Analysis of the role of microsomal triglyceride transfer protein in the liver of tissue-specific knockout mice

A deficiency in microsomal triglyceride transfer protein (MTP) causes the h uman lipoprotein deficiency syndrome abetalipoproteinemia. However, the rol e of MTP in the assembly and secretion of VLDL in the liver is not precisel y understood. It is not clear, for instance, whether MTP is required to mov e the bulk of triglycerides into the lumen of the endoplasmic reticulum (ER ) during the assembly of VLDL particles. To define MTP's role in hepatic li poprotein assembly, we recently knocked out the mouse MTP gene (Mttp). Unfo rtunately, achieving our objective was thwarted by a lethal embryonic pheno type. In this study, we produced mice harboring a "floxed" Mttp allele and then used Cre-mediated recombination to generate liver-specific Mttp knocko ut mice. Inactivating the Mttp gene in the liver caused a striking reductio n in VLDL triglycerides and large reductions in both VLDL/LDL and HDL chole sterol levels. The Mttp inactivation lowered apo B-100 levels in the plasma by >95% but reduced plasma apo B-48 levels by only similar to 20%. Histolo gic studies in liver-specific knockout mice revealed moderate hepatic steat osis. Ultrastructural studies of wild-type mouse livers revealed numerous V LDL-sized lipid-staining particles within membrane-bound compartments of th e secretory pathway (ER and Golgi apparatus) and few cytosolic lipid drople ts. In contrast, VLDL-sized lipid staining particles were not observed in M TP-deficient hepatocytes, either in the ER or in the Golgi apparatus, and t here were numerous cytosolic fat droplets. We conclude that MTP is essentia l for transferring the bulk of triglycerides into the lumen of the ER for V LDL assembly and is required for the secretion of apo B-100 from the liver.