Control of Sterol and Lipoprotein Homeostasis by miRNA

Summary

Principal Investigator: Angel Baldán
Abstract: DESCRIPTION (provided by applicant): Atherosclerosis is the primary cause of heart attack, stroke, and peripheral artery disease, which collectively account for >30% of all deaths in the US. Multiple studies recognized abnormal cholesterol homeostasis as a risk factor for the development of atherosclerosis. We and others have recently reported on miR-33, a conserved microRNA that is encoded within intron 16 of SREBP-2. The clinical importance of SREBP-2 is revealed in hypercholesterolemic patients treated with statins, which reduce LDL-cholesterol levels by increasing hepatic expression of SREBP-2 and its target the LDL-receptor. Our published and preliminary studies show that physiological targets of miR-33 include ABCA1, a transporter critical for HDL lipidation and reverse cholesterol transport, and ATP8B1, a phospholipid flippase linked to intrahepatic cholestasis. The broad goal of this proposal is to determine the role of miR-33 on cholesterol, bile and lipoprotein homeostasis. We hypothesize that miR-33 controls key aspects of sterol mobilization, bile excretion and HDL metabolism. Importantly, since statins are usually prescribed to hypercholesterolemic patients, and statins induce the expression of miR-33, we speculate that statin-treated patients will have elevated levels of miR-33 and persistent down regulation of ABCA1 and ATP8B1 by miR-33. To address these questions, we propose the following 3 specific aims: 1) Determine the role of miR-33 in hepatic sterol homeostasis in primary hepatocytes and in mice, by measuring the effect of over expression or silencing of miR-33 on lipoprotein secretion and bile excretion;2) Test the hypothesis that altered macrophage miR-33 expression results in changes in reverse cholesterol transport and atherosclerotic lesion size, by performing experiments in vivo to determine the role of macrophage miR-33 expression on cholesterol -/- mobilization and progression of atherosclerotic lesions in Ldlr mice;and 3) Test the hypothesis that systemic silencing of miR-33 is atheroprotective in vivo, by characterizing the composition and biological properties of HDL generated following systemic silencing of miR-33, and by evaluating whether anti-miR-33 oligonucleotides synergize with the atheroprotective effects of statins in ApoE*3Leiden W hCETP mice. There are still multiple aspects of cholesterol homeostasis, cholestasis and atherogenesis that remain obscure. Our data suggest that the cholesterol-miR-33 axis modulates key aspects of hepatocyte and macrophage biology. We anticipate that our studies will provide new clues into the complex regulatory networks that control intracellular cholesterol levels, bile excretion and circulating lipoproteins. If our hypothesis is true, miR-33 might be a target for novel therapies to manage dyslipidemias and/or cholestasis. ! PUBLIC HEALTH RELEVANCE: We propose to characterize miR-33, which defines a novel pathway that controls cholesterol, bile and lipoprotein homeostasis. We hypothesize that miR-33 modulates the expression of key genes involved in different aspects of sterol metabolism. The results of these studies might lead to novel, improved ways to manage patients with hypercholesterolemia and/or patients with cholestasis. !
Funding Period: 2011-05-01 - 2016-03-31
more information: NIH RePORT

Top Publications

  1. pmc Mir-33 regulates cell proliferation and cell cycle progression
    Daniel Cirera-Salinas
    Department of Medicine, Leon H Charney Division of Cardiology and Cell Biology and Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    Cell Cycle 11:922-33. 2012
  2. pmc Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33
    Ryan M Allen
    From the Edward A Doisy Department of Biochemistry and Molecular Biology R M A, T J M, J J J, A B and Center for Cardiovascular Research R M A, T J M, A B, St Louis University, St Louis, MO
    Circ Res 115:10-22. 2014
  3. pmc Quest for new biomarkers in atherosclerosis
    Yoonsang Cho
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, USA
    Mo Med 110:325-30. 2013
  4. pmc Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids
    Montse Pauta
    Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain
    J Hepatol 59:731-7. 2013
  5. pmc Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration
    Abdoulaye Sene
    Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
    Cell Metab 17:549-61. 2013
  6. pmc MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor
    Thomas Q de Aguiar Vallim
    Departments of Biological Chemistry, University of California, Los Angeles, 90095 7345, USA
    Circ Res 112:1602-12. 2013
  7. pmc MicroRNAs in metabolic disease
    Carlos Fernandez-Hernando
    Departments of Medicine and Cell Biology, Leon H Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    Arterioscler Thromb Vasc Biol 33:178-85. 2013
  8. pmc Anti-miR-33 therapy does not alter the progression of atherosclerosis in low-density lipoprotein receptor-deficient mice
    Tyler J Marquart
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
    Arterioscler Thromb Vasc Biol 33:455-8. 2013
  9. pmc Cholesterol efflux analyses using stable isotopes and mass spectrometry
    Robert J Brown
    Department of Biochemistry, Memorial University of Newfoundland, St John s, NL A1B 3X9, Canada
    Anal Biochem 433:56-64. 2013
  10. pmc miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity
    Ryan M Allen
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO, USA
    EMBO Mol Med 4:882-95. 2012

