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A more recent version of this article appeared on May 1, 2003

Papers In Press, published online ahead of print February 16, 2003
J. Lipid Res., doi:10.1194/jlr.M300020-JLR200
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Submitted on January 14, 2003
Revised on February 14, 2003
Accepted on February 14, 2003

Blocking microsomal triglyceride transfer protein Interferes with apolipoprotein B secretion Without causing retention or stress in the endoplasmic reticulum

Wei Liao, To Y. Hui, Stephen G. Young, and Roger A. Davis

Biology Dept., San Diego State University, San Diego, CA 92182

Corresponding Author: rdavis{at}sunstroke.sdsu.edu

Microsomal triglyceride transfer protein (MTP) is an intraluminal protein in the endoplasmic reticulum (ER) that is essential for the assembly of apoB-containing lipoproteins. In this study, we examine how the livers of mice respond to two distinct methods of blocking MTP function: Cre-mediated disruption of the gene for MTP and chemical inhibition of MTP activity. Blocking MTP significantly reduced plasma levels of triglycerides, cholesterol, and apoB-containing lipoproteins in both wild-type C57BL/6 and low density lipoprotein receptor–deficient mice. While treating low density lipoprotein receptor–deficient mice with a MTP inhibitor for 7 days lowered plasma lipids to control levels, liver triglyceride levels were increased by only 4-fold. Plasma levels of apoB100 and apoB48 fell by >90% and 65%, respectively, but neither apoB isoform accumulated in hepatic microsomes. Surprisingly, loss of MTP expression was associated with a nearly complete absence of apoB100 in hepatic microsomes. Levels of microsomal luminal chaperone proteins (e.g., PDI, GRP78 and GRP94) and cytosolic heat shock proteins (e.g., HSP60, HSC, HSP70 and HSP90) were unaffected by MTP inhibition. These findings show that the liver responds rapidly to inhibition of MTP by degrading apoB and preventing its accumulation in the endoplasmic reticulum. The rapid degradation of secretion-incompetent apoB in the endoplasmic reticulum may block the induction of proteins associated with unfolded protein and heat-shock responses.


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