修回日期: 2013-02-20
接受日期: 2013-03-08
在线出版日期: 2013-03-28
维生素D是一种具有广泛生物学活性的重要开环甾醇类激素, 对机体细胞增殖、分化、凋亡、免疫调节等均有重要作用. 近年的研究表明维生素D不足或缺乏与非酒精性脂肪性肝病(non alcoholic fatty liver disease, NAFLD)相关. NAFLD患者血清25(OH)D水平低于对照人群, 低血清25(OH)D水平与患者的肝组织脂肪变性、炎症、纤维化程度有相关关系. 维生素D缺乏饮食可加重NAFLD模型动物肝组织炎症, 补充维生素D可减轻肝组织病理改变. 维生素D对NAFLD作用可能通过其受体VDR介导, 经众多基因调控实现. 维生素D对肝星状细胞的调节可能是其抗非酒精性脂肪性肝纤维化的重要机制. 至今的研究提示维生素D有望成为NAFLD的治疗药物, 但需要更多高质量实验和循证医学的证据.
引文著录: 朴熙绪, 韩红梅. 维生素D与非酒精性脂肪性肝病关系的研究进展. 世界华人消化杂志 2013; 21(9): 766-772
Revised: February 20, 2013
Accepted: March 8, 2013
Published online: March 28, 2013
Vitamin D is an important secosteroid hormone with pleiotropic effects, including regulation of cell proliferation, differentiation, apoptosis, and immunomodulation. Recently certain evidence has indicated that insufficiency of vitamin D or vitamin D deficiency is related to nonalcoholic fatty liver disease (NAFLD). Subjects with NAFLD have lower serum vitamin D levels than controls, and low vitamin D levels are closely associated with histologic severity of steatosis, necrosis, inflammation and fibrosis in NAFLD. Vitamin D-deficient diet aggravated high fat diet-induced hepatic inflammation in NAFLD models, while vitamin D supplementation improved hepatic histopathology. Vitamin D may act as a regulator in NAFLD through activating VDR and controlling various genes. Modulating hepatic stellate cells is an important mechanism underlying the antifibrotic effect of vitamin D in NAFLD. Vitamin D is a potential drug for treatment for NAFLD, and further prospective RCT studies are required to acquire sufficient evidence.
- Citation: Piao XX, Han HM. Relationship between vitamin D and nonalcoholic fatty liver disease. Shijie Huaren Xiaohua Zazhi 2013; 21(9): 766-772
- URL: https://www.wjgnet.com/1009-3079/full/v21/i9/766.htm
- DOI: https://dx.doi.org/10.11569/wcjd.v21.i9.766
维生素D是一种人体必需的脂溶性甾醇类衍生物, 因其生物学作用广泛而视为一种甾醇类激素. 人们最熟知的维生素D的作用是其钙磷代谢的调节和抗佝偻病作用. 近年的研究表明, 维生素D参与细胞的增殖、分化及凋亡, 具有免疫调节、抗炎、抗氧化、抗纤维化、抗肿瘤等多种生物学功能[1-11]. 维生素D的这些功能与不同病因的慢性肝病的发生发展有一定关系[12-16]. 本文对维生素D代谢、机体维生素D不足及其与非酒精性脂肪性肝病(non alcoholic fatty liver disease, NAFLD)关系的研究现状做简要综述.
