title: Pharmacologic inhibition of phospholipid transfer protein activity reduces apolipoprotein-B secretion from hepatocytes.
abstract: Phospholipid transfer protein (PLTP) plays an important role in atherogenesis, and its function goes well beyond that of transferring phospholipids between lipoprotein particles. Previous studies showed that genetic deficiency of PLTP in mice causes a substantially impaired hepatic secretion of apolipoprotein-B (apoB), the major protein of atherogenic lipoproteins. To understand whether the impaired apoB secretion is a direct result from lack of PLTP activity, in this study, we further investigated the function of PLTP in apoB secretion by using PLTP inhibitors. We identified a series of compounds containing a 3-benzazepine core structure that inhibit PLTP activity. Compound A, the most potent inhibitor, was characterized further and had little cross-reactivity with microsomal triglyceride transfer protein. Compound A reduced apoB secretion in human hepatoma cell lines and mouse primary hepatocytes. Furthermore, we confirmed that the reduction of apoB secretion mediated by compound A is PLTP-dependent, because the PLTP inhibitor had no effect on apoB secretion from PLTP-deficient hepatocytes. These studies provided evidence that PLTP activity regulates apoB secretion and pharmacologic inhibition of PLTP may be a new therapy for dyslipidemia by reducing apoB secretion.
authors.affiliation: Department of Cardiovascular and Metabolic Diseases, Pfizer Global Research Division, Pfizer Inc., Groton, CT 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: Benjamin
authors.initials: B
authors.lastname: Reidich
authors.forename: George
authors.initials: G
authors.lastname: Chang
authors.forename: Mary
authors.initials: M
authors.lastname: Macdougall
authors.forename: Marie-Claire
authors.initials: MC
authors.lastname: Peakman
authors.forename: Xian-Cheng
authors.initials: XC
authors.lastname: Jiang
mesh_terms: D000818:Animals; D001055:Apolipoproteins B / Q000378:metabolism*; D001552:Benzazepines / Q000737:chemistry / Q000494:pharmacology*; D045744:Cell Line, Tumor; D022781:Hepatocytes / Q000187:drug effects* / Q000378:metabolism; D057166:High-Throughput Screening Assays; D006801:Humans; D066298:In Vitro Techniques; D051379:Mice; D018345:Mice, Knockout; D049294:Phospholipid Transfer Proteins / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000235:genetics; D013329:Structure-Activity Relationship
chemical_list: D001055:Apolipoproteins B; D001552:Benzazepines; D049294:Phospholipid Transfer Proteins