Role of Group 1B Phospholipase A2 on Diet-induced Metabolic Diseases

Summary

Principal Investigator: David Y Hui
Abstract: DESCRIPTION (provided by applicant): Genome-wide association studies have identified significant association between PLA2G1B gene polymorphisms and central adiposity in humans. This gene encodes the Group 1B phospholipase A2 protein (PLA2G1B) that hydrolyzes phospholipids to generate free fatty acids and lysophospholipids (lysoPL) in the digestive tract. Recent lipidomic analyses have also identified elevated lysoPL as a major obesity risk factor in humans, thus suggesting that PLA2G1B-mediated production of lysoPL may contribute to obesity and its related metabolic consequences. This project has documented previously that Pla2g1b inactivation in mice decreases intestinal lysoPL absorption, and as a consequence decreases hepatic fatty acid oxidation in protection against diet-induced obesity and glucose intolerance. This renewal application will delineate the mechanism by which intestinal lysoPL absorption suppresses hepatic fatty acid oxidation, and test the hypothesis that PLA2G1B-mediated lysoPL absorption and transport to the liver is a major contributing factor for diet-induced metabolic diseases including obesity, diabetes, and atherosclerosis. The second goal of this application is to delineate the molecular mechanism linking the common PLA2G1B polymorphism with decreased adiposity in humans. Aim 1 will test the hypothesis that lysoPL suppresses hepatic fatty acid oxidation and promote diet-induced obesity and glucose intolerance by inducing transient opening of mitochondrial permeability transition pores and/or activating JNK stress signaling to suppress PPAR activity. The direct role of hepatic lysoPL toward these metabolic disorders will be assessed by determining if converting lysoPL to phospholipids by increasing lysoPC acyltransferase specifically in liver will improve fatty acid oxidation and ameliorate diet-induced metabolic disorders in Pla2g1b+/+ mice similar to that in Pla2g1b-/- mice. Aim 2 is a proof of concept pre-clinical study to evaluate the efficacy of oral Pla2g1b inhibitor therapy in suppressing atherosclerosis in hypercholesterolemic Ldlr-null mice. The specific role of Pla2g1b will be ascertained in complementary studies comparing atherosclerosis development between Pla2g1b+/+Ldlr-/- and Pla2g1b-/- Ldlr-/- mice. Aim 3 will identify the mechanism by which the common PLA2G1B polymorphism (rs5637;allelic frequency ~20%) is associated with reduced obesity in humans, testing the hypothesis that the synonymous G-to-A mutation alters an exon splicing enhancer sequence within exon 3 of the PLA2G1B gene, resulting in alternative splicing and deletion of the exon 3 domain to yield an inactive enzyme. Taken together, these studies will not only contribute valuable information toward understanding the mechanism by which PLA2G1B-induced lysoPL promotes metabolic disorders, thereby accelerating the development of PLA2G1B inhibitors for disease intervention, but will also help identify subjects that may benefit the most from this novel therapeutic strategy.
Funding Period: 2004-12-01 - 2015-04-30
more information: NIH RePORT

Top Publications

  1. pmc Group 1B phospholipase A2-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia
    Eric D Labonté
    Department of Pathology, Genome Research Institute, University of Cincinnati, 2120 E Galbraith Rd, Cincinnati, OH 45237 0507, USA
    Diabetes 55:935-41. 2006
  2. pmc Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity
    Eric D Labonté
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 2120 E Galbraith Rd, Cincinnati, OH 45237, USA
    FASEB J 24:2516-24. 2010
  3. pmc Pancreatic acinar cell-specific overexpression of group 1B phospholipase A2 exacerbates diet-induced obesity and insulin resistance in mice
    J G Cash
    Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    Int J Obes (Lond) 35:877-81. 2011
  4. pmc Group 1B phospholipase A₂ deficiency protects against diet-induced hyperlipidemia in mice
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    J Lipid Res 52:2005-11. 2011
  5. pmc Phospholipase A(2) enzymes in metabolic and cardiovascular diseases
    David Y Hui
    Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237 0507, USA
    Curr Opin Lipidol 23:235-40. 2012
  6. pmc Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in function
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Biochim Biophys Acta 1841:888-95. 2014
  7. pmc Group 1B phospholipase A₂ inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    Atherosclerosis 234:377-80. 2014

