JCEM：FXR影响空腹血糖和游离脂肪酸水平

在动物模型中，胆汁酸信号通过法尼醇X受体（FXR）调节血糖和血脂水平、脂肪组织、以及肝脏脂肪变性。为了了解FXR在人类代谢中的作用，探讨在FXR编码基因NR1H4常见单核苷酸多态性（SNP）与糖和脂类代谢、体脂含量、肝脏脂肪含量的关系，来自德国蒂宾根大学附属医院内分泌科Hans-Ulrich Häring教授及其团队进行了一项研究，该研究发现，在人类，FXR影响空腹血糖和游离脂肪酸（FFA）水平独立于不健康的体脂蓄积，这个受体表现出一种令人关注的影响脂质和糖代谢的靶点。该研究结果在线发表在2013年5月2日的美国《临床内分泌代谢杂志》（The journal of clinical endocrinology & metabolism）上。
该研究对2166例健康德国受试者NR1H4中的7个标记SNPS（rs35735、rs1030454、rs11110415、rs11610264、rs17030285、rs4764980和rs11110390）进行基因分型，覆盖100%常见基因变异（等位基因频率＞10%）。通过口服葡萄糖耐量试验评价受试者代谢特征。在亚组中，进行高胰岛素–正常葡萄糖钳夹试验，并通过1H–磁共振波谱分析肝脏脂肪定量。
该研究结果表明，SNP rs4764980与空腹血糖显著相关（P=0.0043），并与空腹和葡萄糖负荷后的FFA水平名义上相关（P=0.01）。基于对公开的葡萄糖和胰岛素相关特性数据荟萃分析的疑问，rs4764980与空腹血糖的相关性是重复的（葡萄糖和胰岛素相关特性荟萃分析，P=0.005）。另外，SNP rs11110390显示与空腹（P=0.0054）和负荷后(P=0.0051)FFA水平显著相关。没有一个被研究的SNPs检测到与胰岛素分泌或敏感性、体脂含量或肝脏脂肪含量相关。
该研究发现，在人类，FXR影响空腹血糖和游离脂肪酸（FFA）水平，且独立于不健康的体脂蓄积。FXR受体表现出一种令人关注的影响脂质和葡萄糖代谢的靶点。

Genetic Variation in NR1H4 Encoding the Bile Acid Receptor FXR Determines Fasting Glucose and Free Fatty Acid Levels in Humans.
Abstract
Context:Bile acid signaling via farnesoid X receptor (FXR) regulates glucose and lipid levels, fat mass, and hepatic steatosis in animal models.Objective: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.Design:We genotyped 2166 healthy German subjects for 7 tagging SNPs within NR1H4 (rs35735, rs1030454, rs11110415, rs11610264, rs17030285, rs4764980, and rs11110390) covering 100% of a common genetic variation (minor allele frequency > 10%).Outcome Measures:Subjects were metabolically characterized by an oral glucose tolerance test. In subgroups, hyperinsulinemic-euglycemic clamp and liver fat quantification by 1H-magnetic resonance spectroscopy were performed.Results: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, the associations with insulin secretion or sensitivity, body fat mass, or liver fat content were detected.Conclusions: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.