| Microsomal triglyceride transfer protein (MTP) is an intraluminal protein in the endoplasmic reticulum that is essential for the assembly of apolipoprotein B (apo-B) containing lipoproteins. What makes MTP therapy unique when compared to other lipid management therapies is its ability to affect the production of cholesterol in both the liver and intestine, as shown in the drawings below. 
The use of microsomal triglyceride transfer protein inhibitors (MTPI’s) for decreasing serum lipids including cholesterol and triglycerides as well as the potential use in treating atherosclerosis, obesity and pancreatitis has been studied by various labs throughout the world. The microsomal triglyceride transfer protein catalyzes the transport of triglyceride (TG), cholestery1 ester (CE), and phosphatidylcholine (PC) between small unilamellar vesicles (SUV) (Wetterau & Zilversmit, Chem. Phys. Lipids 38, 205022 (1985)). When transfer rates are expressed as the precent of the donor lipid transferred per time, MTP expresses a distinct preference for neutral lipid transport (TG and CE), relative to phospholipid transport. In vitro, MTP catalyzes the transport of lipid molecules between phospholipid membranes. Presumably, it plays a similar role in vivo, and thus plays some role in lipid metabolism. The subcellular (lumen of the microsomal fraction) and tissue distribution (liver and intestine) of MTP have led to speculation that it plays a role in the assembly of plasma lipoproteins, as these are the sites of plasma lipoprotein assembly. The ability of MTP to catalyze the transport of TG between membranes is consistent with this hypothesis, and suggests that MTP may catalyze the transport of TG from its site of synthesis in the endoplasmic reticulum (ER) membrane to nascent lipoprotein particles within the lumen of the ER. Because of this mechanism of action and its ability to inhibit apo B-containing lipoproteins from both intestinal and hepatic sources, MTP-inhibitors held great promise as a form of monotherapy treatment for lipids that could provide unprecedented reductions in LDL-C as well as TGs. Early trials demonstrated this potential with reductions in LDL-C as much as 86% in one trial. However, these very efficacious doses were also associated with relatively high rates of adverse events. Therefore the current development efforts at Aegerion Pharmaceuticals are focused on “recalibrating” the development of MTP-inhibitors with a focus on doses 1/5th to 1/10th of what had been used in previous development efforts. The overall goal of this development program is to provide clinically significant reductions in LDL-C and TGs, both as monotherapy as well as in combination with other classes of currently marketed lipid-lowering therapies, while minimizing the potential for adverse events.
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