LIPID AND LIPOPROTEIN METABOLISM IN ATHEROSCLEROSIS

Summary

Principal Investigator: Alan M Fogelman
Abstract: This Program Project received a priority score of 155 on March 20, 2008. In this amended application we have corrected each and every one of the weaknesses identified by the Special Review Committee (SRC). These changes have included dropping specific aims or sub-aims in Projects 3-4-5-6, obtaining additional expertise (Project 6), adding experiments suggested by the reviewers (all Projects) and providing power calculations (Projects 3 and 5) as requested by the reviewers. We have also responded to the review by proposing a sophisticated integrated database system that will be maintained in Core D as recommended by the SRC. The intersection of inflammation and lipid metabolism in atherosclerosis is the theme of this Program Project. Project 1 will identify the pivotal regulators of a gene network that responds to oxidized phospholipids (Ox-PAPC/PEIPC) using cell biology and bioinformatics approaches. Project 2 will determine the mechanisms by which apolipoprotein mimetic peptides dramatically reduce inflammation and atherosclerosis. Project 3 will focus on Matrix Gla Protein (MGP) and the hepatic ABC transporter 6 (Abcc6) to determine the molecular mechanisms regulating vascular calcification and atherosclerosis. Project 4 will determine the molecular and cellular mechanisms by which ABC transporter G1 (ABCG1) regulates intracellular sterol movement and alters macrophage and lymphocyte function in atherosclerosis. Project 5 will use an integrative genetics approach to study the interactions of vascular cells, macrophages, and lipids as they relate to atherogenesis. Project 6 will determine the mechanisms by which interferon regulatory factor 3 (IRF3) signaling regulates the function of the liver X receptor (LXR) and cholesterol metabolism in atherosclerosis and the mechanisms by which the NR4A nuclear receptors mediate metabolic-immune crosstalk in atherosclerosis. 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.
Funding Period: 1997-08-01 - 2015-03-31
more information: NIH RePORT

Top Publications

  1. pmc FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors
    Anna C Calkin
    Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
    Proc Natl Acad Sci U S A 108:20107-12. 2011
  2. pmc Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine
    Vitaliy Starosta
    Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Office N611, Chicago, IL 60637, USA
    Am J Respir Cell Mol Biol 46:331-41. 2012
  3. pmc Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model
    Imran N Mungrue
    Division of Cardiology and Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Arterioscler Thromb Vasc Biol 31:2806-12. 2011
  4. pmc A biochemical fluorometric method for assessing the oxidative properties of HDL
    Theodoros Kelesidis
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    J Lipid Res 52:2341-51. 2011
  5. pmc Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes
    Cecilia Morgantini
    Department of Internal Medicine, University of Pisa, Pisa, Italy
    Diabetes 60:2617-23. 2011
  6. pmc The regulation of valvular and vascular sclerosis by osteogenic morphogens
    KRISTINA I BOSTROM
    Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, 10833 LeConte Ave, Los Angeles, CA 90095, USA
    Circ Res 109:564-77. 2011
  7. pmc Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule
    Juyong Brian Kim
    Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA
    Arterioscler Thromb Vasc Biol 31:2624-33. 2011
  8. pmc Salutary effects of hemodialysis on low-density lipoprotein proinflammatory and high-density lipoprotein anti-inflammatory properties in patient with end-stage renal disease
    Nosratola D Vaziri
    Division of Nephrology and Hypertension, University of California, Irvine Medical Center, 101 The City Dr, 4th Floor City Tower, Orange, CA 92868, USA
    J Natl Med Assoc 103:524-33. 2011
  9. pmc Strategies for aggregating gene expression data: the collapseRows R function
    Jeremy A Miller
    Interdepartmental Program for Neuroscience, UCLA, Los Angeles, California, USA
    BMC Bioinformatics 12:322. 2011
  10. pmc Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma
    David Meriwether
    Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA
    J Lipid Res 52:1795-809. 2011

Research Grants

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013

Detail Information

Publications277 found, 100 shown here

  1. pmc FERM-dependent E3 ligase recognition is a conserved mechanism for targeted degradation of lipoprotein receptors
    Anna C Calkin
    Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at University of California, Los Angeles, CA 90095, USA
    Proc Natl Acad Sci U S A 108:20107-12. 2011
    ....
  2. pmc Differential regulation of endothelial cell permeability by high and low doses of oxidized 1-palmitoyl-2-arachidonyl-sn-glycero-3-phosphocholine
    Vitaliy Starosta
    Lung Injury Center, Section of Pulmonary and Critical Medicine, Department of Medicine, University of Chicago, 5841 S Maryland Ave, Office N611, Chicago, IL 60637, USA
    Am J Respir Cell Mol Biol 46:331-41. 2012
    ....
  3. pmc Abcc6 deficiency causes increased infarct size and apoptosis in a mouse cardiac ischemia-reperfusion model
    Imran N Mungrue
    Division of Cardiology and Cardiovascular Research Laboratory, David Geffen School of Medicine, University of California, Los Angeles, CA, USA
    Arterioscler Thromb Vasc Biol 31:2806-12. 2011
    ..The spectrum of PXE has been noted in Abcc6-deficient mice, including dystrophic cardiac calcification. We tested the role of Abcc6 in response to cardiac ischemia-reperfusion (I/R) injury...
  4. pmc A biochemical fluorometric method for assessing the oxidative properties of HDL
    Theodoros Kelesidis
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    J Lipid Res 52:2341-51. 2011
    ..This new fluorometric method offers an inexpensive, accurate, and rapid means for determining the oxidative properties of HDL that is applicable to large-scale clinical studies...
