The many intersecting pathways underlying apolipoprotein B secretion and degradation

Abstract

Because the levels of secreted apolipoprotein B (apoB) directly correlate with circulating serum cholesterol levels, there is a pressing need to define how the biosynthesis of this protein is regulated. Most commonly, the concentration of a secreted, circulating protein corresponds to transcriptionally and/or translationally regulated events. By contrast, circulating apoB levels are controlled by degradative pathways in the cell that select the protein for disposal. This article summarizes recent findings on two apoB disposal pathways, endoplasmic reticulum (ER)-associated degradation and autophagy, and describes a role for post-ER degradation in the increased circulating lipid levels in insulin-resistant diabetics.

Figure 1

Schematic summary of apoB secretory regulation. ApoB is initially synthesized on ER membrane-bound ribosomes. (a) With adequate lipid ligands, apoB is translocated into the ER where it is folded and stabilized in the proper conformation. Primordial VLDL particles are formed (pre-VLDL) and transported to the Golgi apparatus in COPII vesicles. Insulin promotes a post-ER transfer of apoB-lipoproteins to a nonproteasomal degradation process, possibly autophagy [86], either before or after entry into the Golgi. When polyunsaturated fatty acids (PUFA) comprise a critical complement of lipid species associated with apoB lipoproteins, lipid peroxides are produced that damage and cross-link apoB, most likely in the Golgi as part of the VLDL maturation process. Eventually, aggregates are formed that are degraded by autophagy. At subcritical PUFA levels, VLDL matures normally and is secreted. With insufficient lipid ligands (b), nascent apoB translocation into the ER lumen is inefficient and domains of apoB are exposed to the cytosol where the particle is selected by chaperones for ERAD. The ubiquitin E3-ligase gp78 attaches poly-ubiquitin, and the protein is degraded by the proteasome.