机体维生素D的主要来源是皮肤合成, 少部分来自饮食. 植物含维生素D2, 动物含D3. 在阳光中波长290-315 nm的紫外线作用下皮肤内胆固醇代谢物7-脱氢胆固醇转化为维生素D3的前体物, 后者以热依赖过程迅速转化为维生素D3, 但过度的阳光照射并不引起维生素D中毒, 因为过量的维生素D还可被阳光破坏[17]. 机体内少量的维生素D来自饮食, 如肥鱼、蛋黄、受紫外线照射的蘑菇类、补充食品等. 饮食来源的维生素D2和D3在胆汁酸作用下由肠道吸收并以乳糜微粒形式经淋巴引流入静脉血流. 皮肤和饮食来源的维生素D可储藏在体内脂肪细胞或可直接到达肝脏, 在肝脏25羟化酶作用下经羟化反应形成25羟维生素D[25(OH)D]. 25羟化酶是细胞色素P450的亚型, 包括微粒体CYP2R1和线粒体CYP27A1酶. 25(OH)D是血液中维生素D的主要形式, 尚无生物学活性, 因其半衰期较长(2-3 wk), 常作为检测机体维生素D储备状态的指标. 血液中25(OH)D绝大多数(88%)与维生素D连接蛋白(vitamin D-binding protein, DBP)结合. DBP是分子量58 kDa的a-巨球蛋白, 在肝内合成, 是位于第4号染色体的白蛋白基因家族成员之一, 与白蛋白, 甲胎蛋白有高度同源系列[18]. DBP有多态性, 常见亚型有Gc1F、Gc1S和Gc2, 其中Gc1F对维生素D的亲和力最强, 这些亚型分布有显著的种族差异[19]. DBP除了携带维生素D的作用外还具有抗炎和免疫调节的作用[20,21].
维生素D活化的最后步骤是25(OH)D在肾脏近曲小管内1a羟化酶(CYP27β1)作用下经1a羟化反应形成具有生物学活性的1,25二羟维生素D[1,25(OH)2D], 这一反应也可少量地发生于非肾脏组织细胞, 如淋巴细胞和甲状旁腺组织. 1,25(OH)2D大多(85%)与维生素D连接蛋白结合, 其半衰期仅约4 h. 维生素D的1a羟化作用受血清钙磷浓度, 甲状旁腺激素, 降钙素, 成纤维细胞生长因子2,3和CYP27β1基因多态性的影响. 机体1,25(OH)2D的状态受负反馈调节, 过量时自身合成减少或可通过上调25羟维生素D-24-羟化酶(CYP24A1)表达促进1,25(OH)2D的分解, 其分解代谢产物由胆汁排泄[22]. 1,25(OH)2D是激活维生素D受体(vitamin D receptor, VDR)的配体. 细胞核内VDR通常与类维生素AX受体形成二聚体, 经维生素D激活与靶基因启动区的维生素D反应元件连接而发挥转录因子的作用, 介导各种生理学反应. 1,25(OH)2D还有一种更迅速的非基因途径的作用, 即配体直接连接到细胞壁小凹的VDR而起作用, 如在胰岛β细胞或心肌细胞中这一途径增加细胞内可利用钙, 经钙依赖信号途径调节各种生理反应[23,24]. 1,25(OH)2D是激活基因途径还是非基因途径VDR取决于其构象的变化. 1,25(OH)2D构象的改变是随机发生还是主动调节尚不清楚, 但这种构象的改变和配体-VDR复合体形成的模式, 有助于理解维生素D更广泛的生理学作用[25].
VDR在机体许多组织细胞中表达, 包括肝、胰腺和几种免疫细胞-单核细胞、巨噬细胞、T淋巴细胞、B淋巴细胞、自然杀伤(naturalkiller cell, NK)细胞等, 特别在胃肠道上皮细胞中表达最丰富. 作为1,25(OH)2D激活的转录因子VDR直接或间接调节200种以上基因的表达, 从而影响细胞增殖, 分化和凋亡, 调节免疫和血管的生成等. 利用VDR敲除小鼠的研究正在兴起, 将揭示维生素D更为广泛的生理学功能[22].
血清25(OH)D浓度是反映机体维生素D储备的客观指标, 但其正常范围的界定并不完全一致. 一般认为正常人血清25(OH)D浓度为75-120 nmol/L(30-50ng/mL), 25(OH)D<50nmol/L(<20ng/mL)定义为维生素D缺乏, 50-75nmol/L(20-30ng/mL)为维生素D不足[26-29]. 按此定义估计,全球约10亿人有维生素D不足或缺乏[30].
