Department of Internal Medicine, Division of Endocrinology, University Hospital, Eberhard Karls University Tübingen, 72076 Tübingen, Germany.
J Clin Endocrinol Metab. 2013 Jul;98(7):E1224-9. doi: 10.1210/jc.2013-1177. Epub 2013 May 2.
Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models.
To understand the role of FXR in human metabolism, we investigated associations of common single-nucleotide polymorphisms (SNPs) in the FXR-encoding gene NR1H4 with glucose and lipid metabolism, body fat mass, and liver fat content.
We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of common genetic variation (minor allele frequency > 10%).
Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by (1)H-magnetic resonance spectroscopy were performed.
SNP rs4764980 was significantly associated with fasting glycemia (P = .0043) and nominally associated with fasting and postglucose load free fatty acid (FFA) levels (P = .01). Upon interrogation of publicly available Meta-Analyses of Glucose and Insulin-related traits Consortium data, the association of rs4764980 with fasting glycemia was replicated (Meta-Analyses of Glucose and Insulin-related traits Consortium, P = .005). Additionally, SNP rs11110390 showed significant associations with fasting (P = .0054) and postload (P = .0051) FFA levels. For none of the investigated SNPs, associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected.
We conclude that FXR contributes to fasting glucose and FFA levels in humans independent of unhealthy body fat accumulation. The receptor represents an interesting target to influence lipid and glucose metabolism.
法尼醇 X 受体（FXR）通过胆汁酸信号传导调节动物模型中的葡萄糖和脂质水平、脂肪量和肝脂肪变性。
为了了解 FXR 在人体代谢中的作用，我们研究了 FXR 编码基因 NR1H4 中的常见单核苷酸多态性（SNP）与葡萄糖和脂质代谢、体脂肪量和肝脂肪含量的关联。
我们对 2166 名德国健康受试者进行了 NR1H4 内的 7 个标记 SNP（rs35735、rs1030454、rs11110415、rs11610264、rs17030285、rs4764980 和 rs11110390）的基因分型，涵盖了 100%常见的遗传变异（次要等位基因频率 > 10%）。
通过口服葡萄糖耐量试验对受试者进行了代谢特征分析。在亚组中，通过（1）H 磁共振波谱进行了高胰岛素正葡萄糖钳夹和肝脂肪定量。
SNP rs4764980 与空腹血糖显著相关（P =.0043），与空腹和餐后游离脂肪酸（FFA）水平有显著关联（P =.01）。在对公开的葡萄糖和胰岛素相关特征荟萃分析联盟数据进行调查时，rs4764980 与空腹血糖的关联得到了复制（葡萄糖和胰岛素相关特征荟萃分析联盟，P =.005）。此外，SNP rs11110390 与空腹（P =.0054）和餐后（P =.0051）FFA 水平显著相关。对于所有研究的 SNP，均未发现与胰岛素分泌或敏感性、体脂肪量或肝脂肪含量相关。
我们得出结论，FXR 独立于不健康的体脂肪积累，对人体的空腹血糖和 FFA 水平有贡献。该受体是一个有趣的影响脂质和葡萄糖代谢的靶点。
