Apo B variant composition of triglyceride-rich lipoproteins (TRL) has an influence on the catabolic fate of the lipoprotein (Lp) particle. Although differences in apo BH (higher Mr apo B) and apo BL (lower Mr apo B) metabolism have been reported, reasons for the heterogeneity remain to be explored. Receptor-mediated Lp removal has been studied extensively and recent evidence suggests that apo BL does not interact with the chylomicron (CM) remnant receptor pathway in the liver. Thus, reasons for heterogenous apo B metabolism probably occur prior to receptor events and are a property of particles. Rats, in contrast to rabbits and humans, have both apo B variants in hepatically synthesized TRL. TRL modification by lipases (lipoprotein lipase and/or hepatic lipase) is necessary before preferential hepatic apo BL clearance is observed. Other factors which determine Lp clearance include apo C composition, apo CIII:CII ratio, apo E content, triglyceride vs. cholesterol ester content, physical size, and metabolic state. What is not known is how these events alter Lp structure in a way as to affect the subsequent catabolic fate of the Lp. The hypothesis to be tested is that observed heterogeneous metabolism of apo B-containing Lps relates to apo B expression which in turn is influenced by particle lipid and apoprotein composition. Study of hepatic clearance of Lp apo B is proposed stressing pre-receptor events (synthetic and lipolytic) which alter Lp composition. Favorable apoprotein composition for hepatic clearance of Lps will be determined and will be related to hepatic clearance pathways. We have developed monoclonal antibodies (mAbs) to rat apoproteins which will be used to isolate subpopulations of Lps of unique epitope composition for catabolic studies. Other mAbs will also be used in sensitive immunoassays for conformational epitopes present on Lps to allow development of two site assays in order to determine other apo B epitopes and apoprotein epitopes present on particles. Proposed experiments will continue studies of apo B turnover in vivo and in liver perfusion. Models of altered metabolic circumstances will include the streptozotocin diabetic, PAN-nephrotic and cholesterol-fed rat and we will extend catabolic studies to primary rat and rabbit hepatocyte cultures. Particle composition of apo B Lps is seen as critical to hepatic clearance. Studies assume importance considering the relationship of apo B-Lps as positive risk factors in atherogenesis.
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