HEPATIC CLEARANCE OF APOLIPOPROTEIN B

载脂蛋白 B 的肝脏清除率

• 批准号: 3340889
• 负责人: CHARLES Edward SPARKS
• 金额: $ 9.56万
• 依托单位: UNIVERSITY OF ROCHESTER
• 依托单位国家: 美国
• 财政年份: 1983
• 资助国家: 美国
• 起止时间: 1983-04-01 至 1986-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3340889
• 关键词: apolipoproteins; cholesterol; cholesterol esters; cholestyramine; density gradient ultracentrifugation; dietary carbohydrates; dietary lipid; electrofocusing; electron microscopy; estrogens; fasting; gel electrophoresis; gel filtration chromatography; hormone regulation /control mechanism; isolation perfusion; liver metabolism; molecular rearrangement; nephrosis; nutrition related tag; phospholipids; radiotracer; thin layer chromatography; triglycerides

Work in my laboratory first directly demonstrated the rapid hepatic clearance of apolipoprotein B of lower molecular weight (apo B1) from rat plasma compared to apolipoprotein B of higher molecular weight (apo Bh). The use of SDS-gel filtration column chromatography enabled a direct comparison of apo B1 label in whole serum to liver homogenates, allowing a direct calculation of hepatic apo B1 clearance rates. In rats apo B1 represents a secretory protein of liver and intestine as opposed to apo Bh which is an hepatic secretory protein. Apo Bh containing secretory lipoproteins (Lps) undergo progressive delipidation and eventually apo Bh constitutes the major apo B protein of LDL. Recent experiments described in this proposed provide an explanation. The liver has a binding site for apo B1 enriched Lps which allows discrimination from apo Bh containing Lps. Hepatic recognition requires prior lipase interaction with Lps. Once bound the apo B1 enriched Lps are internalized and degraded. The apo Bh-Lps remain in the plasma in LDL with a slow catabolic rate. I propose studies using isolated liver perfusion to characterize the apo B1 hepatic binding site. These experiments will involve study of characterized Lp particles which vary in apoprotein composition. Using apo B1-Lps the binding site will be characterized in terms of affinity, saturation, turnover, apoprotein specificity and lysosomal interaction. A calculation of receptor number will be made and it will be determined whether dietary or metabolic state alters the number. Using particles of mixed composition, favorable apoprotein composition for hepatic clearance of Lps will be determined with particular interest in the role of surface protein (apo C, apo E and apo A-1) on binding of apo B1-Lps. Considering the evidence that apo E may mediate Lp interaction with liver, a reasonable hypothesis is that apo E increases the hepatic sinusoidal concentration of Lps for action as a substrate for sinusoidal lipases. Apo B1 recognition may occur only following lipase modification and apo B1 hepatic clearance would, therefore, be facilitated by apo E present on the Lp. Particle composition of apo B1-Lps is seen as critical to their eventual hepatic catabolism. These studies assume importance because of the relationship of apo B-Lps, especially IDL and LDL, in development and progression of human atherosclerosis.

我实验室的工作首先直接证明了肝细胞的快速生长