ROLE OF LIPID-SYNTHESIS, CHAPERONE PROTEINS AND PROTEASOMES IN THE ASSEMBLY AND SECRETION OF APOPROTEIN B-CONTAINING LIPOPROTEINS FROM CULTURED LIVER-CELLS

1. Apolipoprotein B (apoB) is necessary for the assembly and secretion of both chylomicrons from the small intestine and very low-density li poprotreins (VLDL) from the liver, ApoB is also the major protein in l ow-density lipoproteins (LDL) and is the ligand for the LDL receptor, Studies in humans suggest that increased production of apoB-containing lipoproteins, particularly VLDL, is a common abnormality in dyslipida emias. 2. Studies in primary and long-term cultures of hepatocytes and hepatoma cells indicate that a significant proportion of newly synthe sized apoB is rapidly degraded and that this is the major mechanism fo r regulation of apoB secretion, The availability of newly synthesized lipids, particularly triglyceride and cholesteryl ester, appears to be a critical factor in targeting apoB for secretion rather than degrada tion. 3. ApoB is an atypical secretory protein in that cotranslational translocation across the endoplasmic reticulum membrane, a feature of all secretory proteins, seems to slow or stop in the absence of adequ ate lipid availability (or in the absence of microsomal triglyceride t ransfer protein), allowing for rapid degradation of apoB. 4. The degra dation of apoB seems to be facilitated by the association of nascent a poB with the major cytosolic chaperone protein, heat shock protein 70, Additionally, degradation of nascent apoB appears to occur, to a larg e degree, via the proteasomal pathway for degradation of cytosolic pro teins.