Overexpression of cholesterol transporter StAR increases in vivo rates of bile acid synthesis in the rat and mouse

Bile acid synthesis (BAS) occurs mainly via two pathways: the "neutral" pathway, which is initiated by highly regulated microsomal CYP7A1, and an "acidic" pathway, which is initiated by mitochondrial CYP27A1. Previously, we have shown that overexpression of the steroidogenic acute regulatory protein (StAR), a mitochondrial cholesterol transport protein, increases bile acid biosynthesis more than 5-fold via the acidic pathway in primary rat hepatocytes. This observation suggests that mitochondrial cholesterol transport is the rate-limiting step of BAS via this pathway. The objective of this study was to determine the effect of increased StAR on rates of BAS in vivo. Overexpression of StAR and CYP7A1 were mediated via infection with recombinant adenoviruses. BAS rates were determined in chronic biliary-diverted rats and mice, and in mice with an intact enterohepatic circulation. The protein/messenger RNA levels of StAR and CYP7A1 increased dramatically following overexpression. Overexpression of StAR or CYP7A1 led to a similar 2-fold (P