Regulation of the translocation, degradation and secretion of apolipoprotein B.

摘要

Apolipoprotein (apo) B is the major protein component required for the secretion of hepatic very low density lipoprotein (VLDL) particles and intestinal chylomicrons. The plasma level of apo B-containing lipoproteins correlates with the incidence of atherosclerotic vascular disease. Excessive VLDL secretion by the liver can cause familial hypertriglyceridemia and familial combined hyperlipidemia, two of the most common causes of premature atherosclerosis. This work examined the regulation of VLDL secretion by focusing on its two regulatory steps: apo B translocation across the endoplasmic reticulum and its intracellular degradation. Using somatic cell genetic approach, the individual processes involved in apo B translocation and degradation were examined. Apo B translocation-arrest was found to occur in CHO cells, human hepatoma HepG2 cells and in human hepatocytes. Loss of functional microsomal triglyceride transfer protein (MTP) in human genetic disease abetalipoproteinemia resulted in incomplete apo B translocation across the endoplasmic reticulum and its subsequent degradation in the cell. MTP is an ER lumenal protein whose function is to transfer lipids to nascent lipoprotein particles and is required for apoB-containing lipoprotein secretion. Examining the regulation of apo B degradation, translocation-arrested apo B was found to be degraded by the ubiquitin-proteasome proteolytic system, which can be modulated by sterol metabolism through the expression of liver-specific enzyme cholesterol 7