HETEROGENEOUS EXPRESSION OF CHOLESTEROL 7-ALPHA-HYDROXYLASE AND STEROL 27-HYDROXYLASE GENES IN THE RAT LIVER LOBULUS

We investigated the lobular localization and molecular level of expres sion of cholesterol 7 alpha-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and perice ntral hepatocytes and by in situ hybridization of rat liver. Enzyme ac tivity, mRNA, and gene transcription of cholesterol 7 alpha-hydroxylas e were predominant in pericentral hepatocytes of control rats, being 7 .9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respect ively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcripti on, respectively, was found in pericentral hepatocytes. Interruption o f the enterohepatic circulation with colestid resulted in upregulation of these parameters for both enzymes, as a consequence of stimulated gene expression mainly in the periportal zone. In contrast, mRNA level s and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase s howed opposite lobular distribution. Selective periportal expression f or the latter was enhanced, but remained local, after colestid treatme nt. In situ hybridization showed unambiguously that cholesterol 7 alph a-hydroxylase mRNA is localized exclusively in the pericentral zone an d that sterol 27-hydroxylase mRNA is expressed preferentially in the p ericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobu lus. In conclusion, we suggest that cholesterol 7 alpha-hydroxylase an d sterol 27-hydroxylase are coordinately regulated by the bile acid gr adient over the lobulus, resulting in predominant expression in the pe ricentral zone. Opposite lobular localization of cholesterol and bile acid synthesis provides an alternative view to interregulation of thes e metabolic pathways.