Abstract
The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. Here, LDL receptor (LDLR(-/-)) or apolipoprotein E (apoE(-/-)) female or male mice were fed a Western diet and treated with a potent synthetic FXR agonist, WAY-362450. Activation of FXR blocked diet-induced hypertriglyceridemia and elevations of non-HDL cholesterol and produced a near complete inhibition of aortic lesion formation. WAY-362450 also induced small heterodimer partner (SHP) expression and repressed cholesterol 7alpha-hydroxylase (CYP7A1) and sterol 12 alpha-hydroxylase (CYP8B1) expression. To determine if SHP was essential for these protective activities, LDLR(-/-)SHP(-/-) and apoE(-/-)SHP(-/-) mice were similarly treated with WAY-362450. Surprisingly, a notable sex difference was observed in these mice. In male LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. In contrast, in the female LDLR(-/-)SHP(-/-) or apoE(-/-)SHP(-/-) mice, WAY-362450 only slightly repressed CYP7A1 and CYP8B1 expression and did not reduce non-HDL cholesterol or aortic lesion size. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR(-/-) or apoE(-/-) mice lacking SHP of both sexes. These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.
Highlights
The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear
We demonstrate that WAY-362450 has the ability to abolish atherosclerotic lesion formation in both apolipoprotein E and LDRL2/2 mice and demonstrate that this effect is dependent upon small heterodimer partner (SHP) in female but not in male mice
A trend toward WAY-362450 reduction of HDL cholesterol occurred in LDLR2/2, achieving significance only in males
Summary
The role of farnesoid X receptor (FXR) in the development of atherosclerosis has been unclear. In male LDLR2/2SHP2/2 or apoE2/2SHP2/2 mice, WAY-362450 still repressed CYP7A1 and CYP8B1 expression by 10-fold and still strongly reduced non-HDL cholesterol levels and aortic lesion area. WAY-362450 inhibition of hypertriglyceridemia remained intact in LDLR2/2 or apoE2/2 mice lacking SHP of both sexes These results suggest that activation of FXR protects against atherosclerosis in the mouse, and this protective effect correlates with repression of bile acid synthetic genes, with mechanistic differences between male and female mice.—Hartman, H. SHP functions to repress activity of LRH-1 and HNF4 [2,3,4,5,6] These two factors drive expression of cholesterol 7a-hydroxylase (CYP7A1) and sterol 12 a-hydroxylase (CYP8B1), the two enzymes controlling the bile acid pool size and the hydrophobicity of the bile acid pool [7, 8]. The basis for the differences between the apoE2/2FXR2/2 and LDR2/2FXR2/2 studies is not readily apparent nor is it evident whether similar results would be obtained with Western diets containing cholesterol levels more typically present in human diets
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