A deficiency of microsomal triglyceride transfer protein reduces apolipoprotein B secretion

Microsomal triglyceride transfer protein (MTP) transfers lipids to apolipop rotein B (apoB) within the endoplasmic reticulum, a process that involves d irect interactions between apoB and the large subunit of MTP, Recent studie s with heterozygous MTP knockout mice have suggested that half-normal level s of MTP in the liver reduce apoB secretion. We hypothesized that reduced a poB secretion in the setting of half-normal MTP levels might be caused by a reduced MTP:apoB ratio in the endoplasmic reticulum, which would reduce th e number of apoB-MTP interactions. If this hypothesis were true, half-norma l levels of MTP might have little impact on lipoprotein secretion in the se tting of half-normal levels of apoB synthesis (since the ratio of MTP to ap oB would not be abnormally low) and might cause an exaggerated reduction in lipoprotein secretion in the setting of apoB overexpression (since the MTP apoB ratio would be even lower). To test this hypothesis, we examined the effects of heterozygous MTP deficiency on apoB metabolism in the setting of normal levels of apoB synthesis, half-normal levels of apoB synthesis (het erozygous Apob deficiency), and increased levels of apoB synthesis (transge nic overexpression of human apoB), Contrary to our expectations, half-norma l levels of MTP reduced the plasma apoB100 levels to the same extent (simil ar to 25-35%) at each level of apoB synthesis. In addition, apoB secretion from primary hepatocytes was reduced to a comparable extent at each level o f apoB synthesis. Thus, these results indicate that the concentration of MT P within the endoplasmic reticulum rather than the MTP:apoB ratio is the cr itical determinant of lipoprotein secretion. Finally, we found that heteroz ygosity for an apoB knockout mutation lowered plasma apoB100 levels more th an heterozygosity for am MTP knockout allele, Consistent with that result, hepatic triglyceride accumulation was greater in heterozygous apoB knockout mice than in heterozygous MTP knockout mice.