修回日期: 2012-05-03
接受日期: 2012-05-18
在线出版日期: 2012-06-08
胆固醇7α-羟化酶(cholesterol 7-alpha hydroxylase, CYP7A1)是胆汁酸合成代谢经典途径的限速酶. 其表达不仅具有昼夜节律, 而且可由基因多态性、饮食、激素、细胞因子及药物等多种因素调节. CYP7A1的基因多态性与疾病及对药物的治疗反应存在相关性, 同时多种核受体参与了CYP7A1的表达的调控, 共同组成了转录激活/抑制级联网络, 维持体内胆汁酸合成及脂质动态平衡. 本文主要对CYP7A1表达、调控及与疾病及治疗反应的相关性等方面的研究进行综述.
引文著录: 邢万佳, 高聆, 赵家军. 胆固醇7α-羟化酶CYP7A1表达及调控相关研究进展. 世界华人消化杂志 2012; 20(16): 1439-1446
Revised: May 3, 2012
Accepted: May 18, 2012
Published online: June 8, 2012
Cholesterol 7-alpha hydroxylase (CYP7A1) is the first and rate-limiting enzyme in the neutral pathway of bile acids synthesis. The expression of CYP7A1 can be regulated not only by diurnal rhythm, but also by gene polymorphism, diet, hormones, cytokines and drugs. CYP7A1 gene polymorphism is associated not only with some diseases but also with response to drug therapy. A cascade network consisting of multiple nuclear receptors is involved in the regulation of CYP7A1 expression to control bile acid synthesis and lipid metabolism.
- Citation: Xing WJ, Gao L, Zhao JJ. Expression and regulation of cholesterol 7 alpha-hydroxylase: An update. Shijie Huaren Xiaohua Zazhi 2012; 20(16): 1439-1446
- URL: https://www.wjgnet.com/1009-3079/full/v20/i16/1439.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v20.i16.1439
胆固醇7α-羟化酶(Cholesterol 7-alpha hydroxylase, CYP7A1)是胆汁酸合成经典途径的限速酶[1], 催化胆固醇在肝脏分解为胆汁酸, 属肝脏特异性微粒体细胞色素P450酶系. 人体内近50%的胆固醇通过CYP7A1的催化转化为胆汁酸排除体外[1], 因此CYP7A1基因作为胆固醇合成通路中最重要的调控基因[2], 在维持胆固醇稳态及胆汁酸合成中发挥重要作用[3]. CYP7A1基因定位于第8号染色体8q11-q12区域, 其基因序列长度约11 kb, 由5个外显子和6个内含子组成[4]. 在人类, CYP7A1的表达局限于肝脏. 其表达水平受基因多态性、胆汁酸水平、饮食、昼夜节律、激素、细胞因子、药物等因素影响. 下面将有关CYP7A1表达及调控方面的研究进展作一综述.
单核苷酸多态性分析显示, CYP7A1启动子区域多态性在基因表达中具有重要作用[5], 早期研究认为该区域多态性与血浆低密度脂蛋白胆固醇(low density lipoprotein cholesterol, LDL-C)水平及胆囊结石相关[6]. 其中Couture等[7]研究发现, 在男性中与C等位基因阴性者相比, CYP7A1启动子区域-204位存在至少一个C等位基因的个体, 其血浆LDL-C水平升高. Horfman等[8]发现在高甘油三酯血症患者中, 与CYP7A1-278位为AC杂合子或CC纯合子相比, 该位点为AA纯合子者具有较高的胆固醇水平(增高23%, P = 0.005). 也有研究持相反观点, Sánchez-Cuén等[9]在墨西哥人群中发现, CYP7A1-204位C等位基因在胆囊胆固醇结石患者中的频率较正常人群无差异(25.74% vs 27.72%, P = 0.653), AA基因型频率、CA基因型频率及CC基因型频率在两组中亦无差异(58.42% vs 55.45%, P = 0.670; 31.68% vs 33.66%, P = 0.764; 9.90% vs 10.89%, P = 0.818), 故认为CYP7A1基因204位多态性在胆石症高发的墨西哥人群中与发病无明显相关性.