  5. pmc Anti-inflammatory and antioxidant properties of HDLs are impaired in type 2 diabetes
    Cecilia Morgantini
    Department of Internal Medicine, University of Pisa, Pisa, Italy
    Diabetes 60:2617-23. 2011
    ..We sought to determine whether HDL function is impaired in type 2 diabetic (T2D) patients and whether 4F treatment improves HDL function in T2D patient plasma in vitro...
  6. pmc The regulation of valvular and vascular sclerosis by osteogenic morphogens
    KRISTINA I BOSTROM
    Department of Medicine, Division of Cardiology, David Geffen School of Medicine at UCLA, 10833 LeConte Ave, Los Angeles, CA 90095, USA
    Circ Res 109:564-77. 2011
    ..These inhibitory pathways and their regulators afford the development of novel therapeutic strategies to prevent and treat valve and vascular sclerosis...
  7. pmc Paraoxonase-2 modulates stress response of endothelial cells to oxidized phospholipids and a bacterial quorum-sensing molecule
    Juyong Brian Kim
    Department of Medicine, Division of Cardiology, University of California, Los Angeles, CA, USA
    Arterioscler Thromb Vasc Biol 31:2624-33. 2011
    ..We now report the response of human aortic endothelial cells (HAECs) to 3OC12-HSL and oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphocholine (Ox-PAPC) in relation to PON2 expression...
  8. pmc Salutary effects of hemodialysis on low-density lipoprotein proinflammatory and high-density lipoprotein anti-inflammatory properties in patient with end-stage renal disease
    Nosratola D Vaziri
    Division of Nephrology and Hypertension, University of California, Irvine Medical Center, 101 The City Dr, 4th Floor City Tower, Orange, CA 92868, USA
    J Natl Med Assoc 103:524-33. 2011
    ..Hemodialysis partially improves LDL and HDL inflammatory activities. The salutary effects of hemodialysis are in part mediated by heparin, which is known to possess lipolytic and antioxidant properties...
  9. pmc Strategies for aggregating gene expression data: the collapseRows R function
    Jeremy A Miller
    Interdepartmental Program for Neuroscience, UCLA, Los Angeles, California, USA
    BMC Bioinformatics 12:322. 2011
    ..Several standard statistical summary techniques can be used, but network methods also provide useful alternative methods to find representatives. Currently few collapsing functions are developed and widely applied...
  10. pmc Enhancement by LDL of transfer of L-4F and oxidized lipids to HDL in C57BL/6J mice and human plasma
    David Meriwether
    Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA, USA
    J Lipid Res 52:1795-809. 2011
    ....
  11. pmc Matrix Gla protein deficiency causes arteriovenous malformations in mice
    Yucheng Yao
    Division of Cardiology, David Geffen School of Medicine, UCLA, Los Angeles, California 90095 1679, USA
    J Clin Invest 121:2993-3004. 2011
    ..Because lack of MGP also causes arterial calcification, our findings demonstrate that the same gene defect has drastically different effects on distinct vascular beds...
  12. pmc Network for activation of human endothelial cells by oxidized phospholipids: a critical role of heme oxygenase 1
    Casey E Romanoski
    Department of Human Genetics, University of California, Los Angeles, CA, USA
    Circ Res 109:e27-41. 2011
    ..Oxidized palmitoyl arachidonyl phosphatidylcholine (Ox-PAPC) accumulates in atherosclerotic lesions, is proatherogenic, and influences the expression of more than 1000 genes in endothelial cells...
  13. pmc Mechanisms underlying adverse effects of HDL on eNOS-activating pathways in patients with coronary artery disease
    Christian Besler
    Cardiology, Cardiovascular Center, University Hospital Zurich, Zurich, Switzerland
    J Clin Invest 121:2693-708. 2011
    ....
  14. pmc Comparative analysis of proteome and transcriptome variation in mouse
    Anatole Ghazalpour
    Department of Medicine Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS Genet 7:e1001393. 2011
    ..In light of the widespread use of high-throughput technologies in both clinical and basic research, the results presented have practical as well as basic implications...
  15. pmc The IDOL-UBE2D complex mediates sterol-dependent degradation of the LDL receptor
    Li Zhang
    Howard Hughes Medical Institute, University of California at Los Angeles School of Medicine, USA
    Genes Dev 25:1262-74. 2011
    ..These results identify the IDOL-UBE2D complex as an important determinant of LDLR activity, and provide insight into molecular mechanisms underlying the regulation of cholesterol uptake...
  16. pmc Coordinate regulation of neutrophil homeostasis by liver X receptors in mice
    Cynthia Hong
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, UCLA, Los Angeles, California, USA
    J Clin Invest 122:337-47. 2012
    ..These results provide mechanistic insight into the molecular events orchestrating neutrophil homeostasis and advance our understanding of LXRs as integrators of phagocyte function, lipid metabolism, and cytokine gene expression...
  17. pmc D-4F-mediated reduction in metabolites of arachidonic and linoleic acids in the small intestine is associated with decreased inflammation in low-density lipoprotein receptor-null mice
    Mohamad Navab
    Department of Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    J Lipid Res 53:437-45. 2012
    ..05). We conclude that D-4F administration reduces levels of free metabolites of arachidonic and linoleic acids in the small intestine and this is associated with decreased inflammation in LDL receptor deficient mice...
  18. pmc A model-based approach for analysis of spatial structure in genetic data
    Wen Yun Yang
    Interdepartmental Program in Bioinformatics, University of California, Los Angeles, California, USA
    Nat Genet 44:725-31. 2012
    ..These regions include SNPs in the well-characterized LCT region, as well as at loci including FOXP2, OCA2 and LRP1B...
  19. pmc Genetic locus on mouse chromosome 7 controls elevated heart rate
    Elaine M Smolock
    Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, New York 14642, USA
    Physiol Genomics 44:689-98. 2012
    ..The peak association was observed for 17 SNPs that are localized within three GABA(A) receptor genes. In summary, we used a combined genetic approach to fine map a novel elevated HR locus on mouse chromosome 7...
