J Lipid Res：郑辉等发现胆固醇水平影响受体功能

中科院广州生物医药与健康研究院郑辉博士研究组发现，在人胚胎肾细胞（HEK）、原代培养的大鼠海马区神经细胞以及成年小鼠体内，低于正常的胆固醇水平会阻碍μ型阿片受体的信号转导和其介导的镇痛作用。研究组与北京中日友好医院合作，发现病人血液总胆固醇水平与手术麻醉时使用的芬太尼的剂量成负相关。

研究表明，虽然高胆固醇水平会增加罹患心血管疾病的几率，但过低的胆固醇水平会阻碍部分G蛋白偶联受体（以μ型阿片受体受体为代表）的正常功能，进而影响药物的疗效。由于目前市场上40%以上的药物都是以G蛋白偶联受体为作用靶标，该项研究对胆固醇水平的临床调控具有指导意义。

该研究成果已于近日在国际期刊Journal of Lipid Research在线发表（生物谷Bioon.com）

doi:10.1194/jlr.M024455
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Cholesterol level influences opioids signaling in cell models and analgesia in mice and humans

Hui Zheng1,*, Haibo Zou2, Xiaopeng Liu1, Ji Chu3, Yali Zhou3, Horace H. Loh3 and Ping-Yee Law3

Cholesterol regulates the signaling of μ-opioid receptor in cell models, but has not been demonstrated in mice or humans. In addition, whether cholesterol regulates the signaling by mechanism other than supporting the entirety lipid raft microdomains is still unknown. By modulating cholesterol-enriched lipid raft microdomains and/or total cellular cholesterol contents in human embryonic kidney cells stably expressing μ-opioid receptor, it is concluded that cholesterol stabilized opioid signaling both by supporting the lipid raft's entirety and by facilitating G protein coupling in heterologous expression system. Similar phenomena were also observed in the primary rat hippocampal neurons. In addition, reducing the brain cholesterol level with simvastatin impaired the analgesia effect of opioids in mice, whereas opioid analgesic effect was enhanced in mice fed with high-cholesterol diet. Furthermore, when the records of patients were analyzed, an inverse correlation between cholesterol levels and fentanyl doses used for anesthesia was identified, which suggested the mechanisms above could also be applicable in humans. Current results identified the interaction between opioids and cholesterol, which should be considered in clinic as a probable route for drug-drug interaction. The studies also suggested that low cholesterol level could lead to clinical issues such as the observed impairment in opioid functions.