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Regulation of Hepatic Low-Density Lipoprotein Receptor, 3-Hydroxy-3-Methylglutaryl Coenzyme A Reductase, and Cholesterol 7-Hydroxylase mRNAs in Human Liver

Centers for Metabolism and Endocrinology (M.R., B.A., E.R.), Gastroenterology (H.O., C.E.), and Nutrition and Toxicology (M.R., B.A., H.O.), Departments of Medicine (M.R., B.A., C.E.), Clinical Pharmacology (L.S.), Surgery (E.R., H.O.), and Clinical Chemistry (I.B.), Karolinska Institute at Huddinge University Hospital, S-141 86 Stockholm, Sweden; and Department of Surgery (S.S.), Danderyd Hospital, S-182 88 Danderyd, Sweden

Address all correspondence and requests for reprints to: Mats Rudling, M.D., Ph.D., CME, M63, Huddinge University Hospital, S-141 86 Stockholm, Sweden. E-mail: . mats.rudling{at}cnt.ki.se

Abstract

To characterize the coordinate regulation of cholesterol metabolism in human liver, we simultaneously quantified mRNA levels of cholesterol 7-hydroxylase (CYP7A1), 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMGR), and low- density lipoprotein receptors (LDLRs) in liver biopsies from 76 patients undergoing cholecystectomy. The three transcript levels were not different between untreated gallstone and gallstone-free patients and not significantly altered by 10-d exclusion of dietary cholesterol. Treatment with chenodeoxycholic acid suppressed CYP7A1 and to a lesser extent HMGR mRNA levels. Cholestyramine treatment increased CYP7A1, but also HMGR and LDLR mRNA, and statins only increased HMGR mRNA. Resin + statin treatment increased all mRNA species. In untreated patients, the mRNA levels of HMGR and LDLR were more strongly correlated (r = +0.60) than those of CYP7A1 and HMGR (r = +0.49) or CYP7A1 and LDLR (r = +0.21). In the treated patients, in whom bile acid synthesis was suppressed or stimulated, mRNA levels of CYP7A1 and HMGR (r = +0.84) as well as CYP7A1 and LDLR (r = +0.62) were more strongly correlated than those of HMGR and LDLR (r = +0.59). The coordinate control of HMGR and LDLR mRNA levels reflects their common regulation by shared transcriptional activation. In contrast, following changes in bile acid flux through the liver, CYP7A1 gene expression becomes a strong modulator of hepatic cholesterol metabolism.

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