Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4alpha.
Hepatocyte nuclear factor 4alpha (HNF4alpha) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4alpha (HNF4alphaDeltaL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4alpha-floxed (HNF4alphaF/F) mice. The expression of genes involved in the hydroxylation and side chain beta-oxidation of cholesterol, including oxysterol 7alpha-hydroxylase, sterol 12alpha-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4alphaDeltaL mice. Cholesterol 7alpha-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4alphaDeltaL mice, whereas expression in the light cycle was not different between HNF4alphaDeltaL and HNF4alphaF/F mice. Because CYP8B1 expression was reduced in HNF4alphaDeltaL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4alphaDeltaL mice. An HNF4alpha binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4alpha-dependent transcription. Surprisingly, cholic acid-derived BAs, produced as a result of CYP8B1 activity, were still observed in the serum and gallbladder of these mice. These studies reveal that HNF4alpha plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain beta-oxidation of cholesterol in vivo.
Inoue
Yusuke
Y
Laboratory of Metabolism, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Yu
Ai-Ming
AM
Yim
Sun Hee
SH
Ma
Xiaochao
X
Krausz
Kristopher W
KW
Inoue
Junko
J
Xiang
Charlie C
CC
Brownstein
Michael J
MJ
Eggertsen
Gösta
G
Björkhem
Ingemar
I
Gonzalez
Frank J
FJ
D000818:Animals; D001483:Base Sequence; D001647:Bile Acids and Salts / Q000096:biosynthesis*; D001665:Binding Sites / Q000235:genetics; D002790:Cholesterol 7-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism; D002940:Circadian Rhythm; D018076:DNA, Complementary / Q000235:genetics; D003624:Darkness; D005786:Gene Expression Regulation; D051557:Hepatocyte Nuclear Factor 4 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D006706:Homeostasis; D008099:Liver / Q000378:metabolism; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D011401:Promoter Regions, Genetic; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013253:Steroid 12-alpha-Hydroxylase / Q000235:genetics / Q000378:metabolism
D001647:Bile Acids and Salts; D018076:DNA, Complementary; D051557:Hepatocyte Nuclear Factor 4; C496593:Hnf4a protein, mouse; D012333:RNA, Messenger; D002790:Cholesterol 7-alpha-Hydroxylase; C502772:Cyp7a1 protein, mouse; D013253:Steroid 12-alpha-Hydroxylase