ABSTRACT
Keywords: isotope dilution mass spectrometry, biomarker, cholesterol synthesis, bile acid synthesis, mevalonate, oxysterol
Pathways for Cholesterol and Bile Acid Biosynthesis Cholesterol homeostasis in human is maintained by two input pathways, comprised of dietary absorption and de novo synthesis, and two output pathways, comprised of direct secretion from liver to bile and conversion into bile acids (Everson, 1992). e rate-limiting step in the de novo cholesterol synthesis is the conversion of 3-hydroxy-3-methylglutaryl-CoA (HMG-CoA) into mevalonic acid (MVA) by HMG-CoA reductase (HMGCR) (Dietschy and Brown, 1974). In contrast, the bile acid biosynthetic pathway is initiated by either hepatic 7αhydroxylation or hepatic and extrahepatic 27-hydroxylation of cholesterol. e former is catalyzed by microsomal cholesterol 7α-hydroxylase (CYP7A1), the rst and rate-limiting enzyme in the classic pathway, while the latter is catalyzed by mitochondrial sterol 27-hydroxylase (CYP27A1), a key enzyme in the alternative pathway (Vlahcevic et al. 1992). Bile acid synthesis by the classic pathway accounts for more than 90% of total bile acids in humans (Duane and Javitt, 1999) while less than 50% of total bile acids is produced by this pathway in rats (Vlahcevic et al. 1997) and mice (Schwarz et al. 1996). erefore, the measurement of CYP7A1 activity is more important than that of CYP27A1 activity for the evaluation of bile acid biosynthesis in humans.
