Cholic acid as key regulator of cholesterol synthesis, intestinal absorption and hepatic storage in mice.
To study the effects of cholic acid (CA) feeding on hepatic cholesterol metabolism, male sterol 12alpha-hydroxylase (CYP8B1) knockout (-/-) mice and wildtype controls (+/+) were fed either a control diet or the same diet supplemented with CA (0.1% or 0.5% w/w) or cholesterol (1% w/w). During feeding of the control diet, cholesterol synthesis was increased in CYP8B1-/- compared to +/+ mice. Both cholesterol and CA feeding down regulated mRNA expression of cholesterogenic genes and hepatic de novo cholesterol synthesis as also reflected by a concomitant decrease in the nuclear factor SREBP-2 precursor protein and increased hepatic free cholesterol levels. Mice with an intact CYP8B1 gene (CYP8B1+/+ and C57Bl/6 mice) accumulated higher concentrations of cholesteryl esters (24- and 25-fold, respectively) in their livers compared to CYP8B1-/- mice (8-fold). Feeding of CA increased intestinal cholesterol absorption in CYP8B1+/+ mice by 23% and in CYP8B1-/- mice by 50%. While plasma cholesterol did not differ between CYP8B1+/+ and -/- mice under control conditions and cholesterol feeding a decrease was seen in CYP8B1-/- but not CYP8B1+/+ mice fed CA. This study indicates that CA is an important determinant for intestinal cholesterol absorption and that the levels of the transcription factor SREBP-2 in the liver are dependent upon the combined effect of CA on intestinal cholesterol absorption and CYP7A1. The possibility is discussed that inhibition of CYP8B1 and thus CA synthesis may be beneficial for the treatment of hyperlipidemic disorders.
Department of Laboratory Medicine, Division of Clinical Chemistry, Karolinska University Hospital, 14186 Stockholm, Sweden.
Charlotte
C
Murphy
Paolo
P
Parini
Jin
J
Wang
Ingemar
I
Björkhem
Gösta
G
Eggertsen
Mats
M
Gåfvels
D000818:Animals; D001647:Bile Acids and Salts / Q000378:metabolism; D002784:Cholesterol / Q000096:biosynthesis*; D019826:Cholic Acid / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000378:metabolism; D007408:Intestinal Absorption; D008099:Liver / Q000378:metabolism*; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D013253:Steroid 12-alpha-Hydroxylase / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors / Q000378:metabolism
D001647:Bile Acids and Salts; D004268:DNA-Binding Proteins; C497391:Srebf2 protein, mouse; D051782:Sterol Regulatory Element Binding Protein 2; D014157:Transcription Factors; D002784:Cholesterol; D013253:Steroid 12-alpha-Hydroxylase; D019826:Cholic Acid