Abstract
The major pathway for elimination of cholesterol in mammals is via secretion into bile. Biliary cholesterol secretion is mediated by the ATP-binding cassette (ABC) transporters ABCG5 (G5) and ABCG8 (G8) and is stimulated by cholesterol and by the non-cholesterol steroids cholate and diosgenin. To define the relationship between G5G8 expression and biliary cholesterol secretion, we measured G5 and G8 mRNA levels and biliary cholesterol concentrations in genetically manipulated mice expressing 0, 1, 2, 5, 10, or 16 copies of the two genes. Biliary cholesterol levels varied directly with G5G8 copy number and hepatic mRNA levels over a >16-fold range. Thus neither delivery of cholesterol to the transporter nor levels of cholesterol acceptors in bile were limiting under these conditions. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2-3-fold. The increase in biliary cholesterol content was dependent on expression of G5 and G8; neither steroid increased biliary cholesterol levels in G5G8-/- mice. Cholate treatment was associated with a farnesoid X receptor (FXR)-dependent increase in hepatic mRNA and protein levels of G5 and G8. In contrast to cholate, diosgenin treatment did not affect G5G8 expression. Diosgenin increased the expression of several pregnane X receptor (PXR) target genes and the choleretic effect of diosgenin was reduced by approximately 70% in PXR knock-out mice. Thus G5 and G8 are required to modulate biliary cholesterol secretion in response to cholate and diosgenin, but the choleretic effects of these two steroids are mediated by different mechanisms requiring FXR and PXR, respectively.
Highlights
Cholesterol is an essential constituent of cell membranes that can be acquired by de novo synthesis from acetyl-CoA or obtained from the diet
Whereas biliary cholesterol secretion is markedly reduced in G5G8Ϫ/Ϫ mice, transgenic mice overexpressing human G5 and G8 have increased biliary cholesterol concentrations and increased rates of fecal neutral sterol excretion [6]
Biliary Cholesterol Secretion Is Linearly Related to Copy Number and Expression Levels of G5 and G8 —To determine the relationship between G5G8 expression and biliary cholesterol secretion, we measured biliary cholesterol concentrations in genetically manipulated mice in which G5G8 expression varied over a wide range
Summary
Cholesterol is an essential constituent of cell membranes that can be acquired by de novo synthesis from acetyl-CoA or obtained from the diet. In wild-type mice, cholate and diosgenin both increased biliary cholesterol concentrations 2–3-fold. Cholate Feeding Does Not Promote Biliary Cholesterol Secretion in G5G8Ϫ⁄Ϫ Mice—Cholate feeding was associated with a 3-fold increase in biliary cholesterol concentrations in wild-type mice (Fig. 3A).
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