High plasma lipids and lipoproteins are risk factors for various cardiovascular and metabolic disorders. An approach to lower plasma lipids is to inhibit apoB-lipoprotein biosynthesis, a process critically dependent on an endoplasmic reticulum (ER) resident chaperone, microsomal triglyceride transfer protein (MTP). MTP inhibitors decrease apoB-lipoprotein secretion and lower plasma cholesterol. However, they increase plasma aminotransferases, such as ALT and AST, indicating liver injury. We hypothesize that increases in plasma hepatic enzymes associated with MTP inhibition are due to increases in microsomal free cholesterol, induction of ER stress and cell death. We further hypothesize that reducing cellular free cholesterol along with MTP inhibition might reduce hyperlipidemias and avoiding toxicities associated with MTP antagonists. In the first aim, Alb-Cre-MTPfl/fl or MTPfl/fl mice will be fed T-0901317, a LXR agonist to induce free cholesterol efflux;lovastatin, a HMG Co-A reductase antagonist to inhibit cellular cholesterol biosynthesis;or WY14643, a PPAR1 agonist to enhance 2-oxidation of fatty acids, for 3 or 24 weeks. In another group, &-3 fatty acids, PPAR1/4 agonists, will be injected intraperitoneally to reduce hepatic triglyceride and free cholesterol. In addition, Alb-Cre-MTPfl/fl mice will be fed a western diet and then treated with T-0901317, lovastatin, WY14643, or &-3 fatty acids. Experiments will then be performed in C57Bl/6J mice fed a western diet and fed daily with MTP inhibitors. Additionally, they will be fed olive oil alone or with other compounds described above to determine if toxicities associated with MTP inhibitors can be avoided by these treatments. Outcome measurements will involve changes in apoB-lipoproteins and hepatic enzymes in the plasma;hepatic triglycerides, esterified cholesterol, and free cholesterol;quantification of candidate mRNAs and proteins involved in cholesterol and triglyceride biosynthesis, ER stress, as well as AST/ALT isoforms. These studies will show that toxicities associated with MTP inhibition can be avoided by reducing hepatic free cholesterol.
The second aim i s to test the hypothesis that release of hepatic enzymes in the plasma is due to the induction of the ER stress and apoptosis. We will first demonstrate that MTP inhibition increases microsomal free cholesterol. Second, we will identify the ER stress pathways activated by MTP ablation/inhibition. Third, we will establish that MTP inhibition induces apoptosis. Fourth, a link between the ER stress and induction of apoptosis will be established. Fifth, importance of the ER stress pathways will be substantiated using ATF6-/-, CHOP-/- and Alb-Cre-Ire11fl/fl mice fed MTP inhibitors. Sixth, we will determine if induction of ER stress by tunicamycin increases plasma AST/ALT levels. At the completion of these studies, we will find out molecular mechanisms responsible for unwanted side effects associated with MTP therapy and suggest solutions to avoid these toxicities. These studies may lead to new therapeutic modalities for the treatment of various hyperlipidemias and have immediate potential for translational use.
This proposal is to find out why MTP drugs cause unwanted side effects and to come up with novel solutions to avoid these effects. These studies will explain molecular mechanisms involved in toxicities associated with MTP inhibitors and genetic ablations. Proposed studies may lead to new therapeutic modalities for the treatment of various disorders associated with high plasma lipids.
|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|
|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|
|Walsh, Meghan T; Iqbal, Jahangir; Josekutty, Joby et al. (2015) Novel Abetalipoproteinemia Missense Mutation Highlights the Importance of the N-Terminal ?-Barrel in Microsomal Triglyceride Transfer Protein Function. Circ Cardiovasc Genet 8:677-87|
|Iqbal, Jahangir; Walsh, Meghan T; Hammad, Samar M et al. (2015) Microsomal Triglyceride Transfer Protein Transfers and Determines Plasma Concentrations of Ceramide and Sphingomyelin but Not Glycosylceramide. J Biol Chem 290:25863-75|
|Bakillah, Ahmed; Tedla, Fasika; Ayoub, Isabelle et al. (2015) Plasma Nitration of High-Density and Low-Density Lipoproteins in Chronic Kidney Disease Patients Receiving Kidney Transplants. Mediators Inflamm 2015:352356|
|Prince, Esther; Lazare, Farrah B; Treem, William R et al. (2014) ?-3 fatty acids prevent hepatic steatosis, independent of PPAR-? activity, in a murine model of parenteral nutrition-associated liver disease. JPEN J Parenter Enteral Nutr 38:608-16|
|Dikkers, Arne; Annema, Wijtske; de Boer, Jan Freark et al. (2014) Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice. J Lipid Res 55:816-25|
|Hussain, M Mahmood (2014) Intestinal lipid absorption and lipoprotein formation. Curr Opin Lipidol 25:200-6|
Showing the most recent 10 out of 20 publications