Abstract

Current lipid-lowering drugs are often unable to achieve low density lipoprotein cholesterol (LDL-C) goals. Moreover, despite LDL-C lowering mostly by statins, a considerable residual vascular risk remains. This is partly associated with atherogenic dyslipidemia where apolipoprotein (apo) B-containing lipoproteins predominate. Mitochondrial Triglyceride (TG) transfer protein (MTP) is a key enzyme for apoB-containing lipoprotein assembly and secretion. This is mostly attributed to its capacity to transfer lipid components (TGs, cholesterol esters and phospholipids) to the endoplasmic reticulum lumen, where these lipoproteins are assembled. Several agents were developed to inhibit MTP wherever it is expressed, namely the liver and/or the intestine. Liver-specific MTP inhibitors reduce secretion of very low density lipoproteins (VLDL) mostly containing apoB100, while the intestine-specific ones reduce secretion of chylomicrons containing apoB48. These drugs can significantly reduce total cholesterol, LDL-C, TGs, VLDL cholesterol, as well as apoB levels in vivo. They may also exert anti-atherosclerotic and insulin-sensitizing effects. Limited clinical data suggest that these compounds can also improve the serum lipid profile in patients with homozygous familial hypercholesterolemia (HoFH). The accumulation of unsecreted fat in the liver and intestinal lumen is associated with elevation of aminotransferases and steatorrhea. Liver steatosis can be avoided by the use of intestine-specific MTP inhibitors, while steatorrhea by low-fat diet. Future indications for these developing drugs may include dyslipidemia associated with insulin resistant states, familial combined hyperlipidemia and HoFH. Future clinical trials are warranted to assess the efficacy and safety of MTP inhibitors in various clinical states.

Keywords: Mitochondrial transfer protein, cholesterol, cardiovascular disease, fatty liver.