Activation of farnesoid X receptor prevents atherosclerotic lesion formation in LDLR-/- and apoE-/- mice.
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.
Hartman
Helen B
HB
Cardiovascular and Metabolic Disease Research, Wyeth Research, Collegeville, PA 19426, USA.
Gardell
Stephen J
SJ
Petucci
Chris J
CJ
Wang
Shuguang
S
Krueger
Julie A
JA
Evans
Mark J
MJ
D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000235:genetics / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D001381:Azepines / Q000494:pharmacology; D001647:Bile Acids and Salts / Q000378:metabolism; D002790:Cholesterol 7-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D050171:Dyslipidemias / Q000235:genetics / Q000378:metabolism / Q000517:prevention & control; D005260:Female; D015870:Gene Expression / Q000187:drug effects; D007211:Indoles / Q000494:pharmacology; D008055:Lipids / Q000097:blood; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018160:Receptors, Cytoplasmic and Nuclear / Q000819:agonists* / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D011973:Receptors, LDL / Q000172:deficiency* / Q000235:genetics; D013253:Steroid 12-alpha-Hydroxylase / Q000037:antagonists & inhibitors / Q000235:genetics; D000099150:Receptor, Farnesoid X-Activated
D001057:Apolipoproteins E; D001381:Azepines; D001647:Bile Acids and Salts; D002790:Cholesterol 7-alpha-Hydroxylase; D007211:Indoles; D008055:Lipids; D018160:Receptors, Cytoplasmic and Nuclear; D011973:Receptors, LDL; D013253:Steroid 12-alpha-Hydroxylase; D000099150:Receptor, Farnesoid X-Activated; C540004:WAY-362450; C099713:nuclear receptor subfamily 0, group B, member 2; C502772:Cyp7a1 protein, mouse