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Heterogeneous expression of cholesterol 7α-hydroxylase and sterol 27- hydroxylase genes in the rat liver lobulus

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Author: Twisk, J. · Hoekman, M.F.M. · Mager, W.H. · Moorman, A.F.M. · Boer, P.A.J. de · Scheja, L. · Princen, H.M.G. · Gebhardt, R.
Institution: Instituut voor Verouderings- en Vaatziekten Onderzoek TNO
Source:Journal of Clinical Investigation, 3, 95, 1235-1243
Identifier: 232865
Keywords: Health · 3 hydroxy 3 methylglutaryl coenzyme a · alanine aminotransferase · cholesterol 7alpha monooxygenase · colestipol · glutamate ammonia ligase · glyceraldehyde 3 phosphate dehydrogenase · messenger rna · pyruvate kinase · sterol 27 hydroxylase · unclassified drug · animal cell · animal experiment · bile acid synthesis · controlled study · enterohepatic circulation · enzyme isolation · enzyme localization · gene expression · in situ hybridization · liver metabolism · sterol analysis · Animal · Biological Markers · Blotting, Northern · Cell Separation · Cholesterol 7-alpha-Hydroxylase · Colestipol · Cytochrome P-450 Enzyme System · Gene Expression Regulation, Enzymologic · In Situ Hybridization · Liver · Male · Rats · Rats, Sprague-Dawley · RNA, Messenger · Steroid Hydroxylases · Support, Non-U.S. Gov't · Tissue Distribution · Transcription, Genetic


We investigated the lobular localization and molecular level of expression of cholesterol 7α-hydroxylase and sterol 27-hydroxylase, two key enzymes in bile acid synthesis, in isolated periportal and pericentral hepatocytes and by in situ hybridization of rat liver. Enzyme activity, mRNA, and gene transcription of cholesterol 7α-hydroxylase were predominant in pericentral hepatocytes of control rats, being 7.9-, 9.9-, and 4.4-fold higher than in periportal hepatocytes, respectively. Similar localization was found for sterol 27-hydroxylase: 2.9-, 2.5-, and 1.7-fold higher enzyme activity, mRNA, and gene transcription, respectively, was found in pericentral hepatocytes. Interruption of 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 levels and gene transcription of 3-hydroxy-3-methylglutaryl CoA reductase showed opposite lobular distribution. Selective periportal expression for the latter was enhanced, but remained local, after colestid treatment. In situ hybridization showed unambiguously that cholesterol 7α-hydroxylase mRNA is localized exclusively in the pericentral zone and that sterol 27-hydroxylase mRNA is expressed preferentially in the pericentral region, though less pronounced. Administration of colestid led to expression of both genes within a larger area of the liver lobulus. In conclusion, we suggest that cholesterol 7α-hydroxylase and sterol 27-hydroxylase are coordinately regulated by the bile acid gradient over the lobulus, resulting in predominant expression in the pericentral zone. Opposite lobular localization of cholesterol and bile acid synthesis provides an alternative view to interregulation of these metabolic pathways. Chemicals/CAS: 3 hydroxy 3 methylglutaryl coenzyme A, 1553-55-5; alanine aminotransferase, 9000-86-6, 9014-30-6; cholesterol 7alpha monooxygenase, 9037-53-0; colestipol, 25085-17-0, 37296-80-3, 50925-79-6; glutamate ammonia ligase, 9023-70-5; glyceraldehyde 3 phosphate dehydrogenase, 9001-50-7; pyruvate kinase, 9001-59-6; sterol 27 hydroxylase, 134712-57-5; Biological Markers; Cholesterol 7-alpha-Hydroxylase, EC; Colestipol, 50925-79-6; Cytochrome P-450 Enzyme System, 9035-51-2; cytochrome P-450C27/25, EC 1.14.-; RNA, Messenger; Steroid Hydroxylases, EC 1.14.-