阳光紫外线暴露不足是人体维生素D不足的最主要因素. 现代工业所致空气污染阻滞维生素D合成必需的紫外线辐射, 现代人类生活方式如服饰、工作、旅游和室内运动等均可减少皮肤紫外线照射. 为防止皮肤老化和癌症, 人们越来越有意识地利用太阳伞或防晒化妆品来减少阳光照射也是造成机体维生素D不足的重要因素. 随着社会发展人类生命逐渐延长, 且维生素D的皮肤合成和肠道吸收均随年龄增长而减少. 现代许多非强化食物所含维生素D明显少于野生的含油海鱼、淡水鱼、鱼肝油和卵黄
等[30,31]. 机体内维生素D的分布也影响血清维生素D含量. 越来越多的肥胖可能通过脂肪细胞内潴留过多而减少血清25(OH)D. 肥胖者与非肥胖者的脂肪组织以同样的浓度储存维生素D, 因此经口摄入或皮肤合成的维生素D在肥胖者大量脂肪组织中稀释, 导致血清维生素D含量下降[32,33]. 各种原因的吸收不良性体重下降时血清维生素D浓度也下降. 可见体质量改变是该领域研究容易混淆的问题. 现在维生素D不足已经越来越成为世界范围倍受关注的问题[34,35]. 另一方面遗传因素也影响机体的维生素D状态. 维生素D轴相关基因多态性与血清维生素D浓度相关, 包括维生素D连接蛋白, 维生素D受体和a1羟化酶基因多态性[36].
NAFLD是影像学或组织学证实的肝脏的脂肪变性而无继发脂肪肝的原因, 如大量饮酒、促脂肪肝药物、遗传性疾病等. NAFLD与代谢危险因素, 如肥胖、糖尿病、脂质紊乱相关. 组织学上可分为非酒精性脂肪肝(nonalcoholic fatty liver, NAFL)和非酒精性脂肪性肝炎(nonalcoholic steatohepatitis, NASH), 后者可发展为肝硬化、肝癌[37]. 在发达国家NAFLD是最常见的肝病, 发病率高达20%-30%[38], 约30%NAFLD患者有组织学证实的NASH[39]. NAFLD与代谢综合征密切相关, 是代谢综合征的组成成分, 其发病机制尚不完全清楚, 一般认为胰岛素抵抗是肝脏脂肪变性的关键.
目前维生素D缺乏与代谢综合征主成分肥胖, 血脂紊乱, 高血糖和高血压等相关研究较多, 相关证据也比较充分[40], 但维生素D与NAFLD相关研究较少.
个别研究结果血清维生素D水平与NAFLD之间并无独立相关性. 在1 630例12-19岁美国青少年为对象的研究中, 将血清ALT>30 U/L定义为可疑NAFLD, 血清25(OH)D含量由低到高4个组的可疑NAFLD构成比分别为12.1%、6.9%、 8.0%和13.17%(P = 0.05), 多元回归分析结果可疑NAFLD与男性及超质量有关, 在排除肥胖因素后维生素D与可疑NAFLD之间并无相关关系[41].
目前多数研究结果支持维生素D缺乏与NAFLD之间有相关关系. 首先, NAFLD患者血清维生素D浓度较低, 低浓度血清维生素D水平增加NAFLD的风险. 意大利糖尿病和代谢病临床就诊的262例个体中, 162例NAFLD患者的血清25(OH)D水平显著低于无NAFLD者(14.8 ng/mL±9.2 ng/mL vs 20.5 ng/mL±9.7 ng/mL, P<0.001, OR 0.95, 95%CI 0.92-0.98), 在调整性别、年龄、甘油三酯、高密度脂蛋白、高血糖等因素后NAFLD与血清25(OH)D水平之间呈独立相关关系(P<0.005), 在调整性别, 年龄, 胰岛素抵抗指数(HOMA-IR)后25(OH)D水平与脂肪肝指数之间呈显著负相关(P<0.007)[42]. 据韩国的一份最新报告, 在6 567例研究对象中, 2 863例NAFLD患者的血清25(OH)D水平低于3 704例正常人(38.7 nmol/L±9.0 nmol/L vs 39.7±9.7 nmol/L, P<0.001), 血清25(OH)D低中高水平者中NAFLD的比例分别为45.9%、45.0%和40.0%(P<0.001), 提示低水平血清维生素D增加NAFLD的风险[43].
