脂多糖对肝细胞烟酸受体表达及胆固醇外流的影响  

Upregulation of niacin receptor GPR109A and reduction of cholesterol efflux to apoA-I in hepatocytes response to LPS treatment

作　　者：李晓宇[1] 杨清[1] 单清[2] 

机构地区：[1]南京医科大学江苏省心血管病分子干预重点实验室,江苏南京210029 [2]江苏省扬州市第一人民医院,江苏扬州225001

出　　处：《实用临床医药杂志》2011年第19期21-25,共5页Journal of Clinical Medicine in Practice

基　　金：国家自然科学基金资助项目(81070120)

摘　　要：目的急性或慢性炎症状态时下高密度脂蛋白和载脂蛋白A-I含量降低。GPR109A是一种G蛋白偶联受体,在脂细胞中介导烟酸抑制的甘油三酯水解。作者的前期研究发现肝细胞中GPR109A过表达,可抑制肝细胞中ABCA1活性,使得肝细胞介导的游离胆固醇向新生apoA-I外流减少,从而降低HDL浓度。但是炎症应激时高密度脂蛋白含量降低是否与GPR109A的活化有关,并不清楚。方法用定量PCR法检测多种巨噬细胞和肝细胞中GPR109A的含量。同时,用酶联免疫吸附法测定肝细胞中环磷腺苷的释放量。最后作者还用液闪计数仪观察了肝细胞中游离胆固醇外流至载脂蛋白A-I的变化。结果作者的研究结果提示,低剂量LPS注射可以在2 h内迅速上调小鼠肝细胞GPR109A的表达,而非仅诱导了Kupffer细胞中GPR109A的表达上调。同时,作者也在人的肝细胞株上验证了相同的结果。此外,作者发现炎症上调的GPR109A抑制了肝细胞中环磷腺苷的释放,也降低了游离胆固醇外流至新生的apoA-I。结论作者的研究表明炎症应激时肝细胞中上调的GPR109A参与了血浆HDL减少的调节,从而增加了心血管事件发病的危险性。Objective I-tDL- C and apoA- I levels are reduced in acute and chronic inflammatory states. The niacin receptor GPR109A is a Gi - protein coupled receptor which mediates the effects of niacin on triglyceride lipolysis in adipocytes, we previously found hepatic overexpressed GPR109A lowered ABCA1 expression leading to reduced hepatic cholesterol efflux to HDL, but whether this pathway involves in HDL metabolism under inflammatory condition is unclear. Methods Real time PCR has been used to measure GPR109A mRNA level in different types of macrophages and hepatocytes. Intracellular cAMP levels have been assayed by ELISA. And the capacities of free cholesterol efflux to apoA- I from HepG2 cells have been surveyed. Results While the basal expression of GPR109A in hepatocytes was low, we found that its expression was markedly unregulated in liver after injection of low- dose endotoxin. Furthermore, we found that this was due to upregulation in hepatocytes and not simple Kupffer cells. Then we confirmed the similar upregulatory effect response to inflanmaation in human hepatocyte cell line. After using HepG2 cells treated with low dose LPS to compare with the control, we confirmed that forskolin- stimulated intracellular cAMP was significantly reduced in LPS treated HepG2 cells. Finally, we demonstrated that LPS treatment reduced ABCA1 mediated free cholesterol efflux to apoA- I from HepG2 cells. Conclusion These data suggest that increased GPR109A expression in hepatocytes response to LPS treatment may lead to reduced hepatocyte ABCA1 activity, decreased cholesterol efflux to nascent apoA - I, and reduced levels of HDL - C. Though speculative, the results suggest that proinflammatory states, such as those associated with obesity and insulin resistance, may be associated with upregulated hepatic expression of GPR109A.

关 键 词：GPR109A 炎症 高密度脂蛋白 

分 类 号：R54[医药卫生—心血管疾病]