近年发现CYP7A1基因多态性与胆囊癌症及其他疾病之间可能也存在相关性. Lenícek等[5]对65例远端结肠切除的炎症性肠病患者及66例正常对照进行CYP7A1基因启动子区域-203位基因分型, 采用HPLC测定血清中的7α-4胆甾烯-3酮(C4), 以C4/总胆固醇比值代表CYP7A1酶活性. 结果显示, 与正常对照相比, 患者CYP7A1酶活性增高(20.4 μgmmol vs 2.3 μgmmol, P<0.001), 且患者CYP7A1启动子区域-203位AA纯合子酶活性是CC纯合子的2倍. 而在正常对照中, 该等位基因多态性与酶活性不相关. 故认为在生理状态下, CYP7A1-203 A>C多态性无临床意义, 但在结肠切除等胆汁酸吸收不良的患者中, 该基因多态性可严重影响CYP7A1酶活性. Srivastava等[10]发现, 胆囊癌患者CYP7A1基因启动子-204位CC基因型频率较健康对照显著增加(23.4% vs 14.5%, P = 0.005), 推测CYP7A1第204位CC基因型是胆囊癌的独立危险因素, 且性别及年龄分组后该多态性与胆囊癌的相关性在女性及高龄患者中更为密切. 另外对希腊绝经后健康女性的研究[11]亦显示, CYP7A1-204 A>C多态性不仅与是否存在动脉粥样硬化斑块相关(P = 0.004), 而且与颈动脉及股动脉中层内膜厚度相关(P分别为0.047, 0.025), 因此CYP7A1-204 A>C多态性与绝经后健康女性的亚临床动脉粥样硬化呈正相关. 此外, Poduri等[12]在265例新诊断的印度冠心病患者中给予阿托伐他汀治疗, 发现CYP7A1基因204位具有CC基因型的患者治疗后总胆固醇及LDL-C降低程度低于野生型患者, 因此认为CYP7A1-204 A>C可能影响冠心病患者对他汀类药物的治疗反应. 对864例美国白人[13]采用160 mg/d非诺贝特治疗, 结果显示CYP7A1-204 A>G的多态性与治疗反应密切相关. 因此, CYP7A1-204位点不同等位基因的差异可能调控了不同个体对降脂治疗的反应.
在CYP7A1基因其他位点的多态性与疾病的相关性研究方面, Juzyszyn等[14]通过对269例症状性胆石症患者的基因分析, 发现尽管之前研究认为CYP7A1启动子-278 A>C与血脂水平及汉族人中胆石症存在相关性, 但在波兰白种人中该位点多态性与胆石症的发生无关. 最新的一项关于男性血脂异常患者采用饮食干预的研究发现[15], CYP7A1-278位为CC纯合子者其血清甘油三酯(triglyceride, TG)水平显著低于AA纯合子(P = 0.02), 校正其他混杂因素后显示与AA纯合子相比, 饮食干预治疗后AC杂合子及CC纯合子的TG水平明显降低, 因此认为在男性血脂异常个体中, CYP7A1启动子-278 A>C基因多态性可对降脂饮食的效果发生作用.
胆汁酸既是CYP7A1的酶促催化反应产物, 又对CYP7A1的表达具有负反馈调节作用[2]. 内源性胆汁酸作为配体, 可以与法尼醇X受体(farnesoid X receptor, FXR)结合, 进而诱导小异二聚体伴侣(SHP), 进而与人甲胎蛋白转录因子相互作用, 最终对CYP7A1基因在转录水平发挥抑制作用[16-18]. 此外, 胆汁酸还能以非FXR/SHP依赖方式, 通过对c-JNK信号反应级联通路的作用而抑制CYP7A1的基因表达[19]. 此外, De Fabiani等[20]证实胆汁酸可以影响肝细胞核因子4α(hepatocyte nuclear factor 4α, HNF4α)对PGC-1α的募集, 进而抑制CYP7A1的表达.
