The microsomal triglyceride (TG) transfer protein (MTP) is a heterodimeric lipid transfer protein that catalyzes the transport of triglyceride, cholesteryl ester, and phosphatidylcholine between membranes. Previous studies showing that the proximal cause of abetalipoproteinemia is an absence of MTP indicate that MTP function is required for the assembly of the apolipoprotein B (apoB) containing plasma lipoproteins, i.e., very low density lipoproteins and chylomicrons. However, the precise role of MTP in lipoprotein assembly is not known. In this study, the role of MTP in lipoprotein assembly is investigated using an inhibitor of MTP-mediated lipid transport, 2-[1-(3, 3-diphenylpropyl)-4-piperidinyl]-2,3-dihydro-lH-isoindol-1-one (BMS-200150). The similarity of the IC50 for inhibition of bovine MTPmediated TG transfer (0.6 ,iM) Genetic studies (1)(2)(3)(4) have demonstrated that an absence of microsomal triglyceride (TG) transfer protein (MTP) causes abetalipoproteinemia, a disease characterized by a defect in the assembly and secretion of apolipoprotein B (apoB) containing plasma lipoproteins. These studies indicate that MTP is required for the production of the apoB containing lipoproteins, very low density lipoproteins and chylomicrons by the liver and intestine. The requirement for MTP for lipoprotein production is further supported by studies using cell lines that are not of hepatic or intestinal origin. When a truncated form of apoB representing 53% of the full-length apoB-100 is expressed in HeLa cells, virtually no apoB is secreted (5). However, when MTP is coexpressed with apoB, apoB is secreted as a lipoprotein particle. Similar findings have been observed in COS cells (6).MTP is found in the lumen of microsomes isolated from liver and intestine (7). The protein purified from bovine liver is a heterodimer consisting of the multifunctional enzyme, protein disulfide isomerase, and a unique, large 97-kDa subunit (8-10). In vitro, MTP A mixture of compound A (62.5 mmol) and Zn dust (438 mmol) in AcOH (250 ml) was heated at reflux for 18 h, cooled to room temperature, filtered through Celite (Aldrich), and concentrated. The residue was dissolved in CH2Cl2 (500 ml), washed with saturated NaHCO3 (2 x 100 ml) and brine (100 ml), dried over MgSO4, and concentrated. The crude product was recrystallized from i-PrOH to yield 2,3-dihydro-2-[1-