Research Grants

  1. The Center for Native and Pacific Health Disparities Research
    MARJORIE K LEIMOMI MALA MAU; Fiscal Year: 2013
  2. Role of cholesteryl ester transfer protein in cellular lipid homeostasis
    Richard E Morton; Fiscal Year: 2013
  3. CELLULAR AND MOLECULAR BIOLOGY OF LIPOPROTEIN METABOLISM
    Michael C Phillips; Fiscal Year: 2013
  4. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
  5. REGULATION OF LIVER GROWTH AND FUNCTION
    Leonard S Jefferson; Fiscal Year: 2013
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
  7. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
  8. Avoiding toxicity associated with MTP ablation
    M Mahmood Hussain; Fiscal Year: 2013
  9. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
  10. Regulation of Hepatic SphK2 by Bile Acids: Effects on Lipid Metabolism
    HUIPING ROSE ZHOU; Fiscal Year: 2013

Detail Information

Publications7

  1. pmc Group 1B phospholipase A2-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemia
    Eric D Labonté
    Department of Pathology, Genome Research Institute, University of Cincinnati, 2120 E Galbraith Rd, Cincinnati, OH 45237 0507, USA
    Diabetes 55:935-41. 2006
    ..These results demonstrated that reduction of lysophospholipid absorption enhances insulin-mediated glucose metabolism and is protective against postprandial hyperglycemia...
  2. pmc Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesity
    Eric D Labonté
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, 2120 E Galbraith Rd, Cincinnati, OH 45237, USA
    FASEB J 24:2516-24. 2010
    ....
  3. pmc Pancreatic acinar cell-specific overexpression of group 1B phospholipase A2 exacerbates diet-induced obesity and insulin resistance in mice
    J G Cash
    Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    Int J Obes (Lond) 35:877-81. 2011
    ....
  4. pmc Group 1B phospholipase A₂ deficiency protects against diet-induced hyperlipidemia in mice
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    J Lipid Res 52:2005-11. 2011
    ..Thus, the inhibition of lysophospholipid absorption via Pla2g1b inactivation may prove beneficial against diet-induced hyperlipidemia in addition to the protection against obesity and diabetes...
  5. pmc Phospholipase A(2) enzymes in metabolic and cardiovascular diseases
    David Y Hui
    Department of Pathology, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH 45237 0507, USA
    Curr Opin Lipidol 23:235-40. 2012
    ..The purpose of this review is to discuss recent findings showing distinct roles of several of these PLA2 enzymes in inflammatory metabolic diseases such as diabetes and atherosclerosis...
  6. pmc Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in function
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, Metabolic Diseases Institute, University of Cincinnati College of Medicine, Cincinnati, OH, USA
    Biochim Biophys Acta 1841:888-95. 2014
    ....
  7. pmc Group 1B phospholipase A₂ inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient mice
    Norris I Hollie
    Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
    Atherosclerosis 234:377-80. 2014
    ....

Research Grants30

  1. 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. ..
  2. 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. ..
  3. 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. ..
  4. Hypo-Lipidemic Actions of Creosote Bush-Derived NDGA
    Salman Azhar; Fiscal Year: 2013
    ....
  5. REGULATION OF LIVER GROWTH AND FUNCTION
    Leonard S Jefferson; Fiscal Year: 2013
    ..Knowledge gained from the project will provide insight into designing strategies for treatment of pathologies resulting from the maladapted whole body metabolism associated with obesity and diabetes. ..
  6. EARLY EVENTS IN ALZHEIMER PATHOGENESIS
    SUE TILTON GRIFFIN; Fiscal Year: 2013
    ..The synergy between our aims, approaches, and measures will enable us to meet our goal of defining early cellular interactions toward development of rational interventions in AD. ..
  7. Center for Gene Therapy of Cystic Firbosis
    John F Engelhardt; Fiscal Year: 2013
    ..These efforts have led to numerous basic and applied research findings that have enhanced the utility of gene therapies to both study and treat genetic diseases. ..
  8. Avoiding toxicity associated with MTP ablation
    M Mahmood Hussain; Fiscal Year: 2013
    ..Proposed studies may lead to new therapeutic modalities for the treatment of various disorders associated with high plasma lipids. ..
  9. Inflammatory responses of vascular cells
    Paul L Fox; Fiscal Year: 2013
    ..abstract_text> ..
  10. Regulation of Hepatic SphK2 by Bile Acids: Effects on Lipid Metabolism
    HUIPING ROSE ZHOU; Fiscal Year: 2013
    ..Also, this study has potential impact on the identification and development of novel therapeutic targets for effective treatment of NAFLD and other related metabolic diseases. ..