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

✍ Scribed by Shunlin Ren; Phillip B. Hylemon; Dalila Marques; Emily Gurley; Patricia Bodhan; Elizabeth Hall; Kaye Redford; Gregorio Gil; William M. Pandak M.D.

Publisher: John Wiley and Sons
Year: 2004
Tongue: English
Weight: 886 KB
Volume: 40
Category: Article
ISSN: 0270-9139
DOI: 10.1002/hep.1840400421

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✦ Synopsis

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 ratelimiting step of BAS via this pathway. The objective of this study was to determine the effect of increased StAR on rates of BAS in viva 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 proteidmessenger RNA levels of StAR and CYP7A1 increased dramatically following overexpression. Overexpression of StAR or CYP7A1 led to a similar 2-fold (P < .01) increase in BAS over up-regulated (approximately 2-fold) 3-day chronic biliary-diverted control rats.

Additionally, overexpression of StAR led to more than 3and 6-fold increases over controls in the rates of BAS in biliary-diverted and intact mice, respectively (P < .01). In conclusion, in both rats and mice in vim, overexpression of StAR led to a marked increase in the rates of BAS initiated by delivery of cholesterol to mitochondria containing CYP27A1. (HEPATOLOGY 2004;40:910-917.) holesterol, a structural component of mammalian cell membranes, also serves as a precursor for C bile acids, steroid hormones, and vitamin D.' Under physiological conditions, cholesterol input into the body equals cholesterol output.1.2 In humans, hepatic

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