Microsomal triglyceride transfer protein is essential for hepatic secretion of apoB-100 and apoB-48 but not triglyceride

Abstract

Despite a complete lack of microsomal triglyceride transfer protein (MTP), L35 rat hepatoma cells secrete triglyceride-containing lipoproteins, albeit at a rate 25% of that of parental FAO hepatoma cells, which express high levels of MTP. The inability to express MTP was associated with a complete block in the secretion of both apolipoprotein (apo)B-100 and apoB-48. Stable expression of a MTP transgene restored the secretion of both apoB-100 and apoB-48 in L35 cells, indicating that MTP is essential for the secretion of both forms of apoB. Treatment with the MTP inhibitor BMS-200150 reduced the secretion of triglyceride by 70% in FAO cells, whereas the inhibitor did not affect the secretion of triglycerides by L35 cells. Thus, in the presence of the MTP inhibitor, both cell types secreted triglycerides at similar rates. Essentially, all of the triglycerides secreted by L35 cells were associated with HDL containing apoA-IV and apoE but devoid of apoB-100 or apoB-48. These results suggest that these triglyceride-containing lipoproteins are assembled and secreted via a pathway that is independent of both apoB and MTP. Our findings support the concept that apoB and MTP co-evolved and provided a means to augment the secretion of triglyceride through the formation of lipoproteins containing large hydrophobic cores enriched with triglycerides. -Hui, T. Y., L. M. Olivier, S. Kang, and R. A. Davis. Microsomal triglyceride transfer protein is essential for hepatic secretion of apoB-100 and apoB-48 but not triglyceride.

The physiological and molecular regulation of lipoprotein assembly and secretion

“…42 Cells lacking MTP can still secrete triglyceride in HDL-like particles, but not to the extent that they would if they packaged triglycerides with full-length apoB to form VLDL. 43 MTP-facilitated translocation, lipidation, and folding of apoB initially produces a nascent HDL-sized particle, which is subsequently modified to form a mature, secretion-competent VLDL in two proposed steps. 44,45 Pulse-chase experiments carried out in the McArdle RH-7777 46,47 or the HepG2 47 hepatoma cell lines show that there is a window of time when lipidation of the particle is sensitive to chemical inhibitors of MTP.…”

A Targeted Peptide Nucleic Acid To Down-Regulate Mouse Microsomal Triglyceride Transfer Protein Expression in Hepatocytes

“…In this study we have explored to the potential of targeted PNA delivery. PNA drugs have been designed against the murine microsomal triglyceride protein (MTP), which is a rate-limiting key enzyme in the assembly of atherogenic apoB100-containing lipoproteins by parenchymal liver cells ( , ). MTP activity was found to correlate with the blood levels of these lipoproteins (), making MTP an excellent target for therapeutic intervention in hyperlipidemia.…”