就胆汁酸的种类而言, 不同的胆汁酸对CYP7A1的抑制程度存在性别差异. 在C57BL/6小鼠[21]中, 研究发现给予去氧胆酸饲食时, 在雄性小鼠中对CYP7A1的抑制程度>雌性小鼠中的抑制程度. 而给予石胆酸及熊去氧胆酸等饲食时, 小鼠肝脏中CYP7A1的mRNA表达水平无性别差异.
作为胆汁酸合成限速酶, CYP7A1的表达受饮食因素的调控. 日本研究者[22]发现在7周龄的SD雄性大鼠中, 给予乳酸发酵的豆奶饲食5 wk后, RT-PCR显示肝组织中CYP7A1的mRNA表达较对照组显著增加(P<0.001), 同时大鼠血清中胆固醇及非高密度脂蛋白胆固醇水平显著降低. 研究已证实在啮齿类短期给予胆固醇饲食可以导致肝脏CYP7A1的上调, 这一调控主要是通过氧固醇感受器-肝脏X受体α(LXRα)实现的. 与短期饲食相比, 慢性长期高胆固醇膳食与人类的饮食状况更接近, 为探讨慢性高胆固醇饲食对小鼠肝脏CYP7A1表达的影响及其机制, 在FVB/NJ小鼠中[23], 采用12 wk的慢性高胆固醇膳食饲食(含量分别为0.2%、1.25%W/W), 结果显示肝脏CYP7A1 mRNA表达在高胆固醇膳食组显著降低(在0.2%、1.25%高胆固醇膳食组分别为0.27±0.14、0.44±0.26, 对照组为1.11±0.51, P<0.05), 同时CYP7A1的上游正向调控核因子PGC-1α的表达在高胆固醇膳食组也降低达78%, 而CYP7A1的负向调控核因子成纤维细胞生长因子15(fibroblast growth factor 15, FGF15)在结肠中的表达上调. 因此, 认为慢性长期高胆固醇膳食在小鼠中可以通过对PGC-1α表达的抑制及FGF15表达的激活而抑制肝脏CYP7A1的表达.
Li等[24]在过表达大鼠CYP7A1基因的转基因(CYP7A1-tg)小鼠中发现, 给予高脂饮食(HFD、42%脂肪、0.2%胆固醇)2-4 mo, CYP7A1酶活性较野生型增加2倍, mRNA水平升高, 肝脏胆固醇及TG水平较同样饲以HFD的野生型小鼠显著降低. 此外, CYP7A1-tg小鼠不仅对HFD诱导的体质量增加呈抵抗, 且糖耐量实验证实其对胰岛素的敏感性增加. 因此, 认为CYP7A1在维持机体的糖、脂及能量代谢方面具有重要作用, 诱导CYP7A1表达可能在治疗诸如脂肪肝、肥胖及糖尿病方面具有良好的前景. 在大鼠中的研究提示, 短期摄取加工食物及快餐中含有的胆固醇氧化产物(cholesterol oxidation products, COPs), 对大鼠生长及脂代谢均有影响, 在♂SD大鼠中的研究[25]发现给予7 d含0.5%COPs的饮食后, 与对照组相比COPs组中肝脏CYP7A1 mRNA水平显著降低, 从而影响胆固醇的分解代谢. 在卵巢切除的仓鼠中添加钙饲食[26], 其肝脏CYP7A1 mRNA表达水平增加, 同时血浆中总胆固醇、TG及非高密度脂蛋白胆固醇水平降低, 因此认为钙剂对血脂谱的改善作用是通过上调CYP7A1基因表达实现的.
