Genomes and Genes
Role of Group 1B Phospholipase A2 on Diet-induced Metabolic Diseases
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
- Group 1B phospholipase A2-mediated lysophospholipid absorption directly contributes to postprandial hyperglycemiaEric 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...
- Postprandial lysophospholipid suppresses hepatic fatty acid oxidation: the molecular link between group 1B phospholipase A2 and diet-induced obesityEric 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....
- Pancreatic acinar cell-specific overexpression of group 1B phospholipase A2 exacerbates diet-induced obesity and insulin resistance in miceJ 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....
- Group 1B phospholipase A₂ deficiency protects against diet-induced hyperlipidemia in miceNorris 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...
- Phospholipase A(2) enzymes in metabolic and cardiovascular diseasesDavid 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...
- Micromolar changes in lysophosphatidylcholine concentration cause minor effects on mitochondrial permeability but major alterations in functionNorris 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....
- Group 1B phospholipase A₂ inactivation suppresses atherosclerosis and metabolic diseases in LDL receptor-deficient miceNorris I Hollie
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, OH 45237, USA
Atherosclerosis 234:377-80. 2014....
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