  20. pmc Genome-wide association mapping with longitudinal data
    Nicholas A Furlotte
    Department of Computer Science, University of California, Los Angeles, California 90095 1596, USA
    Genet Epidemiol 36:463-71. 2012
    ..The software implementing this method may be found at http://genetics.cs.ucla.edu/longGWAS/...
  21. pmc Evidence for the importance of OxPAPC interaction with cysteines in regulating endothelial cell function
    James R Springstead
    Department of Medicine and University of California at Los Angeles, Los Angeles, CA 90095, USA
    J Lipid Res 53:1304-15. 2012
    ..Overall, we provide evidence for the importance of OxPAPC-cysteine interactions in regulating HAEC function...
  22. pmc Apolipoprotein A-I mimetic peptides inhibit expression and activity of hypoxia-inducible factor-1α in human ovarian cancer cell lines and a mouse ovarian cancer model
    Feng Gao
    Department of Obstetrics Gynecology, University of California, 650 Charles E Young Drive South, CHS 24 127, Los Angeles, CA 90095, USA
    J Pharmacol Exp Ther 342:255-62. 2012
    ....
  23. pmc Crossveinless 2 regulates bone morphogenetic protein 9 in human and mouse vascular endothelium
    Yucheng Yao
    Division of Cardiology, David Geffen School of Medicine at University of California, Los Angeles UCLA, Los Angeles, CA 90095 1679, USA
    Blood 119:5037-47. 2012
    ..Thus, mutual regulation by BMP-9 and CV2 is essential in regulating the development of the vascular endothelium...
  24. pmc LXRα is uniquely required for maximal reverse cholesterol transport and atheroprotection in ApoE-deficient mice
    Cynthia Hong
    Howard Hughes Medical Institute, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA, USA
    J Lipid Res 53:1126-33. 2012
    ..These studies reveal a previously unrecognized requirement for hepatic LXRα for optimal reverse cholesterol transport in mice...
  25. pmc Understanding the sexome: measuring and reporting sex differences in gene systems
    Arthur P Arnold
    Department of Integrative Biology and Physiology, University of California, Los Angeles, California 90095 7239, USA
    Endocrinology 153:2551-5. 2012
    ..The global search for sites and mechanisms of sex-specific regulation in diverse tissues will provide unanticipated insights into physiological regulation and targets for novel therapies...
  26. pmc HDL mimetics inhibit tumor development in both induced and spontaneous mouse models of colon cancer
    Feng Su
    Department of Obstetrics and Gynecology, University of California Los Angeles, Los Angeles, CA 90095, USA
    Mol Cancer Ther 11:1311-9. 2012
    ..Our results, for the first time, identify HDL mimetics as a novel therapeutic strategy for the treatment of colon cancer...
  27. pmc Transcriptional integration of metabolism by the nuclear sterol-activated receptors LXR and FXR
    Anna C Calkin
    Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California, 675 Charles E Young Drive South, Los Angeles, California 90095, USA
    Nat Rev Mol Cell Biol 13:213-24. 2012
    ..Mounting evidence indicates that these nuclear receptors have essential roles, not only in the regulation of cholesterol and bile acid metabolism but also in the integration of sterol, fatty acid and glucose metabolism...
  28. pmc Metalloproteinase processing of HBEGF is a proximal event in the response of human aortic endothelial cells to oxidized phospholipids
    Sangderk Lee
    Department of Pathology, University of California Los Angeles, Los Angeles, CA, USA
    Arterioscler Thromb Vasc Biol 32:1246-54. 2012
    ..The goal of this study was to identify the proximal events leading to induction of IL-8 by Ox-PAPC in vascular endothelial cells...
  29. pmc Interpreting meta-analyses of genome-wide association studies
    Buhm Han
    Department of Computer Science, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS Genet 8:e1002555. 2012
    ..In addition to helping interpretation, the new framework also allows us to develop a new association testing procedure taking into account the existence of effect...
  30. pmc A role for VEGFR2 activation in endothelial responses caused by barrier disruptive OxPAPC concentrations
    Anna A Birukova
    Section of Pulmonary and Critical Medicine, Department of Medicine, Lung Injury Center, University of Chicago, Chicago, Illinois, United States of America
    PLoS ONE 7:e30957. 2012
    ..This study examined a role of VEGFR2 in barrier dysfunction caused by high concentrations of OxPAPC and evaluated downstream signaling mechanisms resulting from the effect of OxPAPC in EC from pulmonary and systemic circulation...
  31. pmc Loss of FXR protects against diet-induced obesity and accelerates liver carcinogenesis in ob/ob mice
    Yanqiao Zhang
    Department of Integrative Medical Sciences, Northeast Ohio Medical University, Rootstown, Ohio 44272, USA
    Mol Endocrinol 26:272-80. 2012
    ..Together these data indicate that loss of FXR prevents diet-induced or genetic obesity and accelerates liver carcinogenesis under diabetic conditions...
  32. pmc Concise review: applying stem cell biology to vascular structures
    KRISTINA I BOSTROM
    Division of Cardiology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA
    Stem Cells 30:386-91. 2012
    ..Loss and dysregulation of feedback control cause a variety of diseases that involve ectopic tissue formation, including atherosclerotic lesion formation and calcification, diabetic vasculopathies, and arteriovenous malformations...
  33. pmc Dysfunctional high-density lipoprotein and the potential of apolipoprotein A-1 mimetic peptides to normalize the composition and function of lipoproteins
    Satoshi Imaizumi
    Department of Medicine, University of California, Los Angeles, CA, USA
    Circ J 75:1533-8. 2011
    ..This review focuses on recent studies of dysfunctional HDL in animal models and human disease, and the potential of apoA-I mimetic peptides to normalize the composition and function of lipoproteins...
