Abstract
Hepatocyte nuclear factor 4α (HNF4α) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4α (HNF4αΔL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4a-floxed (HNF4α F/F) mice. The expression of genes involved in the hydroxylation and side chain β-oxidation of cholesterol, including oxysterol 7α-hydroxylase, sterol 12α-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4αΔL mice. Cholesterol 7α-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4αΔL mice, whereas expression in the light cycle was not different between HNF4αΔL and HNF4αF/F mice. Because CYP8B1 expression was reduced in HNF4αΔL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4α ΔL mice. An HNF4α binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4α-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 HNF4α plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain β-oxidation of cholesterol in vivo.
| Original language | English (US) |
|---|---|
| Pages (from-to) | 215-227 |
| Number of pages | 13 |
| Journal | Journal of Lipid Research |
| Volume | 47 |
| Issue number | 1 |
| DOIs | |
| State | Published - Jan 2006 |
| Externally published | Yes |
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Keywords
- Cholic acid
- Conditional knockout mice
- Oxysterol 7α-hydroxylase
- Sterol 12α-hydroxylase
- Sterol carrier protein x
ASJC Scopus subject areas
- Endocrinology
Cite this
Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α. / Inoue, Yusuke; Yu, Aiming; Sun, Hee Yim; Ma, Xiaochao; Krausz, Kristopher W.; Inoue, Junko; Xiang, Charlie C.; Brownstein, Michael J.; Eggertsen, Gösta; Björkhem, Ingemar; Gonzalez, Frank J.
In: Journal of Lipid Research, Vol. 47, No. 1, 01.2006, p. 215-227.Research output: Contribution to journal › Article
}
TY - JOUR
T1 - Regulation of bile acid biosynthesis by hepatocyte nuclear factor 4α
AU - Inoue, Yusuke
AU - Yu, Aiming
AU - Sun, Hee Yim
AU - Ma, Xiaochao
AU - Krausz, Kristopher W.
AU - Inoue, Junko
AU - Xiang, Charlie C.
AU - Brownstein, Michael J.
AU - Eggertsen, Gösta
AU - Björkhem, Ingemar
AU - Gonzalez, Frank J.
PY - 2006/1
Y1 - 2006/1
N2 - Hepatocyte nuclear factor 4α (HNF4α) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4α (HNF4αΔL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4a-floxed (HNF4α F/F) mice. The expression of genes involved in the hydroxylation and side chain β-oxidation of cholesterol, including oxysterol 7α-hydroxylase, sterol 12α-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4αΔL mice. Cholesterol 7α-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4αΔL mice, whereas expression in the light cycle was not different between HNF4αΔL and HNF4αF/F mice. Because CYP8B1 expression was reduced in HNF4αΔL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4α ΔL mice. An HNF4α binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4α-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 HNF4α plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain β-oxidation of cholesterol in vivo.
AB - Hepatocyte nuclear factor 4α (HNF4α) regulates many genes that are preferentially expressed in liver. Mice lacking hepatic expression of HNF4α (HNF4αΔL) exhibited markedly increased levels of serum bile acids (BAs) compared with HNF4a-floxed (HNF4α F/F) mice. The expression of genes involved in the hydroxylation and side chain β-oxidation of cholesterol, including oxysterol 7α-hydroxylase, sterol 12α-hydroxylase (CYP8B1), and sterol carrier protein x, was markedly decreased in HNF4αΔL mice. Cholesterol 7α-hydroxylase mRNA and protein were diminished only during the dark cycle in HNF4αΔL mice, whereas expression in the light cycle was not different between HNF4αΔL and HNF4αF/F mice. Because CYP8B1 expression was reduced in HNF4αΔL mice, it was studied in more detail. In agreement with the mRNA levels, CYP8B1 enzyme activity was absent in HNF4α ΔL mice. An HNF4α binding site was found in the mouse Cyp8b1 promoter that was able to direct HNF4α-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 HNF4α plays a central role in BA homeostasis by regulation of genes involved in BA biosynthesis, including hydroxylation and side chain β-oxidation of cholesterol in vivo.
KW - Cholic acid
KW - Conditional knockout mice
KW - Oxysterol 7α-hydroxylase
KW - Sterol 12α-hydroxylase
KW - Sterol carrier protein x
UR - http://www.scopus.com/inward/record.url?scp=30844454448&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=30844454448&partnerID=8YFLogxK
U2 - 10.1194/jlr.M500430-JLR200
DO - 10.1194/jlr.M500430-JLR200
M3 - Article
VL - 47
SP - 215
EP - 227
JO - Journal of Lipid Research
JF - Journal of Lipid Research
SN - 0022-2275
IS - 1
ER -