代谢通路的昼夜节律调控是维持生理稳态的重要组成部分, 尽管早在30年前已发现CYP7A1的表达具有昼夜节律[27], 但关于参与这一调控的转录因子及确切机制始终存在争议. Rev-erbα作为核受体超家族成员, 不仅是生物钟基因之一, 也是生物钟调节基因[28,29]. Le Martelot等[30]构建了Rev-erbα基因敲除(Rev-KO)小鼠及过表达Rev-erb的转基因(TgRev)小鼠, 观察发现在Rev-KO小鼠中CYP7A1 mRNA的表达幅度及时相均发生显著变化, 昼夜节律受到影响, 全天CYP7A1 mRNA表达水平仅相当于野生型小鼠的60%; 而在TgRev小鼠中CYP7A1 mRNA表达水平增高, 昼夜变化与野生型一致. 因此认为Rev-erbα参与了CYP7A1的昼夜节律调控, 其机制可能由于Rev-erbα活性周期性增高时, 抑制Insig的转录, 从而使固醇反应元件结合蛋白(sterol regulatory element binding protein, SREBP)在细胞核内堆积, 后者上调胆固醇合成限速酶HMGCR, 其酶促反应产物氧固醇进而通过LXRα发挥对CYP7A1的正向调控.
除Rev-erbα外, 在诸多调控CYP7A1的转录因子中, Dbp、Dec2、Rev-erbβ在正常动物均有显著的昼夜节律. 日本的研究[31]发现, 与野生型小鼠中存在明显昼夜节律不同, 生物钟基因突变(clock-/clock-)小鼠其肝脏上述基因的表达几乎完全消失, 但CYP7A1 mRNA昼夜节律显著增加, 仅表现为表达幅度降低. 提示上述3种转录因子不参与生物钟基因突变小鼠的CYP7A1表达调控. 对CYP7A1表达具有下调作用的E4BP4及具有上调作用的HNF4α mRNA表达均明显增强, 但节律消失; 在野生型中表达无节律的LXRα在突变小鼠中仍无节律性, 但表达水平明显增加. Rev-erbβ在突变小鼠中表达减少, 节律性增强; 过氧化物酶体增生激活受体α(peroxisome proliferator activated receptor α, PPARα)mRNA在突变型中尽管节律消失, 但总体表达水平未改变. 采用SiRNA沉默Rev-erbα/β后, 观察到CYP7A1 mRNA表达部分降低, 提示Rev-erbα/β为CYP7A1表达的正向调控因子, EMSA也显示Rev-erbα/β能直接与CYP7A1基因启动子区域结合. 因此, 认为在小鼠中完整的生物钟调控着肝脏CYP7A1的昼夜节律性表达, 且多种转录因子, 诸如DBP、Rev-erbα/β、DEC2、LXRα、HNF4α及PPARα等共同参与了对CYP7A1昼夜节律性表达的调控.
与上述研究结果不同, Duez等[32]对Rev-erbα缺陷小鼠的研究发现, 其肝脏中对CYP7A1表达起负调控的SHP及E4bp4的mRNA表达增加, 但节律性消失; 同时CYP7A1尽管节律性仍与野生型中基本保持一致, 但mRNA表达幅度减低. 在腺病毒介导的Rev-erbα过表达小鼠中, CYP7A1的表达可被诱导增加. 转染试验及CHIP均证实Rev-erbα可通过位于启动子区域的Rev反应元件抑制SHP及E4bp4的转录. 因此, 认为Rev-erbα是通过抑制SHP及E4bp4的转录, 发挥对CYP7A1表达及昼夜节律的调控作用.
CYP7A1表达除受昼夜节律及基因多态性影响外, 还可被激素、细胞因子等多种因素调控. 其表达调控主要发生在转录水平, 受到包括FXR[33]、HFN-4α[17]、SHP[34]、SREBP-1C[35]、PGC-1α[36]等诸多核因子调控.