其次, NAFLD患者的血清维生素D水平与肝脏组织学严重程度相关. Targher等[44]报告, 60例肝活检证实的NAFLD患者的血清25(OH)D浓度显著低于年龄、性别、体质量指数相配对的健康对照(51.0 nmol/L±22.0 nmol/L vs 74.5 nmol/L±15.0 nmol/L, P<0.001), 下降的血清25(OH)D浓度与肝组织脂肪变性、坏死性炎症、纤维化严重程度密切相关(P<0.001). 另有一组64例活检证实的NAFLD儿童(平均年龄12.6岁±2.7岁)中平均血清25(OH)D3浓度21.9 ng/mL±10.2 ng/mL, 35例肝纤维化患儿的25(OH)D3水平显著低于29例无纤维化患儿(17.1 ng/mL±7.4 ng/mL vs 27.7 ng/ mL±10.3 ng/mL, P<0.0001), 低水平25(OH)D3与肝组织纤维化(P<0.0001)及炎症坏死程度(P = 0.024)相关; 低25(OH)D3水平预测肝纤维化的敏感性为79%, 特异性达63%[45].
少数实验研究也支持维生素D与NAFLD相关. Nakano等[46]在胆碱缺乏饮食诱导的大鼠非酒精性脂肪性肝炎模型中, 用人工阳光照射结果, 随着活性维生素D3水平的升高, 肝组织炎症和纤维化得到显著改善. 高脂饮食加维生素D缺乏饮食饲养的SD幼鼠与单纯高脂饮食饲养者比较显示更明显的肝小叶炎症, NAFLD活动性积分(NAS)显著升高(3.20±0.47 vs 1.50±0.48, P<0.05)[47]. 蛋氨酸-胆碱缺乏饮食诱导的小鼠NAFLD模型中腹腔注射1,25(OH)2D3可降低血清丙氨酸氨基转移酶和谷草转氨酶, 改善肝组织脂肪变性和血管周围炎症细胞浸润程度[48].
维生素D对NAFLD的作用机制尚不完全清楚. 可能与其促进胰岛素分泌, 改善胰岛素抵抗, 抑制肝组织脂肪生成, 促进脂肪酸氧化作用有关, 其作用经VDR介导, 可能与其多种基因的调控作用有关. 维生素D通过对肝星状细胞的调节发挥其抗非酒精性脂肪性肝纤维化的作用.
NAFLD与糖尿病及胰岛素抵抗密切相关, 因此维生素D的抗NAFLD作用可能与其促进胰岛素分泌, 改善胰岛素抵抗作用有关. 早在上世纪80年代初就已发现维生素D在胰腺的靶细胞可能是胰岛β细胞, 维生素D缺乏可抑制胰岛素分泌[49,50]. 新近的体外实验表明, 维生素D3通过与其受体结合, 降低细胞因子诱导的胰腺β细胞凋亡,改善胰岛素分泌[51], 可通过调节胰岛β细胞内钙浓度, 抵抗β细胞凋亡, 促进β细胞增殖等途径影响胰岛素分泌[52].
已有不少研究提示, 维生素D不足与胰岛素抵抗相关, 补充维生素D可改善胰岛素抵抗. 494例日本成年人群中血清25(OH)D水平与胰岛素抵抗指标HOMA-IR呈显著逆相关(P = 0.01), 与25(OH)D含量正常组相比HOMA-IR指数在25(OH)D不足组高5%, 25(OH)D缺乏组高18%, 提示维生素D状态与胰岛素抵抗相关[53].
肝组织脂肪生成过多和分解减少是肝内脂肪过多沉积的直接原因. 给SD大鼠分别给予正常饮食, 高脂饮食或高脂饮食加1.0、2.5和5.0 μg/kg 1,25(OH)2D3隔日1次腹腔内注射8 wk, 结果表明1,25(OH)2D3可预防HFD诱导的大鼠体质量和肝脏重量增加, 剂量依赖地减轻肝脏脂肪变性, 下调肝组织中参与脂肪生成的胆固醇调节元件蛋白-1c(SREBP-1c)及其靶基因乙酰辅酶A羧化酶和脂肪酸合成酶mRNA表达, 上调肝组织中参与脂肪酸氧化过程的过氧化物酶体增殖物激活受体(peroxisome proliferator activated receptor γ, PPARγ)及其靶基因肉毒碱棕桐酰转移酶mRNA表达, 提示1,25(OH)2D3预防大鼠肝脏脂肪变性的作用与其抑制肝组织脂肪生成, 促进脂肪酸氧化作用有关[54].
