Avoiding toxicity associated with MTP ablation

Summary

Principal Investigator: M Mahmood Hussain
Abstract: DESCRIPTION (provided by applicant): 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 is 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. PUBLIC HEALTH RELEVANCE: 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.
Funding Period: 2010-02-01 - 2015-01-31
more information: NIH RePORT

Top Publications

  1. pmc Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice
    Irani Khatun
    School of Graduate Studies, Molecular and Cellular Biology Program, SUNY Downstate Medical Center, Brooklyn, NY 11230, USA
    Hepatology 55:1356-68. 2012
  2. pmc Increased intestinal lipid absorption caused by Ire1β deficiency contributes to hyperlipidemia and atherosclerosis in apolipoprotein E-deficient mice
    Jahangir Iqbal
    Department of Cell Biology, Box 5, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA
    Circ Res 110:1575-84. 2012
  3. pmc Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia
    Irani Khatun
    Molecular and Cellular Biology Program, SUNY Downstate Medical Center, Brooklyn, NY, USA
    J Lipid Res 54:1541-9. 2013
  4. pmc Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST
    Joby Josekutty
    School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA
    J Biol Chem 288:14372-83. 2013
  5. pmc MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion
    James Soh
    School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York, USA
    Nat Med 19:892-900. 2013
  6. pmc Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice
    Arne Dikkers
    Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
    J Lipid Res 55:816-25. 2014

Detail Information

Publications7

  1. pmc Phospholipid transfer activity of microsomal triglyceride transfer protein produces apolipoprotein B and reduces hepatosteatosis while maintaining low plasma lipids in mice
    Irani Khatun
    School of Graduate Studies, Molecular and Cellular Biology Program, SUNY Downstate Medical Center, Brooklyn, NY 11230, USA
    Hepatology 55:1356-68. 2012
    ..Triglyceride transfer activity augmented the biosynthesis of triglyceride-rich lipoproteins by increasing the formation of these particles in the lumen of the endoplasmic reticulum...
  2. pmc Increased intestinal lipid absorption caused by Ire1β deficiency contributes to hyperlipidemia and atherosclerosis in apolipoprotein E-deficient mice
    Jahangir Iqbal
    Department of Cell Biology, Box 5, SUNY Downstate Medical Center, 450 Clarkson Ave, Brooklyn, NY 11203, USA
    Circ Res 110:1575-84. 2012
    ..High fasting serum lipid levels are significant risk factors for atherosclerosis. However, the contributions of postprandial excursions in serum lipoproteins to atherogenesis are less well-characterized...
  3. pmc Loss of both phospholipid and triglyceride transfer activities of microsomal triglyceride transfer protein in abetalipoproteinemia
    Irani Khatun
    Molecular and Cellular Biology Program, SUNY Downstate Medical Center, Brooklyn, NY, USA
    J Lipid Res 54:1541-9. 2013
    ..These studies point out that ABL is associated with the absence of both triglyceride and phospholipid transfer activities in MTP...
  4. pmc Microsomal triglyceride transfer protein inhibition induces endoplasmic reticulum stress and increases gene transcription via Ire1α/cJun to enhance plasma ALT/AST
    Joby Josekutty
    School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York 11203, USA
    J Biol Chem 288:14372-83. 2013
    ..Thus, transcriptional up-regulation of GPT/GOT1 genes is a major mechanism, in response to ER stress, elevating plasma transaminases. Increases in plasma and tissue transaminases might represent a normal response to stress for survival...
  5. pmc MicroRNA-30c reduces hyperlipidemia and atherosclerosis in mice by decreasing lipid synthesis and lipoprotein secretion
    James Soh
    School of Graduate Studies, Molecular and Cell Biology Program, State University of New York Downstate Medical Center, Brooklyn, New York, USA
    Nat Med 19:892-900. 2013
    ..Raising miR-30c levels might be useful in treating hyperlipidemias and associated disorders. ..
  6. pmc Differential impact of hepatic deficiency and total body inhibition of MTP on cholesterol metabolism and RCT in mice
    Arne Dikkers
    Department of Pediatrics, University of Groningen, University Medical Center Groningen, Groningen, The Netherlands
    J Lipid Res 55:816-25. 2014
    ....

Research Grants30

  1. Role of cholesteryl ester transfer protein in cellular lipid homeostasis
    Richard E Morton; Fiscal Year: 2013
    ..Lipid storage in adipocytes is linked to their secretion of hormones that regulate glucose and lipid metabolism, which directly affect processes such as inflammation and atherogenesis. ..
  2. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
    ..The reasons for this protective effect are not understood fully and this project seeks to uncover the molecular mechanisms underlying the beneficial properties of HDL. ..
  3. CEACAM1: A link between metabolic and cardiovascular diseases
    Sonia M Najjar; Fiscal Year: 2013
    ..Answering these questions will delineate new CEACAM1-dependent mechanisms underlying atherosclerosis along the liver/endothelial cell axis, and pinpoint sites of pharmacologic intervention. ..
  4. A Novel Cellular Mechanism for Reducing Hyperlipidemia
    Jingwen Liu; Fiscal Year: 2013
    ....
  5. Functional Consequences of Impaired Autophagy in Aging
    ANA M CUERVO; Fiscal Year: 2013
    ..Significance: These studies may ultimately lead to fundamental insights for understanding, treating or preventing the metabolic alterations and declined cognitive and immune function characteristic of elders. ..
  6. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  7. Regulation of plasma lipids and atherosclerosis by miR-30c
    M Mahmood Hussain; Fiscal Year: 2013
    ..If proven, miR-30c might serve as a potentially new therapeutic agent to treat hyperlipidemia, atherosclerosis and other related metabolic disorders. ..
  8. LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS
    Alan M Fogelman; Fiscal Year: 2013
    ..These six Projects will be supported by four cores and together will form a highly interactive and synergistic Program Project that is focused on lipid and lipoprotein metabolism in atherosclerosis. ..
  9. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
    ..5) To prepare and empower our diverse Native and Pacific People communities to take ownership of their own health and wellness. ..