The liver plays a central role in the regulation of lipoprotein metabolism. It has been shown that cellular catabolism of lipoprotein particles is mediated primarily by a family of lipoprotein receptors, which together constitute the low density lipoprotein receptor (LDLR) gene family The LDLR itself and LDLR-related protein (LRP) are the two endocytic receptors that are highly expressed in hepatocytes. Thus, regulation of the cellular expression of the LDLR and LRP is critical for maintaining an appropriate balance of various lipoprotein particles within the circulation. The high cysteine content of the LDLR and LRP and thus the correct linkage of numerous disulfide bonds within these receptors suggest that correct folding of these receptors within the ER requires the participation of molecular chaperones. Previous studies from our laboratory have shown that a receptor-associated protein (RAP) functions a molecular chaperone/escort protein during the biogenesis of LRP. We hypothesis that RAP functions together with other chaperones/factors to assist the folding and trafficking of both the LDLR and LRP during the biogenesis of these lipoprotein receptors, and that their hepatic expression is regulated by molecular chaperones. Thus, we propose the following specific aims: 1) to examine whether RAO serves as an ER chaperone for the LDLR; 2) to identify other chaperones, factors, and protein modifications that are involved in the folding and biogenesis of the LDLR and LRP; 3) to analyze the effects of LDLR mutations on its folding; and 4) to determine whether misfolded LDLR and LRPO are degraded via the ubiquitin-mediated protein degradation system. The mechanisms thus defined for the biogenesis of the LDLR and LRPO should provide us with certain mutations within these receptors result in their misfolding and/or retention within the ER. These studies may also suggest strategies as to how to modulate the expression and folding of these hepatic receptors for individuals with abnormalities in lipoprotein metabolism.