  34. pmc Gut flora metabolism of phosphatidylcholine promotes cardiovascular disease
    Zeneng Wang
    Department of Cell Biology, Cleveland Clinic, Cleveland, Ohio 44195, USA
    Nature 472:57-63. 2011
    ....
  35. pmc Intestine may be a major site of action for the apoA-I mimetic peptide 4F whether administered subcutaneously or orally
    Mohamad Navab
    Department of Medicine, David Geffen School of Medicine at the University of California, Los Angeles, CA 90095, USA
    J Lipid Res 52:1200-10. 2011
    ..We conclude: i) the dose of 4F administered and not the plasma level achieved determines efficacy; ii) the intestine may be a major site of action for the peptide regardless of the route of administration...
  36. pmc Regulation of ABCG1 expression in human keratinocytes and murine epidermis
    Yan J Jiang
    Metabolism Section, Veterans Affairs Medical Center, Northern California Institute for Research and Education, University of California at San Francisco, San Francisco, CA 94121, USA
    J Lipid Res 51:3185-95. 2010
    ....
  37. pmc L-4F differentially alters plasma levels of oxidized fatty acids resulting in more anti-inflammatory HDL in mice
    Satoshi Imaizumi
    Department of Medicine, and David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1679, USA
    Drug Metab Lett 4:139-48. 2010
    ..i) L-4F differentially alters plasma levels of oxidized fatty acids in vivo. ii) The resistance of the C3H/HeJ strain to atherosclerosis may in part be mediated by a reduced reaction of this strain to these potent lipid oxidants...
  38. pmc Mitogen-activated protein kinase phosphatase-1 deficiency decreases atherosclerosis in apolipoprotein E null mice by reducing monocyte chemoattractant protein-1 levels
    Satoshi Imaizumi
    Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, CA 90095 1679, USA
    Mol Genet Metab 101:66-75. 2010
    ..We also reported that inhibition of tyrosine phosphatases including MKP-1 ameliorated atherosclerotic lesions in mouse models of atherosclerosis...
  39. pmc Identification and validation of genes affecting aortic lesions in mice
    Xia Yang
    Department of Molecular Profiling, Rosetta Inpharmactics LLC, a Wholly Owned Subsidiary of Merck and Co Inc, Seattle, Washington, USA
    J Clin Invest 120:2414-22. 2010
    ..Our findings therefore validate the ability of causality testing procedures to provide insights into the mechanisms underlying atherosclerosis development...
  40. pmc Inhibition of bone morphogenetic proteins protects against atherosclerosis and vascular calcification
    Yucheng Yao
    Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 1679, USA
    Circ Res 107:485-94. 2010
    ..The bone morphogenetic proteins (BMPs), a family of morphogens, have been implicated as mediators of calcification and inflammation in the vascular wall...
  41. pmc Activation of the farnesoid X receptor provides protection against acetaminophen-induced hepatic toxicity
    Florence Ying Lee
    Department of Biological Chemistry, David Geffen School of Medicine at University of California, Los Angeles, Los Angeles, California 90095, USA
    Mol Endocrinol 24:1626-36. 2010
    ..Based on these findings, we propose that FXR plays a role in hepatic xenobiotic metabolism and, when activated, provides hepatoprotection against toxins such as APAP...
  42. pmc Treatment with apolipoprotein A-1 mimetic peptide reduces lupus-like manifestations in a murine lupus model of accelerated atherosclerosis
    Jennifer M P Woo
    Department of Medicine Rheumatology, David Geffen School of Medicine, University of California, 1000 Veteran Avenue, Los Angeles, CA 90095, USA
    Arthritis Res Ther 12:R93. 2010
    ....
  43. pmc Expression quantitative trait loci: replication, tissue- and sex-specificity in mice
    Atila Van Nas
    Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    Genetics 185:1059-68. 2010
    ..We conclude that most local eQTL are highly replicable between mouse crosses, tissues, and sex as compared to distal eQTL, which exhibited modest replicability...
  44. pmc Oxpholipin 11D: an anti-inflammatory peptide that binds cholesterol and oxidized phospholipids
    Piotr Ruchala
    Department of Medicine, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America
    PLoS ONE 5:e10181. 2010
    ..This domain is usually flanked N-terminally by arginine and C-terminally by valine. We used this 14-residue sequence as a template to create a small library of peptides that bind cholesterol and other lipids...
  45. pmc Activation of aortic endothelial cells by oxidized phospholipids: a phosphoproteomic analysis
    Alejandro Zimman
    Department of Pathology and Laboratory Medicine, David Geffen School of Medicine, University of California, Los Angeles, California 90095 1770, USA
    J Proteome Res 9:2812-24. 2010
    ..Many changes in protein phosphorylation induced by Ox-PAPC are reported here for the first time and provide new insights into the mechanism of activation by oxidized lipids, including phosphorylation-based signal transduction...
  46. pmc Impaired development of atherosclerosis in Abcg1-/- Apoe-/- mice: identification of specific oxysterols that both accumulate in Abcg1-/- Apoe-/- tissues and induce apoptosis
    Elizabeth J Tarling
    Department of Biological Chemistry, David Geffen School of Medicine at University of California Los Angeles, Los Angeles, CA 90095 1737, USA
    Arterioscler Thromb Vasc Biol 30:1174-80. 2010
    ..To generate Abcg1(-/-) Apoe(-/-) mice to understand the mechanism and cell types involved in changes in atherosclerosis after loss of ABCG1...
  47. pmc Temporal and tissue-specific patterns of Pon3 expression in mouse: in situ hybridization analysis
    Diana M Shih
    Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095 1679, USA
    Adv Exp Med Biol 660:73-87. 2010
    ..Pon3 mRNA was also detected in the atherosclerotic lesion areas at the aortic root of apoE -/- hearts. Our data revealed that mouse Pon3 is expressed in a wide range of tissues, and that its expression is temporally controlled...
