The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors
The cholesterol-raising factor from coffee beans, cafestol, as an agonist ligand for the farnesoid and pregnane X receptors
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DOI：
10.1210/me.2007-0133
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发表时间：
2007-07-01
影响因子：
--
通讯作者：
Moore, David D.
中科院分区：
文献类型：
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作者：
Ricketts, Marie-Louise;Boekschoten, Mark V.;Moore, David D.
咖啡精是一种存在于未经过滤的咖啡中的二萜类化合物，如斯堪的纳维亚煮咖啡、土耳其咖啡和意大利咖啡，是人类饮食中已知的最有效的胆固醇升高化合物。参与胆固醇稳态的几个基因先前已被证明是胆固醇的靶点，包括胆固醇7 α-羟化酶（CYP 7A 1），胆汁酸生物合成中的限速酶。我们已经研究了黄芪甲苷升高血脂水平的机制。在阿托洛尔处理的APOE 3 Leiden小鼠中观察到几种脂质参数的变化，包括血清甘油三酯水平显著升高。这些小鼠的微阵列分析确定了参与脂质代谢和解毒的基因的肝脏表达的改变，其中许多是由核激素受体法尼醇X受体（FXR）和α-羟色胺X受体（PXR）调节的。进一步的研究表明，阿托伐他汀是FXR和PXR的激动剂配体，并且阿托伐他汀下调野生型小鼠肝脏中胆汁酸稳态基因CYP 7A 1、固醇12 α-羟化酶和Na+-牛磺胆酸盐共转运多肽的表达，但不下调FXR缺失小鼠肝脏中胆汁酸稳态基因CYP 7A 1、固醇12 α-羟化酶和Na+-牛磺胆酸盐共转运多肽的表达。咖啡因不影响野生型小鼠肝脏中已知被FXR上调的基因，但确实增加了肠道中阳性FXR靶基因肠胆汁酸结合蛋白和成纤维细胞生长因子15（FGF 15）的表达。由于FGF 15最近已被证明在肝肠调节途径中起作用，以抑制胆汁酸稳态基因的肝脏表达，因此其在肠道中的直接诱导可能是FGF 15对肝脏基因表达的间接影响。PXR依赖的细胞色素P450 3A 11和其他靶点的基因调控也仅见于肠道。使用双FXR/PXR基因敲除小鼠模型，我们发现这两种受体都有助于肠FGF 15基因表达的阿曲司托依赖性诱导。总之，胆固醇作为FXR和PXR的激动剂配体，这可能有助于其对胆固醇稳态的影响。
Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetiere coffee, is the most potent cholesterol-elevating compound-knownin the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7 alpha-hydroxylase (CYP7A1), the rate-limiting enzyme in bile acid biosynthesis. We have examined the mechanism by which cafestol elevates serum lipid levels. Changes in several lipid parameters were observed in cafestol-treated APOE3Leiden mice, including a significant increase in serum triglyceride levels. Microarray analysis of these mice identified alterations in hepatic expression of genes involved in lipid metabolism and detoxification, many of which are regulated by the nuclear hormone receptors farnesoid X receptor (FXR) and pregnane X receptor (PXR). Further studies demonstrate that cafestol is an agonist ligand for FXR and PXR, and that cafestol down-regulates expression of the bile acid homeostatic genes CYP7A1, sterol 12 alpha-hydroxylase, and Na+-taurocholate cotransporting polypeptide in the liver of wild-type but not FXR null mice. Cafestol did not affect genes known to be upregulated by FXR in the liver of wild-type mice, but did increase expression of the positive FXR-target genes intestinal bile acid-binding protein and fibroblast growth factor 15 (FGF15) in the intestine. Because FGF15 has recently been shown to function in an enterohepatic regulatory pathway to repress liver expression of bile acid homeostatic genes, its direct induction in the gut may account for indirect effects of cafestol on liver gene expression. PXR-dependent gene regulation of cytochrome P450 3A11 and other targets by cafestol was also only seen in the intestine. Using a double FXR/PXR knockout mouse model, we found that both receptors contribute to the cafestol-dependent induction of intestinal FGF15 gene expression. In conclusion, cafestol acts as an agonist ligand for both FXR and PXR, and this may contribute to its impact on cholesterol homeostasis.