Regulation of cholesterol 7alpha-hydroxylase mRNA expression in C57BL/6 mice fed an atherogenic diet.
The nuclear receptors liver X receptor (LXR) alpha and farnesoid X receptor (FXR) are positive and negative regulators of cholesterol 7alpha-hydroxylase (CYP7A1) transcription, respectively. To clarify their roles in the regulation of CYP7A1 in mice, we investigated mRNA expression of their target genes in the livers of C57BL/6 mice fed the following five diets for 2 weeks: a standard diet, cholic acid, cholesterol, cholesterol+high fat, or an atherogenic diet (cholic acid+cholesterol+high fat). The mRNA level of ATP-binding cassette transporter (ABC) A1 gene, one of LXRalpha target genes, significantly increased on the diets containing cholic acid and/or cholesterol+high fat, but not on the diet containing cholesterol alone. On the other hand, the mRNA levels of the FXR target genes ABCB11, ABCC2, and short heterodimer partner increased only on the diet containing cholic acid with or without cholesterol+high fat. Surprisingly, cholesterol alone or cholesterol+high fat did not affect CYP7A1 mRNA level, whereas cholic acid with or without cholesterol+high fat greatly reduced the level. Thus, in the atherogenic diet-fed mice, cholic acid component is needed for the FXR activation, and FXR dominantly regulates CYP7A1 transcription.
Ando
Hitoshi
H
Division of Clinical Pharmacology, Department of Pharmacology, Jichi Medical School, Tochigi 329-0498, Japan.
Tsuruoka
Shuichi
S
Yamamoto
Hisashi
H
Takamura
Toshinari
T
Kaneko
Shuichi
S
Fujimura
Akio
A
D018528:ATP-Binding Cassette Transporters / Q000096:biosynthesis; D000818:Animals; D002784:Cholesterol / Q000032:analysis / Q000494:pharmacology; D002790:Cholesterol 7-alpha-Hydroxylase / Q000096:biosynthesis*; D019826:Cholic Acid / Q000032:analysis / Q000494:pharmacology*; D004268:DNA-Binding Proteins / Q000502:physiology*; D004036:Diet, Atherogenic; D005786:Gene Expression Regulation; D000071518:Liver X Receptors; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger / Q000096:biosynthesis; D018160:Receptors, Cytoplasmic and Nuclear / Q000502:physiology*; D014157:Transcription Factors / Q000502:physiology*; D000099150:Receptor, Farnesoid X-Activated
D018528:ATP-Binding Cassette Transporters; D002784:Cholesterol; D002790:Cholesterol 7-alpha-Hydroxylase; D019826:Cholic Acid; D004268:DNA-Binding Proteins; D000071518:Liver X Receptors; D057093:Orphan Nuclear Receptors; D012333:RNA, Messenger; D018160:Receptors, Cytoplasmic and Nuclear; D014157:Transcription Factors; D000099150:Receptor, Farnesoid X-Activated; C000605214:Nr1h3 protein, mouse