成纤维细胞生长因子19(FGF19)(小鼠中的类似物是FGF15), 属于FGF家族成员[37], 是特异性表达于结肠的细胞因子, 具有激素样效应. 研究显示FGF19/15可有效抑制肝脏中CYP7A1的表达并减少胆汁酸的合成[38-40], 而在FGF15缺陷小鼠中, CYP7A1的基础mRNA水平增加3.5倍[41]. 产后哺乳期大鼠中CYP7A1的表达及胆汁酸池均增加2-3倍, 对产后10 d的大鼠研究[42]发现, 其结肠中表达的FGF15 mRNA水平降低70%, 同时CYP7A1酶活性增加, 进一步确定了FGF15对CYP7A1的负调控作用. 在人原代肝细胞中的研究发现, FXR活化可增加肝脏FGF19的表达, 从而抑制CYP7A1, 故认为FGF19在人类可经自分泌或旁分泌机制抑制CYP7A1的表达[43]. 在具有脂肪肝样症状的FXR基因缺陷小鼠中的研究发现[44], 给予400 μg/(kg•d)的重组FGF19处理3 d, 与安慰剂处理的野生型小鼠相比, FXR基因缺陷小鼠肝脏中CYP7A1 mRNA表达显著减少.
胆汁酸可以引起肝脏Kupffer细胞释放白介素1(interleukin-1, IL-1)及肿瘤坏死因子α(tumor necrosis factor α, TNFα), 这两种细胞因子可以分别通过TNF受体及线粒体激活的蛋白激酶(MAPK)/JNK信号通路对CYP7A1的表达发挥调控作用[45]. 在IL-1α/β基因敲除的Balb/c小鼠模型中[46], 当野生型(WT)与基因敲除(IL-1 KO)小鼠进行性别匹配后, 前者的CYP7A1 mRNA水平为IL-1 KO小鼠的3倍. 因此, IL-1α/β是小鼠CYP7A1的正向调控因子. 进一步的调控机制研究[47]发现, 在IL-1 KO小鼠及性别匹配的WT小鼠中, 肝组织中CYP7A1的上游正向调控核因子HNF4α表达水平与IL-1水平密切相关, 同时, CYP7A1的上游负向调控核因子SHP的mRNA表达在IL-1 KO小鼠肝脏中显著升高. 可见, IL-1不仅对CYP7A1的正向调控核因子有上调作用, 而且可以降调节CYP7A1的负向调控核因子SHP, 其对CYP7A1表达总效应是通过对其上游正向核因子及负向核因子的共同作用实现的.
在人Hep3B肝癌细胞中给予10 μg/L TNFα处理过夜后, 其CYP7A1的上游正向调控核因子PGC-1α的蛋白表达显著降低、启动子荧光素酶报告基因活性也显著受抑制, 推测TNFα也可引起CYP7A1表达抑制[48]. 以TNFα处理人HepG2肝癌细胞株[49]后, 同样发现CYP7A1基因表达受抑制并导致胆固醇水平增高. 最近在FVB/NJ小鼠中给予高胆固醇膳食的研究[23]也显示在高胆固醇条件下, 小鼠血清中炎性细胞因子IL-1β及TNFα的水平均显著增加, 两者均可导致细胞外信号调控激酶(ERK)及JNK的磷酸化, 进而磷酸化的ERK及JNK作为始动因素引起CYP7A1表达的抑制.
肝细胞生长因子(hepatocyte growth factor, HGF)作为调节肝细胞分化、再生的细胞因子, 在肝脏的生理及病理调节中具有重要作用. Chandra等[50]以50 μg/L HGF处理人原代肝细胞后, 6 h内即观察到CYP7A1 mRNA水平降低95%, 即便在生理浓度(5 μg/L)时, HGF也能使CYP7A1 mRNA水平降低70%, 同时C-jun及SHP的mRNA表达迅速升高. 荧光素酶报告基因显示CYP7A1启动子-150至-135区域介导了HGF对CYP7A1的抑制效应. 采用SiRNA干扰HepG2细胞的C-met表达后, HGF对SHP的诱导幅度及对CYP7A1抑制幅度均降低, 提示SHP及C-met在介导HGF对CYP7A1的表达抑制中发挥重要作用.