  48. pmc Arterial colony stimulating factor-1 influences atherosclerotic lesions by regulating monocyte migration and apoptosis
    Zory Shaposhnik
    Department of Medicine, School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095 1679, USA
    J Lipid Res 51:1962-70. 2010
    ..We conclude that the M-CSF pathway contributes to monocyte recruitment and macrophage survival and that this pathway is a potential target for therapeutic intervention...
  49. pmc Systems genetics analysis of gene-by-environment interactions in human cells
    Casey E Romanoski
    Department of Human Genetics, University of California, Los Angeles, CA, 90095, USA
    Am J Hum Genet 86:399-410. 2010
    ....
  50. pmc A high-resolution association mapping panel for the dissection of complex traits in mice
    Brian J Bennett
    Department of Medicine Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, California 90095, USA
    Genome Res 20:281-90. 2010
    ..This resource, termed the Hybrid Mouse Diversity Panel, makes possible the integration of multiple data sets and should prove useful for systems-based approaches to complex traits and studies of gene-by-environment interactions...
  51. pmc Apolipoprotein A-I mimetic peptides prevent atherosclerosis development and reduce plaque inflammation in a murine model of diabetes
    Cecilia Morgantini
    Department of Internal Medicine, University of Pisa, Pisa, Italy
    Diabetes 59:3223-8. 2010
    ..To determine the effect of the apolipoprotein A-I (ApoA-I) mimetic peptide, D-4F, on atherosclerosis development in a pre-existing diabetic condition...
  52. pmc NF-E2-related factor 2 promotes atherosclerosis by effects on plasma lipoproteins and cholesterol transport that overshadow antioxidant protection
    Berenice Barajas
    Department of Medicine, University of California, Center for Health Sciences, Los Angeles, CA 90095, USA
    Arterioscler Thromb Vasc Biol 31:58-66. 2011
    ..To test the hypothesis that NF-E2-related factor 2 (Nrf2) expression plays an antiatherogenic role by its vascular antioxidant and anti-inflammatory properties...
  53. pmc D-4F, an apoA-I mimetic peptide, inhibits proliferation and tumorigenicity of epithelial ovarian cancer cells by upregulating the antioxidant enzyme MnSOD
    Ekambaram Ganapathy
    Department of Obstetrics and Gynecology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA 90095, USA
    Int J Cancer 130:1071-81. 2012
    ..Our results suggest that the inhibitory effects of D-4F on ID8 cell proliferation and tumor development are mediated, at least in part, by the induced expression and activity of MnSOD...
  54. pmc HIV-1 infected patients with suppressed plasma viremia on treatment have pro-inflammatory HDL
    Theodoros Kelesidis
    Division of Infectious Diseases, Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA
    Lipids Health Dis 10:35. 2011
    ..We hypothesized that HIV-1-infected persons on antiretroviral therapy would have pro-inflammatory high density lipoprotein (HDL), and that an apoA-1 mimetic peptide might reverse the inflammatory properties of HDL in these persons...
  55. pmc Targeted disruption of the idol gene alters cellular regulation of the low-density lipoprotein receptor by sterols and liver x receptor agonists
    Elena Scotti
    Howard Hughes Medical Institute, UCLA School of Medicine, Box 951662, Los Angeles, CA 90095 1662, USA
    Mol Cell Biol 31:1885-93. 2011
    ..These results demonstrate that the LXR-Idol pathway is an important contributor to feedback inhibition of the LDLR by sterols and a biological determinant of cellular LDL uptake...
  56. ncbi HDL and cardiovascular disease: atherogenic and atheroprotective mechanisms
    Mohamad Navab
    Department of Medicine, David Geffen School of Medicine, UCLA, 10833 Le Conte Avenue, Los Angeles, CA 90095 1679, USA
    Nat Rev Cardiol 8:222-32. 2011
    ..Robust assays to evaluate the function of HDL are needed to supplement the measurement of HDL-cholesterol levels in the clinic...
  57. pmc L-5F, an apolipoprotein A-I mimetic, inhibits tumor angiogenesis by suppressing VEGF/basic FGF signaling pathways
    Feng Gao
    David Geffen School of Medicine, University of California Los Angeles, 10833 Le Conte Avenue, Los Angeles, CA 90095 5347, USA
    Integr Biol (Camb) 3:479-89. 2011
    ..In conclusion, our data that L-5F inhibits angiogenesis suggests that apoA-I mimetic peptides may serve as novel anti-angiogenesis agents for the treatment of angiogenesis-associated diseases, including cancer...
  58. ncbi Chronic inflammatory disorders and accelerated atherosclerosis: chronic kidney disease
    Kaveh D Navab
    David Geffen School of Medicine, 10833 Le Conte Ave, University of California Los Angeles, CA 90095, USA
    Curr Pharm Des 17:17-20. 2011
    ..Whether HDL mimetic peptides will have therapeutic benefit in patients with renal failure will have to be determined in clinical studies...
  59. pmc Activation of vascular bone morphogenetic protein signaling in diabetes mellitus
    KRISTINA I BOSTROM
    Division of Cardiology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095 1679, USA
    Circ Res 108:446-57. 2011
    ..Diabetes mellitus is frequently complicated by cardiovascular disease, such as vascular calcification and endothelial dysfunction, which have been associated with bone morphogenetic proteins (BMPs)...