Detail Information

Publications12

  1. pmc Mir-33 regulates cell proliferation and cell cycle progression
    Daniel Cirera-Salinas
    Department of Medicine, Leon H Charney Division of Cardiology and Cell Biology and Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    Cell Cycle 11:922-33. 2012
    ..Altogether, these results suggest that Srebp/miR-33 locus may cooperate to regulate cell proliferation, cell cycle progression and may also be relevant to human liver regeneration...
  2. pmc Control of very low-density lipoprotein secretion by N-ethylmaleimide-sensitive factor and miR-33
    Ryan M Allen
    From the Edward A Doisy Department of Biochemistry and Molecular Biology R M A, T J M, J J J, A B and Center for Cardiovascular Research R M A, T J M, A B, St Louis University, St Louis, MO
    Circ Res 115:10-22. 2014
    ..However, conflicting reports exist about the impact of anti-miR-33 therapy on the levels of very low-density lipoprotein-triglycerides (VLDL-TAG)...
  3. pmc Quest for new biomarkers in atherosclerosis
    Yoonsang Cho
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, USA
    Mo Med 110:325-30. 2013
    ..Thus, both MIF and miR-33 are promising therapeutic targets to manage patients at risk of developing atherosclerosis...
  4. pmc Impaired liver regeneration in Ldlr-/- mice is associated with an altered hepatic profile of cytokines, growth factors, and lipids
    Montse Pauta
    Centro Esther Koplowitz, IDIBAPS, CIBERehd, Barcelona, Spain
    J Hepatol 59:731-7. 2013
    ..In addition, the basic mechanisms of this lipid accumulation are not well understood although some studies suggest the participation of the Low Density Lipoprotein Receptor (Ldlr)...
  5. pmc Impaired cholesterol efflux in senescent macrophages promotes age-related macular degeneration
    Abdoulaye Sene
    Department of Ophthalmology and Visual Sciences, Washington University School of Medicine, Saint Louis, MO 63110, USA
    Cell Metab 17:549-61. 2013
    ..Monocytes from older humans with age-related macular degeneration showed similar changes. These findings provide an avenue for therapeutic modulation of macrophage function in common age-related diseases...
  6. pmc MicroRNA-144 regulates hepatic ATP binding cassette transporter A1 and plasma high-density lipoprotein after activation of the nuclear receptor farnesoid X receptor
    Thomas Q de Aguiar Vallim
    Departments of Biological Chemistry, University of California, Los Angeles, 90095 7345, USA
    Circ Res 112:1602-12. 2013
    ..We set out to investigate the molecular mechanisms for FXR-dependent regulation of lipid and lipoprotein metabolism...
  7. pmc MicroRNAs in metabolic disease
    Carlos Fernandez-Hernando
    Departments of Medicine and Cell Biology, Leon H Charney Division of Cardiology and the Marc and Ruti Bell Vascular Biology and Disease Program, New York University School of Medicine, New York, NY, USA
    Arterioscler Thromb Vasc Biol 33:178-85. 2013
    ..We will also discuss how the modulation of specific miRNAs may be a promising strategy to treat metabolic diseases...
  8. pmc Anti-miR-33 therapy does not alter the progression of atherosclerosis in low-density lipoprotein receptor-deficient mice
    Tyler J Marquart
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, Saint Louis, MO 63104, USA
    Arterioscler Thromb Vasc Biol 33:455-8. 2013
    ..To determine the efficacy of long-term anti-miR-33 therapy on the progression of atherosclerosis in high-fat, high-cholesterol-fed Ldlr(-/-) mice...
  9. pmc Cholesterol efflux analyses using stable isotopes and mass spectrometry
    Robert J Brown
    Department of Biochemistry, Memorial University of Newfoundland, St John s, NL A1B 3X9, Canada
    Anal Biochem 433:56-64. 2013
    ..g., apolipoprotein A-I). Taken together, this mass spectrometry-based assay provides new molecular detail to assess cholesterol efflux...
  10. pmc miR-33 controls the expression of biliary transporters, and mediates statin- and diet-induced hepatotoxicity
    Ryan M Allen
    Edward A Doisy Department of Biochemistry and Molecular Biology, Saint Louis University School of Medicine, MO, USA
    EMBO Mol Med 4:882-95. 2012
    ..Importantly, pretreatment of mice with anti-miR-33 oligonucleotides rescues the hepatotoxic phenotype. Therefore, we conclude that miR-33 mediates some of the undesired, hepatotoxic effects of statins...
  11. pmc Perilipin-5 is regulated by statins and controls triglyceride contents in the hepatocyte
    Cédric Langhi
    Edward A Doisy Department of Biochemistry and Molecular Biology, and Center for Cardiovascular Research, Saint Louis University, Saint Louis, MO 63104, United States
    J Hepatol 61:358-65. 2014
    ..Here we tested the hypothesis that statins alter the metabolism of LD in the hepatocyte during physiological conditions, such as fasting-induced steatosis...

