The theme of this proposal is to continue investigation into the molecular basis for regulatory events involving complex lipid reassembly nad apolipoprotein gene expression. The main focus will be studies involving lipoprotein assembly in the intestine while additional studies will extend, in certain instances, to a characterization of suitable model systems in the liver. Studies will address the molecular basis for apo B gene processing in both intestine and liver. Recent work has established that this gene undergoes a unique co- or posttranscriptional modification which results in a single base change in the mRNA, but not the gene. The proposal seeks to characterize the molecular basis and physiologic consequences of apo B mRNA modification and studies are proposed involving models of both developmentally nad hormonally regulated apo B gene expression. Other studies will address the role of cellular lipid flux in mediating the independent regulation of intestinal apolipoprotein gene expression. These studies will specifically establish whether the regulation of intestinal apo A-IV gene expression by acute triglyceride flux involves genes which coordinate the vectorial delivery of fatty acid into chylomicron triglyceride. A final group of studies will extend many of the previous observations concerning intestinal apolipoprotein biosynthesis into an investigation of hepatic apolipoprotein gene expression. Of particular interest will be the influence of alterations in enterohepatic bile salt and cholesterol flux since these manipulations have each been demonstrated to modulate intestinal apolipoprotein gene expression in a manner which is distinct for each of the apolipoprotein genes. Taken together, these studies should provide fundamental information concerning the molecular and cell biology of lipoprotein biogenesis.
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