  60. pmc Constitutive activation of LXR in macrophages regulates metabolic and inflammatory gene expression: identification of ARL7 as a direct target
    Cynthia Hong
    Howard Hughes Medical Institute, Department of Pathology and Laboratory Medicine, University of California at Los Angeles, Los Angeles, CA, USA
    J Lipid Res 52:531-9. 2011
    ..These findings provide further support for an important role of LXRs in the coordinated regulation of lipid metabolic and inflammatory gene programs in macrophages...
  61. pmc Liver X receptor signaling is a determinant of stellate cell activation and susceptibility to fibrotic liver disease
    Simon W Beaven
    Howard Hughes Medical Institute, David Geffen School of Medicine at UCLA, Los Angeles, California 90095, USA
    Gastroenterology 140:1052-62. 2011
    ..We investigated the role of LXR signaling stellate cell activation and susceptibility to fibrotic liver disease...
  62. pmc LXR deficiency confers increased protection against visceral Leishmania infection in mice
    Kevin W Bruhn
    Department of Medicine, Division of Dermatology and Infectious Diseases, Harbor University of California Los Angeles Medical Center and Los Angeles Biomedical Research Institute, Torrance, California, USA
    PLoS Negl Trop Dis 4:e886. 2010
    ....
  63. pmc Hepatic hepatocyte nuclear factor 4α is essential for maintaining triglyceride and cholesterol homeostasis
    Liya Yin
    Department of Integrative Medical Sciences, Northeastern Ohio Universities College of Medicine, 4209 State Rte 44, Rootstown, OH 44272, USA
    Arterioscler Thromb Vasc Biol 31:328-36. 2011
    ..However, the mechanisms underlying the lipid disorders are poorly understood. In this study, we determined the effect of acute loss or augmentation of hepatic HNF4α function on lipid homeostasis...
  64. pmc Treatment of patients with cardiovascular disease with L-4F, an apo-A1 mimetic, did not improve select biomarkers of HDL function
    Catherine E Watson
    Novartis Institutes for BioMedical Research, Cambridge, MA 02139, USA
    J Lipid Res 52:361-73. 2011
    ..In conclusion, in vivo L-4F treatment, delivered by either SC injection or IV infusion, did not improve HDL functional biomarkers despite achieving plasma levels that improved identical biomarkers ex vivo and in animal models...
  65. pmc LXR promotes the maximal egress of monocyte-derived cells from mouse aortic plaques during atherosclerosis regression
    Jonathan E Feig
    Department of Medicine, Division of Cardiology, New York University School of Medicine, New York, New York, USA
    J Clin Invest 120:4415-24. 2010
    ..We conclude that LXR is required for maximal effects on plaque CD68+ cell expression of CCR7 and monocyte-derived cell egress during atherosclerosis regression in mice...
  66. pmc Apolipoprotein A-I (apoA-I) and apoA-I mimetic peptides inhibit tumor development in a mouse model of ovarian cancer
    Feng Su
    Department of Obstetrics and Gynecology, University of California, Los Angeles, CA 90095 5347, USA
    Proc Natl Acad Sci U S A 107:19997-20002. 2010
    ....
  67. pmc Genetic regulation of mouse liver metabolite levels
    Anatole Ghazalpour
    Division of Cardiology, Department of Medicine, UCLA, Los Angeles, CA, USA
    Mol Syst Biol 10:730. 2014
    ..We also integrated the metabolomic data with transcriptomic and clinical phenotypic data to evaluate the extent of co-variation across various biological scales. ..
  68. pmc An epoxyisoprostane is a major regulator of endothelial cell function
    Wei Zhong
    Department of Chemistry and Biochemistry and Department of Medicine, University of California, Los Angeles, 405 Hilgard Avenue, Los Angeles, California 90095, United States
    J Med Chem 56:8521-32. 2013
    ..EI also strongly down-regulates the inflammatory effects of IL-1β, a major inflammatory cytokine. Thus EI, a hydrolytic product of PEIPC, has potent anti-inflammatory function. ..
  69. pmc IPED: inheritance path-based pedigree reconstruction algorithm using genotype data
    Dan He
    1 IBM T J Watson Research, Yorktown Heights, New York
    J Comput Biol 20:780-91. 2013
    ..Indeed it is the first practical method for reconstruction of large pedigrees from genotype data...
  70. pmc Transgenic 6F tomatoes act on the small intestine to prevent systemic inflammation and dyslipidemia caused by Western diet and intestinally derived lysophosphatidic acid
    Mohamad Navab
    Departments of Medicine, David Geffen School of Medicine, University of California at Los Angeles, Los Angeles, CA 90095
    J Lipid Res 54:3403-18. 2013
    ....
  71. pmc Efficiently identifying significant associations in genome-wide association studies
    Emrah Kostem
    1 Computer Science Department, University of California, Los Angeles, California
    J Comput Biol 20:817-30. 2013
    ..Additionally, efficient implementation of our software increases the computational speed relative to the state-of-the-art testing approaches by a factor of 75...
  72. pmc Analysis of allele-specific expression in mouse liver by RNA-Seq: a comparison with Cis-eQTL identified using genetic linkage
    Sandrine Lagarrigue
    Agrocampus Ouest, Unité Mixte de Recherche 1348 Pegase, F 35000 Rennes, France
    Genetics 195:1157-66. 2013
    ..We also identify genes exhibiting parental imprinting and complex expression patterns. Our study demonstrates the importance of biological replicates to limit the number of false positives with RNA-Seq data. ..
  73. pmc Gene expression analyses of mouse aortic endothelium in response to atherogenic stimuli
    Ayca Erbilgin
    From the Departments of Microbiology, Immunology, and Molecular Genetics A E, A J L, Pathology and Laboratory Medicine J B, Medicine A J L, and Human Genetics A J L, University of California, Los Angeles and Bristol Myers Squibb, Applied Genomics, Princeton, NJ N S, P K, W p Y
    Arterioscler Thromb Vasc Biol 33:2509-17. 2013
    ..To address this, we developed a method for determining the global transcriptional changes that occur in the mouse endothelium in response to atherogenic conditions and applied it to investigate inflammatory stimuli...
