Physicians' Academy for Cardiovascular Education

MTP inhibitors

News - Mar. 24, 2011

MTP inhibitors

MTP is an endosomal protein present in hepatocytes and intestinal enterocytes. MTP catalyses the assembly of cholesterol, triglycerides, and apo B to VLDL, or chylomicrons.

Microsomal triglyceride transfer protein Inhibitors (MTP-I) represent a new class of cholesterol and triglyceride lowering agents with the ability to affect the production of lipoproteins in both the liver and intestine.



Mechanism of Action

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.

Microsomal triglyceride transfer protein (MTP) is an intracellular lipid-transfer protein found in the lumen of the endoplasmic reticulum that is responsible for binding and shuttling individual lipid molecules between membranes. Normal concentrations and function of MTP are necessary in the liver and intestine for the proper assembly and secretion of lipoproteins that contain apolipoprotein B (apoB). MTP is responsible for transferring triglycerides (TG) onto apo-B in the assembly of very-low-density lipoprotein (VLDL), the precursor to low density lipoprotein (LDL). MTP binds and shuttles individual lipid molecules from the site of lipid synthesis to the emerging apo-B molecule. If insufficient lipid is transferred, the emerging apo-B is destroyed and lipoprotein secretion is inhibited. Inhibition of MTP activity prevents both hepatic VLDL and intestinal chylomicron secretion, and consequently lowers plasma lipids. This means that compounds that inhibit MTP may have the ability to profoundly reduce serum levels of both cholesterol and TG

MTP is an endosomal protein present in hepatocytes and intestinal enterocytes. MTP catalyzes the assembly of cholesterol, triglycerides, and apo B to VLDL or chylomicrons (Fig. 1 and Fig. 2). A subset of patients with abetalipoproteinemia, a rare recessive genetic disorder, has dysfunctional MTP, resulting in a complete lack of apo B–containing lipoproteins in the circulation. This observation suggests that MTP inhibition may have LDL-C–lowering potential. MTP inhibition impedes the hepatic secretion of VLDL and the intestinal secretion of chylomicrons. The risk associated with MTP inhibition is accumulation of triglycerides in the liver. This concept is supported by fi ndings in patients with familial hypobetalipoproteinemia (FHBL). FHBL is an inherited disorder caused by truncations of the apo B protein that cannot be secreted by the liver. Patients with FHBL have an increased risk for developing hepatic steatosis; nevertheless, they seem to be protected against atherosclerotic disease [50]. FHBL’s clinical features are comparable to those associated with MTP inhibition. Several MTP inhibitors have been studied in animal experiments and clinical trials.

The MTP inhibitor implitapide (BAY 13-9952) has been shown to lower plasma total cholesterol and triglyceride levels, to suppress atherosclerotic plaque development, and to increase survival time in apo E knockout mice [51]. BAY 13-9952 also reduced fatty streak formation in rabbits fed a 0.5% cholesterol-enriched diet for 3 months [52]. In a clinical study, BAY 13-9952 was administered to healthy volunteers for 4 weeks. Preliminary results showed a decrease in total cholesterol, LDL-C, and triglycerides by 45%, 55%, and 29%, respectively, and a reduction in postprandial lipemia [53,54]. Adverse events
that were reported included gastrointestinal disturbances and liver function abnormalities. Another MTP inhibitor, CP 346086, tested in healthy volunteers for 2 weeks resulted in a 47% decrease in total cholesterol, 72% decrease in LDL-C, and a 75% decrease in triglyceride levels, compared with individual baselines or placebo [55]. Administering CP-346086 separately from meals decreased gastrointestinal adverse events. AEGR-733 (BMS-201038) is another potent inhibitor of the MTP. AEGR-733 was administered to patients with homozygous familial hypercholesterolemia using a dose titration scheme for 4 months [56•]. This resulted in reduced LDL-C levels of 51% from baseline at the highest dose. However, AEGR-733 therapy was associated with elevated liver aminotransferase levels and hepatic fat accumulation. In contrast, administering JTT-130 (another MTP inhibitor) to guinea pigs resulted in a 25% reduction of LDL-C and a 30% reduction of triglycerides compared with controls; however, it did not induce hepatic lipid accumulation [57]. JTT-130 is currently being evaluated in phase 2 trials to assess its potential for treating hyperlipidemia.

Overall, MTP inhibitors have been demonstrated to be promising new compounds, but the potential for inducing hepatic lipid accumulation needs further evaluation before assessing its role in lipid-lowering strategies. Enterocyte-selective MTP inhibitors that are not systematically absorbed have also been developed, circumventing MTP inhibitors’ hepatic side effects. For instance, SLx-4090, a small-molecule inhibitor, acts selectively on the enterocytes where it prevents chylomicron formation. Because it is not absorbed into the systemic circulation, toxicity at other sites of MTP expression is prevented. Two phase 1 clinical studies demonstrated that SLx-4090 was well tolerated and signifi cantly lowered postprandial triglyceride levels. A randomized, double-blind, placebo-controlled, phase 2 study in 24 patients with dyslipidemia resulted in clinically significant reductions in postprandial triglycerides and LDL-C. The compound was undetectable in the plasma, and no liver function abnormalities were observed [58]. Enterocyte-selective MTP inhibitors are likely to be effective in lowering chylomicrons, but the question remains whether they sufficiently lower LDL-C and are well tolerated in humans.

MTP inhibition

Teaching slides on the Apolipoprotein B Pathway

MTP is an endosomal protein present in hepatocytes and intestinal enterocytes. MTP catalyses the assembly of cholesterol, triglycerides, and apo B to VLDL, or chylomicrons.

Please view this educational slide kit for an update of the potential role of MTP inhibitors in lipd management

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