Cholesterol and other fats are carried in the bloodstream within lipoprotein particles. These particles distribute these fatty substances to the various tissues under the direction of the apolipoproteins. Our primary interest is to understand both the biosynthesis and the catabolism of the apolipoproteins at the cellular level. We have previously demonstrated that the apolipoproteins are recognized by specific membrane-associated receptors within the human liver. These receptors can effect the removal of apolipoproteins from the extracellular environment and can also affect the synthesis of nascent apolipoproteins. Our studies indicate that the regulation of hepatic apolipoprotein output is primarily posttranslational. We have demonstrated that apolipoproteins A-I and B undergo a variety of posttranslational modifications including glycosylation, phosphorylation, and fatty acid acylation. These prosthetic side chains may play roles in lipoprotein particle assembly and secretion. Studies utilizing tissues from patients with inborn errors of lipoprotein metabolism have been crucial in dissecting the pathophysiologic relevance of these aspects of hepatic apolipoprotein metabolism. We have been utilizing the conceptual framework derived from our basic research of cellular apolipoprotein metabolism to applied research. We evaluate and treat patients with a variety of inborn errors of apolipoprotein and lipid metabolism including familial hypercholesterolemia, cholesteryl ester storage disease, type III hyperlipoproteinemia, abetalipoproteinemia, and hypobetalipoproteinemia. These studies include patients aged 5-70 years, both male and female, and of caucasian, black and hispanic backgrounds. The insights derived from the application of these concepts may have broad implications for the treatment and prevention of cardiovascular disease.