维生素D对NAFLD作用与体内多种受体, 细胞因子及酶的调控相关. Roth等对鼠龄25 d的SD幼鼠分别用低脂饮食, 低脂加维生素D缺乏饮食(LFD+VDD), 高脂饮食(WD)或高脂加维生素D缺乏饮食(WD+VDD)饲养10 wk后观察结果, 含VDD组的25(OH)D比对照组下降29%(95%CI: 23%-36%), 表现出显著的肝脂肪变性, 小叶炎症及较高的NAFLD活动性积分; WD+VDD组的肝组织Toll样受体(Toll-like receptors, TLR)2, TLR4, TLR9, 抵抗素(resistin), 白介素(interleukin, IL)-1β、IL-4、IL-6及氧化应激标志物血红素氧化酶1(heme oxygenase, HO-1)的mRNA表达均显著高于WD组(P<0.05); 逻辑回归分析显示, NAS积分与TLR2、4、9与内毒素受体CD14, PPARγ和HO-1的mRNA表达水平之间呈显著相关关系. 研究者认为, 维生素D缺乏可提高肝组织抵抗素基因表达, 上调炎症和氧化应急基因, 可能通过内毒素, 经TLR引起NAFLD[47]. 25例非酒精性脂肪性肝炎患者的肝组织中用免疫组织化学法检测VDR、 CYP2R1和CYP27A1结果, 肝内胆管细胞VDR表达与脂肪变性严重度(P<0.02), 小叶内炎症(P<0.01)及非酒精性脂肪性肝病积分(P<0.03)呈负相关, 肝内炎症细胞VDR阳性与肝细胞CYP2R1的表达之间呈密切相关, 提示维生素D/VDR系统可能参与NAFLD的发病过程[55].
在蛋氨酸-胆碱缺乏饮食诱导的小鼠NAFLD模型中, 肝组织α平滑肌肌动蛋白(α-smooth muscle actin, α-SMA)和1型胶原mRNA的表达显著升高, 而5 μg/kg 1.25(OH)2D3 2次/wk腹腔注射8 wk使这些指标均显著下降(P = 0.020, P = 0.027), 维生素D可能通过α-SMA和1型胶原基因调控延缓小鼠非酒精性脂肪性肝纤维化的进程[48].
肝星状细胞(hepatic stellate cell, HSC)是各种原因的肝纤维化发生发展的关键细胞. 在各种损伤因子作用下HSC由无活性储脂细胞激活为有活性的成纤维细胞, 激活的HSC最显著标志是a-SMA的表达, 可合成大量的细胞外基质特别是1型胶原在肝组织沉积而引起肝纤维化[56]. HSC还可表达基质金属蛋白酶(metalloproteinase, MMP)和组织金属蛋白酶抑制剂(tissue inhibitor of metalloproteinase, TIMP), MMP具有降解细胞外基质的作用, TIMP则抑制MMP的活性, 因此对肝纤维化的发生发展都有重要作用[57]. 血小板衍生生长因子(platelet-derived growth factor, PDGF)是HSC最有效的促分裂因子, 转化生长因子-β(transforming growth factor β, TGF-β)是HSC细胞外基质蛋白合成的主要刺激因子[58,59].
维生素D抗非酒精性脂肪性肝纤维化的作用可能通过对HSC的调控. 首先VDR在HSC中有明显表达, 提示维生素D可能通过HSC的VDR途径发挥其抗纤维化作用. Fickert等[60]在人肝星状细胞和肝细胞中检测了多种核受体, 包括核胆汁酸受体(famesoid X receptor, FXR), 组织雄烷受体(constitutive androstane receptor, CAR), 孕烷受体(pregnane X receptor, PXR)及VDR等, 结果发现人HSC中表达最多的是VDR, VDR在HSC的表达显著多于肝细胞(16.1±8.3 vs 0.7±0.6, P<0.05).
