Abstract
Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans. The farnesoid X receptor (FXR), the key regulator of bile acid synthesis, was, therefore, identified as an interesting target for drug discovery. We compared the effect of four, structurally unrelated, synthetic FXR agonists in two fat-fed rodent species and observed that the three most potent and selective agonists decreased plasma cholesterol in LDL receptor-deficient (Ldlr (-/-)) mice, but none did so in hamsters. Detailed investigation revealed increases in the expression of small heterodimer partner (Shp) in their livers and of intestinal fibroblast growth factor 15 or 19 (Fgf15/19) in mice only. Cyp7a1 expression and fecal bile acid (BA) excretion were strongly reduced in mice and hamsters by all four FXR agonists, whereas bile acid pool sizes were reduced in both species by all but the X-Ceptor compound in hamsters. In Ldlr (-/-) mice, the predominant bile acid changed from cholate to the more hydrophilic β-muricholate due to a strong repression of Cyp8b1 and increase in Cyp3a11 expression. However, FXR agonists caused only minor changes in the expression of Cyp8b1 and in bile acid profiles in hamsters. In summary, FXR agonist-induced decreases in bile acid pool size and lipophilicity and in cholesterol absorption and synthesis could explain the decreased plasma cholesterol in Ldlr (-/-) mice. In hamsters, FXR agonists reduced bile acid pool size to a smaller extent with minor changes in bile acid profile and reductions in sterol absorption, and consequently, plasma cholesterol was unchanged.
Highlights
Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans
Cholesterol is converted into the primary bile acid (BA) cholic acid (CA) and chenodeoxycholic acid (CDCA) in the liver by a series of enzyme-catalyzed reactions that are summarized in Fig. 1 and have been well reviewed previously [2, 5]
We showed that all four farnesoid X receptor (FXR) agonists dramatically reduced the proportion of CA from ف70% in vehicle-treated mice to 17, 26, 9, and 34%, respectively, in RO5186026, X-Ceptor, 6-ECDCA, and GW4064-treated mice. ␣, , and muricholic acid (MCA) all increased upon treatment with FXR agonists until their joint contribution to the pool reached 73, 65, 83, and 61%, in RO5186026, X-Ceptor, 6-ECDCA, and GW4064treated mice, respectively
Summary
Modulating bile acid synthesis has long been considered a good strategy by which to improve cholesterol homeostasis in humans. FXR agonist-induced decreases in bile acid pool size and lipophilicity and in cholesterol absorption and synthesis could explain the decreased plasma cholesterol in Ldlr ؊/؊ mice. Bile acids (BA) are the major metabolites of cholesterol in mammals They are produced in the liver and secreted into the small intestine where, because of their amphipathic properties, they facilitate the absorption of dietary and biliary lipids, including cholesterol [2]. Repression/feedback regulation of BA synthesis by FXR agonists is mediated by increased expression of small heterodimer partner (Shp, NR0B2) in the liver and by increased expression and secretion of fibroblast growth factor 15 (Fgf15), the mouse homolog of FGF19/Fgf in humans and hamsters, in the small intestine. This report provides, for the first time, a comprehensive picture of the FXRmediated differential regulation of BA synthesis in LDL receptor-deficient (Ldlr Ϫ/Ϫ) mice and hamsters and the consequences of such modulations on dietary cholesterol absorption and plasma cholesterol concentrations
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