作为参与糖脂代谢的重要激素, 胰岛素在脂代谢稳态中的作用日益受到关注. Kovár等[51]在健康男性短期(1 d)分别给予消胆胺(16 g/d)及鹅脱氧胆酸(1-1.5 g/d)后, 观察到代表胆汁酸合成能力及CYP7A1酶活性指标的C4曲线下面积与胰岛素曲线下面积存在相关性, 提示胰岛素可能参与了人类CYP7A1表达的调控. 胰岛β细胞转录因子FOX1作为胰岛素信号级联通路的组分, 在胰岛素信号转导中发挥重要作用. 用SiRNA技术敲除FOX1后[52], 人原代肝细胞中CYP7A1的mRNA表达水平增高6倍, 认为FOX1是对CYP7A1基因表达具有强烈抑制作用的核因子. 进一步分析认为胰岛素对人原代肝细胞的作用具有双相性, 短期作用由于FOX1被释放, 从而将PGC-1α募集至HNF4α, 从而增加CYP7A1 mRNA表达; 延长作用时间则通过诱导成熟的SREBP-1C, 使后者与CYP7A1的染色质结合, 抑制HNF4α与PGC-1α的结合而发挥对CYP7A1 mRNA的降调节. 最新一项在C57BL6小鼠中的研究[53]发现大鼠的CYP7A1启动子活性可被胰岛素-PI3K-AKT-FOX1信号通路所调控, 胰岛素可通过SHP/FOX1依赖的通路对大鼠CYP7A1的表达发挥降调节, 而这一胰岛素依赖的CYP7A1的负调控机制可能就是联系糖代谢与脂代谢的纽带.
作为胰岛素的拮抗激素, 胰高血糖素是在饥饿状态下由胰岛α细胞分泌. 目前关于其参与脂代谢的研究显示, 在人原代肝细胞[54]中可以显著抑制CYP7A1的mRNA表达水平, 进一步由CHIP实验证实胰高血糖的上述效应是通过降低HNF4α与CYP7A1染色质的结合实现的.
关于甲状腺激素在脂肪分解代谢中的作用研究较为深入, 最初在小鼠及大鼠中的研究显示甲状腺激素可以通过对基因转录的直接作用调控CYP7A1的表达[55-57]. 而啮齿类在甲状腺激素作用下, CYP7A1基因转录水平的迅速增加提示甲状腺激素本身在转录水平对CYP7A1的表达产生调控作用[58]. 在甲状腺激素受体(TR)基因敲除小鼠中, 三碘甲腺原氨酸(T3)对CYP7A1的诱导作用消失, 提示TR在介导T3对CYP7A1的刺激效应中发挥作用[59]. 与在啮齿类中的研究结果相反, 在人HepG2细胞中的研究[60]显示T3对CYP7A1具有抑制作用. 随后Drover等[61]证实在人CYP7A1的基因启动子区域存在特异性的T3反应元件, 介导了T3对CYP7A1的抑制效应. Ellis[62]在人原代肝细胞中采用不同剂量T3处理后, 发现CYP7A1的mRNA表达呈剂量依赖性降低. 但在大鼠中的研究[63], 却未能发现甲状腺激素对CYP7A1启动子活性发挥抑制作用. 因此, 关于甲状腺激素对CYP7A1的调控是否存在种属差异及其确切机制还有待进一步研究.
在糖皮质激素与CYP7A1调控的研究中, Liu等[64]在♂大鼠出生1-3 d给予糖皮质激素-地塞米松, 结果发现与对照组相比, 地塞米松处理组大鼠肝组织中CYP7A1的mRNA表达迅速增高. 但也有研究持相反观点, Chen等[65]对败血症的大鼠研究发现, 其肝脏中CYP7A1的mRNA表达水平降低, 而给予地塞米松治疗后, 尽管作为CYP7A1上游调控核因子的视黄酸X受体α的mRNA表达增加, 但CYP7A1的mRNA表达并未增加.