  74. pmc Myeloperoxidase, paraoxonase-1, and HDL form a functional ternary complex
    Ying Huang
    Department of Cellular and Molecular Medicine, Center for Cardiovascular Diagnostics and Prevention, Cleveland Clinic, Cleveland, Ohio 44195, USA
    J Clin Invest 123:3815-28. 2013
    ..HDL thus serves as a scaffold upon which MPO and PON1 interact during inflammation, whereupon PON1 binding partially inhibits MPO activity, and MPO promotes site-specific oxidative modification and impairment of PON1 and APOA1 function. ..
  75. pmc A role for the endothelium in vascular calcification
    Yucheng Yao
    Division of Cardiology, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
    Circ Res 113:495-504. 2013
    ..However, it is not clear whether the vascular endothelium has a role in contributing osteoprogenitor cells to the calcific lesions...
  76. pmc Leveraging reads that span multiple single nucleotide polymorphisms for haplotype inference from sequencing data
    Wen Yun Yang
    Department of Computer Science and Inter Departmental Program in Bioinformatics, University of California, Los Angeles, CA 90095, USA
    Bioinformatics 29:2245-52. 2013
    ..However, this information is generally ignored in existing approaches for haplotype phasing and genotype-calling from short read data...
  77. pmc Reciprocal regulation of hepatic and adipose lipogenesis by liver X receptors in obesity and insulin resistance
    Simon W Beaven
    Howard Hughes Medical Institute and Department of Pathology and Laboratory Medicine, David Geffen School of Medicine at UCLA, Los Angeles, CA, USA
    Cell Metab 18:106-17. 2013
    ..Our data suggest that sterol sensing by LXRs in obesity is critically linked with lipid and glucose homeostasis and provide insight into the complex relationships between LXR and insulin signaling. ..
  78. pmc Effectively identifying eQTLs from multiple tissues by combining mixed model and meta-analytic approaches
    Jae Hoon Sul
    Computer Science Department, University of California, Los Angeles, California, USA
    PLoS Genet 9:e1003491. 2013
    ..Additionally, our method provides an interpretation framework that accurately predicts whether an eQTL has an effect in a particular tissue...
  79. pmc The nuclear receptor LXRα controls the functional specialization of splenic macrophages
    Noelia A-Gonzalez
    Instituto de Investigaciones Biomédicas Alberto Sols de Madrid, Consejo Superior de Investigaciones Cientificas Universidad Autonoma de Madrid, Madrid, Spain
    Nat Immunol 14:831-9. 2013
    ..Our results demonstrate that signaling via LXRα in myeloid cells is crucial for the generation of splenic MZ macrophages and identify an unprecedented role for a nuclear receptor in the generation of specialized macrophage subsets. ..
  80. pmc Hyodeoxycholic acid improves HDL function and inhibits atherosclerotic lesion formation in LDLR-knockout mice
    Diana M Shih
    Division of Cardiology, David Geffen School of Medicine at UCLA, 10833 Le Conte Ave, A2 237 CHS, Los Angeles, CA 90095 1679, USA
    FASEB J 27:3805-17. 2013
    ..In addition, HDCA significantly increased the expression of genes involved in cholesterol efflux, such as Abca1, Abcg1, and Apoe, in a macrophage cell line. Thus, HDCA is a candidate for antiatherosclerotic drug therapy...
  81. pmc Identification of CAD candidate genes in GWAS loci and their expression in vascular cells
    Ayca Erbilgin
    Department of Microbiology, Immunology and Molecular Genetics, David Geffen School of Medicine, Los Angeles, CA, USA
    J Lipid Res 54:1894-905. 2013
    ..Additionally, we highlight the genetic complexity of a subset of CAD loci through the differential expression of multiple candidate genes per locus and the involvement of genes that lie outside linkage disequilibrium blocks...
  82. pmc Fast pairwise IBD association testing in genome-wide association studies
    Buhm Han
    Division of Genetics, Brigham and Women s Hospital and Division of Rheumatology, Brigham and Women s Hospital, Harvard Medical School, Boston, MA 02115, USA, Partners Center for Personalized Genetic Medicine, Boston, MA 02115, USA, Program in Medical and Population Genetics, Broad Institute of Harvard and MIT, Cambridge, MA 02142, USA, Computer Science Department, University of California, Los Angeles, CA 90095, USA, Faculty of Medical and Human Sciences, University of Manchester, Manchester, UK, Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands, Department of Medical Genetics, University Medical Center Utrecht, Utrecht, The Netherlands and Department of Human Genetics, University of California, Los Angeles, CA 90095, USA
    Bioinformatics 30:206-13. 2014
    ....
  83. pmc Reducing Jagged 1 and 2 levels prevents cerebral arteriovenous malformations in matrix Gla protein deficiency
    Yucheng Yao
    Division of Cardiology, David Geffen School of Medicine at UCLA and Molecular Biology Institute, University of California, Los Angeles, CA 90095 1679
    Proc Natl Acad Sci U S A 110:19071-6. 2013
    ..Our results suggest that Notch signaling mediates and can modulate changes in BMP signaling that lead to cerebral AVMs. ..
