Feedback regulation of bile acid synthesis in human liver:: Importance of HNF-4α for regulation of CYP7A1

被引:43
作者
Abrahamsson, A [1 ]
Gustafsson, U
Ellis, E
Nilsson, LM
Sahlin, S
Björkhem, I
Einarsson, C
机构
[1] Karolinska Univ, Huddinge Hosp, Karolinska Inst K63, Dept Med,Div Gastroenterol & Hepatol, S-14186 Huddinge, Sweden
[2] Karolinska Inst, Danderyd Hosp, Dept Surg, SE-18288 Danderyd, Sweden
[3] Karolinska Univ, Huddinge Hosp, Karolinska Inst K63, Dept Lab Med,Div Clin Chem, S-14186 Huddinge, Sweden
关键词
bile acid synthesis; cholestyramine; chenodeoxycholic acid; CYP7A1; CYP8B1; HNF-4; alpha; nuclear factors;
D O I
10.1016/j.bbrc.2005.02.170
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
A great number of nuclear factors are involved in the negative feedback mechanism regulating bile acid synthesis. There are two major ways for the negative feedback to effect the synthesis; the SHP-dependent, involving FXR, and the SHP-independent way, affecting HNF-4 alpha. We studied 23 patients with gallstone disease. Eight patients were treated with chenodeoxycholic acid, 7 with cholestyramine prior to operation, and 8 served as controls. Liver biopsies were analyzed with Real-time-PCR. In the cholestyramine-treated group mRNA levels of CYP7Al were increased about 10-fold. Treatment with CDCA decreased the mRNA levels of CYP7Al by about 70%. The mRNA levels of CYP8Bl, CYP27Al, and CYP7Bl were not significantly altered in the treated groups. The analysis of mRNA levels for HNF-4a showed 64% higher levels in the cholestyramine-treated group compared to the controls. These levels showed positive and highly significant correlation to the levels of mRNA of CYP7Al when studied in all three groups together. FXR, SHP, and LRH-1/FTF were not significantly affected by the different treatments. Our results indicate that when bile acid synthesis is upregulated by cholestyramine treatment the SHP-independent pathway for controlling CYP7Al transcription dominates over the SHP-dependent pathway. (c) 2005 Elsevier Inc. All rights reserved.
引用
收藏
页码:395 / 399
页数:5
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