Schmidt等[66]对C57BL/6小鼠的研究发现, 在野生型小鼠短期(6 h)给予活性维生素D[1,25-(OH)2-D3]可增加肠道FGF15mRNA表达, 降低肝脏中CYP7A1 mRNA水平. 在FGF15基因敲除小鼠及FXR基因敲除小鼠中, 1,25-(OH)2-D3对CYP7A1表达的抑制作用则不存在, 提示在维生素D对CYP7A1基因表达的抑制中, 核受体FXR及FGF15发挥了作用. 在人CYPA71启动子区域BARE-Ⅰ序列可以和维生素D受体(vitamin D receptor, VDR)结合, 导致启动子活性受抑[67].
Kim等[68]将4周龄♂SD大鼠随机分为单纯高脂饮食组(45%脂肪)及高脂饮食加0.1%(W/W)姜黄素组, 饲食8 wk, 观察两组血脂谱及肝脏CYP7A1 mRNA表达水平. 结果发现姜黄素添加组TG水平较单纯高脂饮食组降低27%(P<0.05), 血浆总胆固醇及LDL-C水平也分别显著降低34%及68%(P<0.05), 致动脉粥样硬化指数(atherosclerosis index, AI)也较对照显著降低48%(P<0.05). 同时, CYP7A1 mRNA水平在姜黄素组增高2.6倍(P<0.05). 故认为姜黄素对CYP7A1基因表达的上调作用是其降脂效应的机制之一.
Wang等[69]在小鼠原代肝细胞中给予纯花青素成分矢车菊-3-β-葡萄糖苷处理, 结果发现细胞中CYP7A1表达增加, 胆汁酸合成增加, 且上述变化呈LXRα依赖性. 因此, 认为矢车菊-3-β-葡萄糖苷的促进CYP7A1表达效应是通过其上游调控因子LXRα实现的, 这可能是花青素具有降低胆固醇作用的机制之一. 在人原代肝细胞[70]中, 利福平可以降低CYP7A1的mRNA表达水平. 进一步机制研究显示利福平是通过上调了对CYP7A1具有负调控作用的孕烷X受体(PXR)的表达, 后者通过与HNF4α作用, 最终导致对CYP7A1的抑制效应.
随着研究的深入, CYP7A1及诸多调控其转录的核受体在胆汁酸合成、脂代谢稳态的维持与疾病的相关性及对治疗药物的反应等方面的作用日益受到关注. 新效应及机制的不断阐明, 有望使CYP7A1及各种调控因子作为治疗的新靶点, 为高胆固醇血症、胆道病变等的预防及治疗提供新的研究思路.
近年来, 研究者在肝脏胆固醇分解代谢途径中的限速酶胆固醇7α-羟化酶(CYP7A1)的表达及调控方面进行了大量体内及体外实验, 目的在于探讨CYP7A1与疾病的关系及对降脂药物治疗的反应性, 并明确诸如昼夜节律、饮食、激素、各种细胞因子等对CYP7A1表达的影响.
陈进宏, 副主任医师, 复旦大学附属华山医院外科
目前已有大量研究揭示了CYP7A1的表达调控主要发生在基因转录水平, 但数量众多的上游调控核因子及核因子间相互作用的复杂级联网络, 以及种属间差异的存在, 使得有关CYP7A1表达的调控机制仍未阐明.
本综述在系统回顾CYP7A1基因多态性及表达和调控研究的基础上, 重点对近5年在此领域内的研究进行了综述, 便于把握CYP7A1相关研究的最新动态, 为后续研究提供新的切入点.
CYP7A1基因多态性与疾病的相关性, 可能为临床肝胆病变的筛查提供新的途径. 同时, 明确不同基因位点多态性与降脂治疗后血脂谱的不同变化, 可以为临床个体化降脂方案选择提供依据.
胆固醇7α-羟化酶(CYP7A1): 胆汁酸合成代谢经典途径的限速酶. 多种核受体在CYP7A1的表达中具有重要调控作用, 共同组成了转录激活/抑制级联网络, 调节体内胆汁酸合成及脂质动态平衡.
本综述较全面阐述胆固醇7α-羟化酶CYP7A1表达及调控研究进展, 具有一定的学术价值和参考意义.
编辑:曹丽鸥 电编:闫晋利
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