Cholesterol homeostasis is maintained through coordinate regulation of cholesterol uptake, esterification, synthesis, secretion, and its degradation to bile acids account for approximately half of daily net cholesterol elimination, while remaining 50% takes place almost entirely via biliary cholesterol secretion. Bile acid synthesis from cholesterol occurs via two pathways. The initial/rate-determining enzyme in the major """"""""neural"""""""" pathway of bile acid biosynthesis is microsomal cholesterol 7alpha-hydroxylase (C7alphaH. The """"""""acidic"""""""" pathway of bile acid synthesis is initiated by sterol 27-hydroxylase (S27H). Whereas C7alphaH is present almost exclusively in the liver, S27H is also present in many extrahepatic tissues, where its function remains unclear. The overall objective of the proposed studies is to better define the physiologic role of these key enzymes in the maintenance of hepatic and total body cholesterol homeostasis. More specifically, we propose a systematic series of in vivo and in vitro studies, in both liver and non-liver cells, using recombinant adenovirus to deliver CMV driven genes encoding C7alphaH and S27H. These studies attempt to combine the techniques of molecular biology with recombinant adenoviral gene transfer to determine the kinetic and molecular changes in the pathways of cholesterol homeostasis which follow selective over expression of the genes encoding C7alphaH and S27H . A clearer understanding of the mechanisms which maintain cholesterol homeostasis is needed to continue to lay the groundwork for the development of better therapies for cholesterol related disorders.
| Hall, E; Hylemon, P; Vlahcevic, Z et al. (2001) Overexpression of CYP27 in hepatic and extrahepatic cells: role in the regulation of cholesterol homeostasis. Am J Physiol Gastrointest Liver Physiol 281:G293-301 |
