New approaches to target microsomal triglyceride transfer protein

Abstract

Microsomal triglyceride transfer protein (MTP), a chaperone for the biosynthesis of apolipoprotein B lipoproteins and CD1d, is a therapeutic candidate to decrease plasma lipids and to diminish inflammation. MTP inhibition increases plasma transaminases and tissue lipids, and therefore new approaches are needed to avoid them. Inositol requiring enzyme1beta has been identified as a novel intestine-specific regulator of MTP. A new function of MTP in cholesterol ester biosynthesis has been reported. The importance of the phospholipid transfer activity of MTP in the lipidation of apolipoprotein B and CD1d has been indicated. Diurnal variations in MTP expression and its induction by food availability have been observed. On the basis of these and other findings, we propose that upregulation of inositol requiring enzyme 1beta, a combined reduction of cellular free cholesterol or triglyceride or both and MTP activity, specific inhibition of phospholipid or triglyceride transfer activities, and targeting of apolipoprotein B-MTP protein-protein interactions might be pursued to avoid some of the side effects associated with the inhibition of triglyceride transfer activity of MTP. We further speculate that short-lived MTP antagonists may be useful in controlling plasma and tissue lipids and in avoiding steatosis. We have highlighted the importance of addressing the causal relationship between MTP inhibition and aberrant elevations in plasma liver enzymes. The proposed approaches may show that MTP targeting is a viable approach to lower plasma lipids.