The risk of coronary artery disease (CAD) is positively correlated with the plasma levels of apoprotein B (apoB). ApoB is the major protein component of the lipoprotein particles transporting the bulk of cholesterol and triglycerides from the liver to peripheral tissues, such as the arterial wall. Detailed knowledge of the regulation of hepatic apoB production, therefore, is highly relevant to atherosclerosis, a leading cause of mortality and morbidity in the American population. In contrast to most secretory proteins, hepatic apoB production is controlled not by its rate of synthesis, but by the amount of newly synthesized apoB and the mechanism by which apoB is diverted from the secretory pathway to degradation are not known. To address these issues, the standard in vitro model of human liver lipoprotein metabolism, the HepG2 cell line, has been studies. Fatty acid-deprived HepG2 cells exhibit ER-associated degradation of apoB (ERAD), in which the translocation of the nascent polypeptide across the ER is only partial, resulting in the exposure of apoB domains to the cytosol. The results indicate clearly that the cytosolic structure, the proteasome, degrades apoB in fatty acid-deprived HepG2 cells. In addition, proteasomal degradation involves another cytosolic component, the chaperone Hsp70, which is known to function in the targeting of cellular proteins to degradation. Using approaches from cell and molecular biology, as well as from biophysics, these novel results will be extended to identify the mechanisms of apoB translocation and degradation and the factors regulating these processes. The investigators hope to ultimately develop new strategies to decrease hepatic apoB production and thereby lower the risk of CAD.
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