Lipoprotein(a) is a highly atherogenic lipoprotein species composed of a molecule of apoliprotein(a) [apo(a)] linked covalently to a molecular of apoB100. Apo(a) is one of the most polymorphic mammalian proteins, existing in over 50 distinct isoforms, each differing in size by virtue of the number of repeats of a kringle-like structure (K-IV) similar to that found in its closest homolog, plasminogen. Both of the protein components of Lp(a) are synthesized and secreted by hepatocytes, although details are lacking concerning the factors which regulate the final assembly of Lp(a). A number of studies have pointed to the existence of an inverse relationship between the size of apo(a), which is determined by the number of K-IV repeats, and its secretion efficiency. There is comparatively little information, however, concerning the mechanisms which may ultimately modulate apo(a) secretion. Accordingly, the broad general objective of this application is to undertake studies aimed at elucidating the mechanisms regulating the intracellular synthesis and secretion of apo(a) by hepatocytes. In particular, the proposed studies will examine the relationship between apo(a) size and intracellular, posttranslation processing. The central hypothesis of these studies, supported by several lines of independent preliminary data, is that larger isoforms of apo(a) are secreted less efficiently as a result of differential rates of retention, mediated through interactions with defined chaperone proteins. We propose that these differential rates of processing from distal elements of the secretory pathway eventually lead to a regulated process of retention and intracellular degradation. We propose to address these issues using transfected hepatoma cells expressing apo(a) minigenes containing different numbers of K-IV repeats and will extend this analysis to an investigation of apo(a) transgenic mice. Understanding the biological properties and heterogeneity of these apo(a) minigenes in both cell culture and in vivo systems will eventually provide important insights into Lp(a) production in human subjects.
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