  84. pmc Comparative genome-wide association studies in mice and humans for trimethylamine N-oxide, a proatherogenic metabolite of choline and L-carnitine
    Jaana Hartiala
    From the Department of Preventive Medicine J H, H A and Institute for Genetic Medicine J H, H A, Keck School of Medicine of the University of Southern California, Los Angeles Department of Genetics B J B and Nutrition Research Institute B J B, University of North Carolina, Chapel Hill, Kannapolis Departments of Cardiovascular Medicine W H W T, Z W, S L H and Cellular and Molecular Medicine W H W T, Z W, S L H and Center for Cardiovascular Diagnostics and Prevention W H W T, Z W, S L H, Cleveland Clinic, OH John and Jennifer Ruddy Canadian Cardiovascular Genetics Centre, University of Ottawa Heart Institute, Ottawa, Ontario, Canada A F R S, R R, R M and Departments of Medicine A J L, Human Genetics A J L, and Microbiology, Immunology, and Molecular Genetics A J L, David Geffen School of Medicine of UCLA
    Arterioscler Thromb Vasc Biol 34:1307-13. 2014
    ..The goal of this study was to identify the genetic factors associated with plasma TMAO levels...
  85. pmc Identifying genetic relatives without compromising privacy
    Dan He
    Department of Computer Science, University of California, Los Angeles, Los Angeles, California 90095, USA
    Genome Res 24:664-72. 2014
    ....
  86. pmc HDL lipid composition is profoundly altered in patients with type 2 diabetes and atherosclerotic vascular disease
    C Morgantini
    Department of Internal Medicine, University of Pisa, Italy Scuola Superiore Sant Anna, Pisa, Italy
    Nutr Metab Cardiovasc Dis 24:594-9. 2014
    ..In this study, we examined whether HDL from T2D patients contains elevated levels of oxidized fatty acids and whether those levels correlate with cardiovascular disease (CVD)...
  87. pmc Genome-wide association study for age-related hearing loss (AHL) in the mouse: a meta-analysis
    Jeffrey Ohmen
    Department of Cell and Molecular Biology and Genetics, House Research Institute, Los Angeles, CA, USA
    J Assoc Res Otolaryngol 15:335-52. 2014
    ..These data confirm the utility of this approach and provide new high-resolution mapping information about variation within the mouse genome associated with hearing loss...
  88. pmc Fatty acid epoxyisoprostane E2 stimulates an oxidative stress response in endothelial cells
    Xinmin Yan
    Changzhou No 2 People s Hospital, Diabetes Institute, 29 Xinglong Lane, Changzhou City, Jiangsu Prov 213003, China
    Biochem Biophys Res Commun 444:69-74. 2014
    ..Thus, we demonstrated that EI induced oxidative stress in endothelial cells leading to increased expression of oxidative stress response gene OKL38 and HO-1 via Nrf2 signaling pathway relevant to atherosclerosis. ..
  89. pmc Meta-analysis identifies gene-by-environment interactions as demonstrated in a study of 4,965 mice
    Eun Yong Kang
    Department of Computer Science, University of California, Los Angeles, Los Angeles, California, United States of America
    PLoS Genet 10:e1004022. 2014
    ....
  90. pmc Pluripotent stem cells derived from mouse and human white mature adipocytes
    Medet Jumabay
    Division of Cardiology, Division of Cardiothoracic Surgery, and Department of Obstetrics and Gynecology, David Geffen School of Medicine, and Molecular Biology Institute, University of California, Los Angeles, Los Angeles, California, USA
    Stem Cells Transl Med 3:161-71. 2014
    ..Thus, the adipocyte-derived DFAT cells represent a plastic stem cell population that is highly responsive to changes in culture conditions and may benefit cell-based therapies. ..
  91. ncbi High-density lipoprotein: vascular protective effects, dysfunction, and potential as therapeutic target
    Thomas F Luscher
    From Department of Cardiology, University Heart Center T F L, U L, and Department of Clinical Chemistry A v E, University Hospital Zurich, Zurich, Switzerland Division of Cardiovascular Research, Institute of Physiology, University of Zurich, Zurich, Switzerland T F L, U L and Department of Medicine, University of California, Los Angeles, CA A M F
    Circ Res 114:171-82. 2014
    ....
  92. ncbi Upregulation of endogenous farnesyl diphosphate synthase overcomes the inhibitory effect of bisphosphonate on protein prenylation in Hela cells
    Subhajit Das
    Musculoskeletal Research Programme, Division of Applied Medicine, School of Medicine and Dentistry, University of Aberdeen, Aberdeen, UK
    Biochim Biophys Acta 1841:569-73. 2014
    ..These observations suggest that an increase in the expression of endogenous FPPS could confer at least partial resistance to the pharmacological effect of N-BP drugs such as ZOL in vivo. ..
  93. pmc Testing the iron hypothesis in a mouse model of atherosclerosis
    Léon Kautz
    Department of Medicine, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, CA 90095, USA
    Cell Rep 5:1436-42. 2013
    ..Our results strongly argue against any significant role of macrophage iron in atherosclerosis progression in mice. ..
  94. pmc Systems genetics approaches to understand complex traits
    Mete Civelek
    1 Department of Microbiology, Immunology, and Molecular Genetics, University of California, Los Angeles 2 Department of Human Genetics, University of California, Los Angeles 3 Department of Medicine, A2 237 Center for Health Sciences, University of California, Los Angeles, California 90095 1679, USA
    Nat Rev Genet 15:34-48. 2014
    ....
  95. pmc Branching patterns emerge in a mathematical model of the dynamics of lung development
    Yina Guo
    Department of Medicine, A2 237 Center for Health Sciences, Los Angeles, California, USA 90095 1679 X Zhao Institute of Robotics and Automatic Information Systems, Nankai University, Tianjin 300071, China Email
    J Physiol 592:313-24. 2014
    ..The model provides a number of testable predictions, some of which have already been observed (though not explained) in experimental work. ..

Research Grants30

  1. CENTER FOR GASTROINTESTINAL BIOLOGY AND DISEASE
    Robert S Sandler; Fiscal Year: 2013
    ..Through all of its activities, the Center improves communication, promotes collaboration, develops careers and generally enriches the intellectual climate for digestive disease research. ..