing hyperlipidemia and atherosclerosis by manipulating its levels in the livers using overexpression and chemical antagonism approaches. First, effect of miR-30c, anti-miR-30c, and scramble miR (Scr) on hyperlipidemia will be assessed in male C57/Bl6 mice fed Western diet. Next, we will evaluate the efficacy of miR-30c in reducing plasma lipids in WHHL rabbits. Second, to test the hypothesis that miR-30c reduces atherosclerosis we will express miR-30c, anti-miR-30c and Scr in the livers of Western diet fed Apoe-/- and LDLr-/- mice. Mechanistic experiments will be performed to ascertain that miR-30c lowers hepatic lipoprotein production.
Aim 2 : We will evaluate how miR-30c reduces MTP expression, apoB secretion and hyperlipidemia using primary hepatocytes and mice. First, we will uncover mechanisms that lead to low plasma lipids. We hypothesize that decreases in plasma lipids occur due to reductions in apoB synthesis secondary to increased co-translational degradation. Second, experiments will be planned to document why miR-30c expression is not associated with steatosis despite lower MTP expression. We hypothesize that miR-30c reduces hepatic lipid biosynthesis and avoids steatosis. Third, we will identify mechanisms involved in the interactions between miR-30c and MTP mRNA. Our hypothesis is that interactions at the supplementary site are critical in the down regulation of MTP by miR-30c. We will (a) evaluate the importance of """"""""supplementary sequences"""""""" in MTP/miR-30c interactions, (b) determine optimum base pairs required in the supplementary sequence of miR-30c to reduce MTP levels, and (c) assess the need of an asymmetric loop formation between seed and supplementary sites in inducing MTP mRNA degradation. At the end, we will have a novel understanding about the mode of action of miR-30c, and mechanisms involved in the lowering of hyperlipidemia and atherosclerosis. These studies might show that miR-30c regulates plasma apoB-containing lipoproteins by inducing posttranscriptional degradation of MTP mRNA and co-translational degradation of nascent apoB. Novel information about the molecular interactions between miR- 30c and MTP that lead to MTP mRNA destruction will be garnered. If proven, miR-30c might serve as a potentially new therapeutic agent to treat hyperlipidemia, atherosclerosis and other related metabolic disorders.

Public Health Relevance

Reductions in plasma lipids are positively associated with lower incidence of atherosclerosis. Hence, novel approaches to reduce plasma lipids are needed. This application proposes to evaluate the mechanism of action of miR-30c in lowering plasma lipids and reducing atherosclerosis.

National Institute of Health (NIH)
Veterans Affairs (VA)
Non-HHS Research Projects (I01)
Project #
Application #
Study Section
Cardiovascular Studies A (CARA)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
VA New York Harbor Hlthcare/Sys/Brooklyn
United States
Zip Code
Irani, Sara; Iqbal, Jahangir; Antoni, W James et al. (2018) microRNA-30c reduces plasma cholesterol in homozygous familial hypercholesterolemic and type 2 diabetic mouse models. J Lipid Res 59:144-154
Sirwi, Alaa; Hussain, M Mahmood (2018) Lipid transfer proteins in the assembly of apoB-containing lipoproteins. J Lipid Res 59:1094-1102
Pan, Xiaoyue; Schwartz, Gary J; Hussain, M Mahmood (2018) Oleoylethanolamide differentially regulates glycerolipid synthesis and lipoprotein secretion in intestine and liver. J Lipid Res 59:2349-2359
Zhou, Liye; Hussain, M Mahmood (2017) Human MicroRNA-548p Decreases Hepatic Apolipoprotein B Secretion and Lipid Synthesis. Arterioscler Thromb Vasc Biol 37:786-793
Iqbal, Jahangir; Walsh, Meghan T; Hammad, Samar M et al. (2017) Sphingolipids and Lipoproteins in Health and Metabolic Disorders. Trends Endocrinol Metab 28:506-518
Pan, Xiaoyue; Bradfield, Christopher A; Hussain, M Mahmood (2016) Global and hepatocyte-specific ablation of Bmal1 induces hyperlipidaemia and enhances atherosclerosis. Nat Commun 7:13011
Irani, Sara; Pan, Xiaoyue; Peck, Bailey C E et al. (2016) MicroRNA-30c Mimic Mitigates Hypercholesterolemia and Atherosclerosis in Mice. J Biol Chem 291:18397-409
Bakillah, Ahmed; Hussain, M Mahmood (2016) Mice subjected to aP2-Cre mediated ablation of microsomal triglyceride transfer protein are resistant to high fat diet induced obesity. Nutr Metab (Lond) 13:1
Chen, Xueying; Bakillah, Ahmed; Zhou, Liye et al. (2016) Nitrated apolipoprotein AI/apolipoprotein AI ratio is increased in diabetic patients with coronary artery disease. Atherosclerosis 245:12-21
Costabile, Brianna K; Kim, Youn-Kyung; Iqbal, Jahangir et al. (2016) ?-Apo-10'-carotenoids Modulate Placental Microsomal Triglyceride Transfer Protein Expression and Function to Optimize Transport of Intact ?-Carotene to the Embryo. J Biol Chem 291:18525-35

Showing the most recent 10 out of 17 publications