title: Hyperlipidemia, Disease Associations, and Top 10 Potential Drug Targets: A Network View.
abstract: The prevalence of acquired hyperlipidemia has increased due to sedentary life style and lipid-rich diet. In this work, a lipid-protein-protein interaction network (LPPIN) for acquired hyperlipidemia was prepared by incorporating differentially expressed genes in obese fatty liver as seed nodes, protein interactions from PathwayLinker, and lipid interactions from STITCH4.0. Cholesterol, diacylglycreol, phosphatidylinositol-bis-phosphate, and inositol triphosphate were identified as core lipids that influence the signaling pathways in the LPPIN. RACα serine/threonine-protein kinase (AKT1) was a highly essential central protein. The gastrin-CREB pathway was greatly enriched; all enriched pathways in the LPPIN showed crosstalk with the phosphatidylinositol-3-kinase-Akt pathway, correlating with the central role of AKT1 in the network. The disease clusters identified in the LPPIN were cardiovascular disease, cancer, Alzheimer's disease, and Type II diabetes. In this context, we note that the commercially approved drug targets for hyperlipidemia in each disease cluster may potentially be repurposed for treatment of the specific disease. We report here top 10 potential drug targets that may mediate progression from hyperlipidemia to the respective disease state. ToppGene Suite was employed to identify candidates followed by a) discarding high closeness centrality nodes, and b) selecting nodes with high bridging centrality. Three potential targets could be mapped to specific disease clusters in the LPPIN. Lipids associated with acquired hyperlipidemia and each disease cluster identified may be useful as prognostic fingerprints. These findings provide an integrative view of lipid-protein interactions leading to acquired hyperlipidemia and the associated diseases, and might prove useful in future translational pharmaceutical research.
authors.affiliation: Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology , Dwarka, New Delhi, India .
authors.forename: Sneha
authors.initials: S
authors.lastname: Rai
authors.affiliation: Computational and Structural Biology Laboratory, Division of Biotechnology, Netaji Subhas Institute of Technology , Dwarka, New Delhi, India .
authors.forename: Sonika
authors.initials: S
authors.lastname: Bhatnagar
mesh_terms: D000544:Alzheimer Disease / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D053299:Apolipoprotein B-100 / Q000235:genetics / Q000378:metabolism; D002318:Cardiovascular Diseases / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism; D002784:Cholesterol / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000209:etiology / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control*; D004041:Dietary Fats / Q000008:administration & dosage / Q000009:adverse effects / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D018450:Disease Progression; D005786:Gene Expression Regulation; D006801:Humans; D006949:Hyperlipidemias / Q000150:complications / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism; D000960:Hypolipidemic Agents / Q000627:therapeutic use*; D015544:Inositol 1,4,5-Trisphosphate / Q000378:metabolism; D058990:Molecular Targeted Therapy; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism; D000071449:Proprotein Convertase 9 / Q000235:genetics / Q000378:metabolism; D025941:Protein Interaction Mapping; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics* / Q000378:metabolism; D015398:Signal Transduction
chemical_list: D053299:Apolipoprotein B-100; D002352:Carrier Proteins; D004041:Dietary Fats; D004075:Diglycerides; D000960:Hypolipidemic Agents; D047493:PPAR alpha; D018129:Phosphatidylinositol Phosphates; C106092:microsomal triglyceride transfer protein; D015544:Inositol 1,4,5-Trisphosphate; D002784:Cholesterol; C494918:AKT1 protein, human; D051057:Proto-Oncogene Proteins c-akt; C472125:PCSK9 protein, human; D000071449:Proprotein Convertase 9