研究表明VDR在静止的HSC高度表达, 当HSC激活期间VDR的表达下降40%. 1,25(OH)2D3可提高激活的HSC对VDR表达. 1,25(OH)2D3还可显著抑制PDGF诱导的HSC增殖和Cyclin D1表达50%, 抑制HSC组织金属蛋白酶抑制剂1(tissue inhibitor of metalloprotease 1, TIMP-1)的表达60%, 降下调节1型胶原a1 40%, 并使基质金属蛋白酶9(matrix metalloproteinase 9, MMP-9)的活性增加30%. 该研究还利用shRNA消除VDR的方法证实1,25(OH)2D3对CyclinD1和1型胶原a1表达的抑制作用呈VDR依赖性[61]. Seydel等[62]的研究发现, 游离脂肪酸可刺激体外培养的人肝星状细胞株LX-2细胞a-SMA和TGF-β mRNA的表达增强, 而维生素D可显著抑制游离脂肪酸对LX-2细胞a-SMA和TGF-β mRNA表达的刺激作用. 这些研究表明HSC有VDR, 维生素D可经过VDR介导抑制HSC增殖和激活, 但维生素D对HSC凋亡的影响尚未见文献报道.
机体维生素D主要来自皮肤, 少数从饮食摄取. 体内维生素D在肝内经25羟化反应形成25(OH)D, 在肾脏经1a羟化反应形成1,25(OH)2D. 25(OH)D半衰期较长, 是反应机体维生素D储备的指标, 1,25(OH)2D是维生素D的活性形式, 经VDR介导发挥作用. 现代生活方式及遗传因素与人类维生素D不足相关. NAFLD患者维生素D不足常见, 与其肝组织脂肪变性、炎症、纤维化相关、补充维生素D可改善NAFLD模型动物的肝组织病理变化. 维生素D对NAFLD作用的机制尚不清楚, 可能通过VDR介导的基因调控, 抑制肝内脂肪生成, 促进脂肪酸氧化, 发挥抗炎抗纤维化等作用, 其抗非酒精性脂肪性肝纤维化作用可能通过对HSC的调控. 维生素D可能是防治NAFLD的一种有效药物, 但需要更多高水平实验研究和循证医学的证据来证明.
维生素D是一种人体必需的脂溶性甾醇类衍生物, 因其生物学作用广泛被视为一种甾醇类激素. 人们熟知的维生素D的作用是其钙磷代谢和抗佝偻病作用. 近年的研究表明, 维生素D参与细胞的增殖, 分化与凋亡, 具有免疫调节、抗炎、抗纤维化等多种功能, 并且与代谢综合征, 不同病因的慢性肝病有一定关系. 维生素D与NAFLD相关的研究领域已取得一些进展.
张明辉, 副主任医师, 河北医科大学第一医院肝病中心(传染病); 刘长征, 副教授, 中国医学科学院基础医学研究所
维生素D缺乏在慢性肝病中比较常见, 特别在慢性丙型肝炎患者中维生素D缺乏可预测抗病毒疗效不佳, 补充维生素D可提高慢性丙型肝炎患者持久的病毒学应答. 较多横向和纵向流行病学研究报道维生素D不足或缺乏与代谢综合征及其组分有关, 可能是部分代谢综合征及组分发生的环境因素, 在维生素D不足或缺乏人群中补充维生素D有一定防治代谢综合征的作用. 非酒精性脂肪肝病(NAFLD)是代谢综合征的组成成分, 但有关维生素D与NAFLD相关的研究较少.
本文比较系统地复习了维生素D的代谢和维生素D不足的原因, 阐述了维生素D与NAFLD相关的研究进展, 反映了该领域研究的概况,文献内容较新颖.
本文有助于维生素D不足或缺乏在NAFLD发病中的作用及其机制的理解, 提示维生素D有望成为防治NAFLD的有效药物.
本文比较系统地介绍了维生素D的代谢, 人群中维生素D不足的常见原因, 比较全面地收集了维生素D与NAFLD相关的临床和基础研究的文献, 内容较新颖,具有一定可读性.
编辑:李军亮 电编: 鲁亚静
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