Evaluation of cellular lipoprotein and apolipoprotein metabolism is the primary focus of this laboratory. Utilizing a variety of human cell lines in tissue culture, the ability of lipoproteins to induce delivery and egress of membrane lipids as well as the modulation of intracellular cholesterol biosynthesis and esterification has been evaluated in normal human subjects as well as in patients with a variety of inborn errors of lipoprotein, apolipoprotein, and cellular lipid metabolism. Our previous investigations of receptors for low density lipoproteins and high density lipoproteins and the intracellular enzymes acid cholesteryl ester hydrolase, neutral cholesteryl ester hydrolase, acyl:cholesteroacyltransferase, and 3-hydroxy-3-methylglutaryl coenzyme A reductase have been extended from studies conducted upon isolated cellular membranes to intact human hepatocytes and to the human hepatoma cell line Hep G2. In addition, the regulation of nascent apolipoprotein biosynthesis has been studied. Human hepatocytes regulate the secretion of lipoproteins containing apolipoprotein A-I and apolipoprotein B. The hepatic receptors for high density lipoproteins, low density lipoproteins and chylomicron remnants can alter both the level of mRNA expression for apolipoprotein A-I and apolipoprotein B as well as the secretion of newly synthesized apolipoproteins. These nascent apolipoproteins undergo a variety of post-translational modifications and we have determined that in addition to proteolytic processing, glycosylation, and deamidation, human apolipoproteins undergo covalent fatty acid acylation. The inborn errors of metabolism abetalipoproteinemia, cholesteryl ester storage disease, and familial hypercholesterolemia all have defective hepatic apolipoprotein metabolism at different points in apolipoprotein catabolism and synthesis. These insights into nascent apolipoprotein synthesis complement ongoing clinical trials in our Branch designed to modify apolipoprotein synthesis and secretion.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Intramural Research (Z01)
Project #
1Z01HL002022-06
Application #
3966609
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
6
Fiscal Year
1986
Total Cost
Indirect Cost
Name
U.S. National Heart Lung and Blood Inst
Department
Type
DUNS #
City
State
Country
United States
Zip Code