The central theme of this proposal is to examine the events linking cellular lipid flux to the regulated expression of the major chylomicron apoproteins (A-I, A-IV and B), in-vivo, in liver and intestine. Studies conducted by the investigator have determined that the regulation of intestinal apoprotein synthesis appears to be differentiated into triglyceride-dependent and biliary lipid-dependent mechanisms. There is evidence that each of the major chylomicron apoproteins is regulated independently. The studies will expand upon these observations and extend them to similar studies in the liver. Studies will determine the role of bile salt, phospholipid and cholesterol flux as specific mediators of intestinal apoB expression. The role of triglyceride flux in stimulating jejunal apoA-IV synthesis will be investigated to determine whether a coordinated increase occurs in microvillus membrane and cytosolic fatty acid binding protein (FABP) expression. Studies will also be undertaken using human and rat enterocyte cell-lines. Studies will determine the regulation of hepatic apoB synthesis following perturbations of bile salt and cholesterol flux. Studies will also examine the role of hepatic LDL uptake, using both hamster and rat models. Finally, studies will examine the regulation of apoB synthesis and secretion in Hep G-2 cells by sterol and bile salt flux. Measurements of apoprotein synthesis in-vivo will be complemented by parallel quantitation of mRNA abundance for apoA-I, A-IV, hepatic FABP and intestinal FABP, using cDNA clones to these peptides. These studies should provide detailed understanding of the regulation of intestinal and hepatic apoprotein biosynthesis by specific aspects of cellular lipid flux.
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