奥地利研究人员日前发现，一种名为“FXR”的胆汁酸受体能够降低脂蛋白a的浓度，从而降低患心脑血管疾病的风险。这一发现将有助于研发出降血脂新药。
胆囊上胆汁酸受体有助于降血脂
脂蛋白a主要在肝脏中合成。在人体医学检查中，脂蛋白a指数是反映血脂是否异常的参考指标，其浓度越高，患动脉粥样硬化、急性心肌梗死等心脑血管疾病的风险就越大。
奥地利格拉茨医科大学分子生物学与生物化学研究所的研究人员发现，由于胆道堵塞而出现血液中胆汁酸浓度升高的患者，其体内脂蛋白a的水平却很低，然而，一旦胆道堵塞被消除，脂蛋白a的水平就会升高。
探索两者之间的联系，研究人员发现，在合成胆汁酸过程中发挥重要作用的“FXR”受体，能够在与其拼接的天然或合成分子的作用下，将脂蛋白a的再生能力最多降低90%，从而降低脂蛋白a的浓度。因此，当胆汁酸合成活跃的时候，胆汁酸受体就多，相应地去除的脂蛋白a也多。
这项研究结果刊登在最新一期《临床检查期刊》月刊上。
相关英文论文摘要
Farnesoid X receptor represses hepatic human APOA gene expression
High plasma concentrations of lipoprotein(a) [Lp(a), which is encoded by the APOA gene] increase an individual’s risk of developing diseases, such as coronary artery diseases, restenosis, and stroke. Unfortunately, increased Lp(a) levels are minimally influenced by dietary changes or drug treatment. Further, the development of Lp(a)-specific medications has been hampered by limited knowledge of Lp(a) metabolism. In this study, we identified patients suffering from biliary obstructions with very low plasma Lp(a) concentrations that rise substantially after surgical intervention. Consistent with this, common bile duct ligation in mice transgenic for human APOA (tg-APOA mice) lowered plasma concentrations and hepatic expression of APOA. To test whether farnesoid X receptor (FXR), which is activated by bile acids, was responsible for the low plasma Lp(a) levels in cholestatic patients and mice, we treated tg-APOA and tg-APOA/Fxr–/– mice with cholic acid. FXR activation markedly reduced plasma concentrations and hepatic expression of human APOA in tg-APOA mice but not in tg-APOA/Fxr–/– mice. Incubation of primary hepatocytes from tg-APOA mice with bile acids dose dependently downregulated APOA expression. Further analysis determined that the direct repeat 1 element between nucleotides –826 and –814 of the APOA promoter functioned as a negative FXR response element. This motif is also bound by hepatocyte nuclear factor 4α (HNF4α), which promotes APOA transcription, and FXR was shown to compete with HNF4α for binding to this motif. These findings may have important implications in the development of Lp(a)-lowering medications.
英文论文原文链接：https://www.jci.org/articles/view/45277?search[article_text]=FXR
