Ricketts Marie-Louise, Boekschoten Mark V, Kreeft Arja J, Hooiveld Guido J E J, Moen Corina J A, Müller Michael, Frants Rune R, Kasanmoentalib Soemini, Post Sabine M, Princen Hans M G, Porter J Gordon, Katan Martijn B, Hofker Marten H, Moore David D
Department of Molecular and Cellular Biology, Baylor College of Medicine, BCM 130, One Baylor Plaza, Houston, Texas 77030, USA.
Mol Endocrinol. 2007 Jul;21(7):1603-16. doi: 10.1210/me.2007-0133. Epub 2007 Apr 24.
Cafestol, a diterpene present in unfiltered coffee brews such as Scandinavian boiled, Turkish, and cafetière coffee, is the most potent cholesterol-elevating compound known in the human diet. Several genes involved in cholesterol homeostasis have previously been shown to be targets of cafestol, including cholesterol 7alpha-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 12alpha-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 up-regulated 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.
咖啡醇是一种存在于未经过滤的咖啡冲泡饮品中的二萜类化合物，如北欧煮制咖啡、土耳其咖啡和法式滤压咖啡，它是人类饮食中已知的最有效的胆固醇升高化合物。先前已证明，参与胆固醇稳态的几个基因是咖啡醇的作用靶点，包括胆固醇7α-羟化酶（CYP7A1），它是胆汁酸生物合成中的限速酶。我们研究了咖啡醇升高血清脂质水平的机制。在经咖啡醇处理的载脂蛋白E3 Leiden小鼠中观察到了几个脂质参数的变化，包括血清甘油三酯水平显著升高。对这些小鼠进行的微阵列分析确定了参与脂质代谢和解毒的肝脏基因表达发生了改变，其中许多基因受核激素受体法尼酯X受体（FXR）和孕烷X受体（PXR）的调节。进一步的研究表明，咖啡醇是FXR和PXR的激动剂配体，并且咖啡醇下调野生型小鼠肝脏中胆汁酸稳态基因CYP7A1、固醇12α-羟化酶和Na(+)-牛磺胆酸盐共转运多肽的表达，但对FXR基因敲除小鼠无效。咖啡醇不影响野生型小鼠肝脏中已知由FXR上调的基因，但确实增加了阳性FXR靶点基因肠胆汁酸结合蛋白和成纤维细胞生长因子15（FGF15）在肠道中的表达。由于最近已证明FGF15在肠肝调节途径中发挥作用以抑制胆汁酸稳态基因的肝脏表达，其在肠道中的直接诱导可能解释了咖啡醇对肝脏基因表达的间接影响。咖啡醇对细胞色素P450 3A11和其他靶点的PXR依赖性基因调节也仅在肠道中可见。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咖啡醇依赖性诱导肠道FGF15基因表达。总之，咖啡醇作为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。
