title: Identification and characterization of dual inhibitors for phospholipid transfer protein and microsomal triglyceride transfer protein.
abstract: Phospholipid transfer protein (PLTP) plays an important role in atherogenesis and lipoprotein metabolism. PLTP exerts its functions intracellularly and extracellularly. Both PLTP and microsomal triglyceride transfer protein (MTP) have been shown to regulate the secretion of apolipoprotein B (apoB) in hepatocytes. We have previously reported the characterization of inhibitors that selectively inhibit PLTP activity and reduce apoB secretion in hepatocytes. In the present study, we identified more compounds that inhibit both PLTP and MTP activity to various extents. These dual inhibitors are structurally different from the PLTP-selective inhibitors. In human hepatoma cell lines, dual inhibitors seem to be more effective in reducing apoB secretion than selective PLTP or MTP inhibitors. Furthermore, the dual inhibitors markedly reduced triglyceride secretion from hepatocytes. In the absence of PLTP, the dual inhibitors can further reduce apoB secretion, whereas selective PLTP inhibitors had no effect. We conclude that MTP and PLTP may work coordinately in the process of hepatic apoB assembly and secretion. To avoid liver toxicity mediated by MTP inhibition, selective PLTP inhibitors should be pursued.
authors.affiliation: Department of Cardiovascular Metabolic and Endocrine Disease, Pfizer Global Research Division, Pfizer Inc, Groton,Connecticut 06340, USA. yi.luo@pfizer.com
authors.forename: Yi
authors.initials: Y
authors.lastname: Luo
authors.forename: Lorraine
authors.initials: L
authors.lastname: Shelly
authors.forename: Thomas
authors.initials: T
authors.lastname: Sand
authors.forename: George
authors.initials: G
authors.lastname: Chang
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D000818:Animals; D053299:Apolipoprotein B-100 / Q000378:metabolism; D053283:Apolipoprotein B-48 / Q000378:metabolism; D001055:Apolipoproteins B / Q000378:metabolism; D002352:Carrier Proteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D045744:Cell Line, Tumor; D004353:Drug Evaluation, Preclinical; D022781:Hepatocytes / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D000960:Hypolipidemic Agents / Q000737:chemistry / Q000493:pharmacokinetics*; D053440:Lipoproteins, HDL3 / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D015394:Molecular Structure; D010713:Phosphatidylcholines / Q000378:metabolism; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000378:metabolism; D011994:Recombinant Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D014280:Triglycerides / Q000378:metabolism; D014304:Triolein / Q000378:metabolism
chemical_list: D053299:Apolipoprotein B-100; D053283:Apolipoprotein B-48; D001055:Apolipoproteins B; D002352:Carrier Proteins; D000960:Hypolipidemic Agents; D053440:Lipoproteins, HDL3; D008081:Liposomes; C493430:PLTP protein, human; D010713:Phosphatidylcholines; D049294:Phospholipid Transfer Proteins; D011994:Recombinant Proteins; D014280:Triglycerides; C106092:microsomal triglyceride transfer protein; C510091:phospholipid transfer protein, mouse; D014304:Triolein
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