Research Grants30

  1. 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. ..
  2. Does Diabetic Hyperglycemia Regulate Atherosclerosis Progression and Regression?
    ROBERT RAFFAI; Fiscal Year: 2013
    ..Our long-term goals are to identify mechanisms that could serve as therapeutic targets to delay the progression and accelerate the regression of atherosclerosis as treatments for PAD in diabetic individuals. ..
  3. Regulation of Lipid and Lipoprotein Metabolism by Nuclear Receptors
    Yanqiao Zhang; Fiscal Year: 2013
    ..In addition, completion of the proposed studies may provide novel therapeutic approach(es) for treatment of cardiovascular diseases. ..
  4. Role of PDZK1 in lipid metabolism and atherosclerosis
    Olivier N Kocher; Fiscal Year: 2013
    ..Such studies may provide the necessary background for the development of new therapies promoting reverse cholesterol transport to prevent the formation of atherosclerotic lesions and myocardial infarction. ..
  5. DEVELOPMENT AND CONTROL OF PULMONARY ALVEOLAR STABILITY
    Samuel Hawgood; Fiscal Year: 2013
    ..abstract_text> ..
  6. Characterization of Diet1, a hypercholesterolemia resistance gene
    Karen Reue; Fiscal Year: 2013
    ..Results will further elucidate the mechanisms that control cholesterol homeostasis, and may suggest new strategies for protection or treatment of hypercholesterolemia and related disorders. ..
  7. The regulation of hepatic lipid metabolism by apolipoprotein AIV
    ALISON BLOOM KOHAN; Fiscal Year: 2013
    ....
  8. Cardiac Myosin Binding Protein-C: Structure, Function, and Regulation
    David M Warshaw; Fiscal Year: 2013
    ..abstract_text> ..
  9. Effects of Anti-miR-33 on Atherosclerosis Regression and RCT in Nonhuman Primates
    RYAN EUGENE TEMEL; Fiscal Year: 2013
    ..These studies will greatly aid in assessing anti-miR-33 as a potential clinical treatment for CHD. ..
  10. Mechanisms Regulating Non-biliary Fecal Sterol Loss
    Jonathan Mark Brown; Fiscal Year: 2013
    ..abstract_text> ..
  11. CELLS PROCESSING HIGH DENSITY LIPOPROTEINS
    Salman Azhar; Fiscal Year: 2013
    ..Both bile acids and steroids are synthesized from SR-BI-mediated selectively delivered cholesterol, thus underscoring the relevance of understanding the cellular mechanisms controlling the functional expression of SR-BI. ..
  12. 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. ..
  13. Pathophysiology of Alveolar Epithelial Lung Injury
    Jacob I Sznajder; Fiscal Year: 2013
    ..The insights gained from the data generated from these studies will provide novel molecular targets for the development of new therapeutic strategies to treat patients with lung injury. ..