Research progress on the effect of 1, 25-(OH)2D3 on non-alcoholic fatty liver disease
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关键词:
- 非酒精性脂肪性肝病 /
- 1, 25-二羟维生素D3 /
- 维生素D缺乏
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非酒精性脂肪性肝病(NAFLD)是一类多系统疾病，随着生活水平的提高及生活习惯的改变，其发病率逐渐上升，最终可进展为非酒精性脂肪性肝炎(NASH)、肝硬化，甚至肝癌。1, 25-二羟维生素D3[1, 25-(OH)2D3]是人体内维生素D的最终活性形式，正常人群的维生素D缺乏(VDD)具有广泛性，而NAFLD患者体内的维生素D水平则更低。现将1, 25-(OH)2D3对NAFLD的作用的研究进展综述如下。
1. 概述
NAFLD是一类无过量饮酒史(无饮酒史，或饮酒折合乙醇量男性 < 30 g/d, 女性 < 20 g/d)[1]并排除药物或其他导致脂肪肝等干扰因素的临床综合征，分为非酒精性脂肪肝、NASH、NASH肝硬化、NASH相关性肝细胞癌等组织学类型[2]。随着生活条件的改善，亚洲地区NAFLD的发病率可达25%[3], 有研究[4]汇总各国的流行病学调查结果也显示发病率不同程度上升，并且这种趋势一直在加剧，严重影响了人类的健康。目前已明确肥胖、2型糖尿病、血脂异常、代谢综合征等会增加NAFLD发病风险，同时NAFLD患者2型糖尿病、心血管疾病以及慢性肾脏疾病等的患病风险也会增加[5]。NAFLD的发病机制尚未完全明确，以肝脏甘油三酯蓄积为主要特点，是机体内多种信号通路及复杂调控失衡的结果，目前指南推荐以改变膳食结构及增强锻炼为主要干预方式，但仍缺乏明确推荐的药物治疗方法。1, 25-(OH)2D3是维生素D的活性形式，除具有抗氧化、调节钙磷代谢等作用外，其对糖尿病[6-7]、肺病[8-10]、肿瘤[11-12]、免疫类疾病[13-15]等均有影响。一些前期的动物和体外实验[16]发现1, 25-(OH)2D3可通过抑制肝星状细胞的增殖来延缓肝纤维化进展。近来大量研究表明，活性维生素D参与NAFLD的发生与发展，可缓解NAFLD的疾病进程。
2. NAFLD与VDD
维生素D参与人体多种生理过程，除通过食物获得外，也通过太阳光照催化皮肤中7-脱氢胆固醇(7-DHC)转化为前维生素D3, 在血液中与维生素D结合蛋白(DBP)结合，在肝脏维生素D-25-羟化酶作用下转化为25-羟基维生素D3[25-(OH)D3], 最终在肾脏转化为1, 25-(OH)2D3[17]。久坐、长时间室内工作以及高脂高糖饮食导致VDD普遍存在。Holick M F[18]综合多个国家的调查结果，表明了VDD的广泛性。
少数研究表明维生素D与NAFLD之间并无相关性, Jaruvongvanich V等[19]在一项涉及974例NAFLD患者的临床荟萃分析中，发现非酒精性脂肪性肝病活动度积分(NAS)及纤维化评分的高低与血清25-(OH)D3的水平无显著相关性。Patel Y A等[20]检测维生素D代谢基因(CYP24A1, CYP27, CYP2R1, CYP3A4, VDR)的肝脏表达后，发现这些基因的表达与NAFLD严重程度之间没有任何关系，证明NAFLD的组织学特征与维生素D水平之间缺乏关联。
目前多数研究结果支持维生素D和NAFLD之间具有相关性, Roth C L等[21]在动物实验中发现高脂高糖饮食合并VDD的SD大鼠相比低脂组及高脂伴维生素D含量正常组的大鼠，肝脏炎性因子肿瘤坏死因子-α(TNF-α)、白介素-6(IL-6)和白介素-1β(IL-1β)表达上调更明显，同时提出VDD通过脂多糖(LPS)结合CD14/LBP增敏系统激活Toll样受体(TLR)2和TLR4的信号通路，刺激下游炎症信号分子导致脂肪变性和炎症，推动NAFLD的进一步发展。Sharma等[22]发现母体钙和维生素D的缺乏会使雌性后代脂质代谢异常，导致肝脏脂肪变性。
Beilfuss A等[23]对106例NAFLD患者的肝脏活检标本进行分析，发现NAFLD患者血清维生素D水平降低，肝组织中的维生素D受体(VDR)基因表达增加。敲减VDR基因表达后会增加转化生长因子-β(TGF-β)诱导的α-平滑肌肌动蛋白(α-SMA)的表达。Nelson等[24]将190例经组织学检查确定为NASH的患者按血清维生素D水平分类，其中55%患者有VDD(< 20 ng/mL), 在调整年龄、性别、种族、体质量指数(BMI)、谷丙转氨酶(ALT)和糖尿病状态后，表明VDD与NASH独立相关。韩国学者[25]的一项横断面研究发现，在调整代谢综合征和内脏脂肪后，男性VDD与NAFLD之间存在显著关系。中国一项包含2 960名参与者的大样本临床实验中，调整年龄、吸烟、检查季节、血清钙、甲状旁腺激素和所有可能的混杂因素，单变量相关分析显示男性血清25-(OH)D3与肝脏脂肪含量显著相关，女则性不然[26]。Targher G等[27]收集冬季门诊确诊NAFLD的60例患者与60名正常志愿者的整体参数比较，前者血清25-(OH)D3浓度显著降低，并发现25-(OH)D3与NAFLD组织病理学之间是线性相关的。另外，国外学者[28]发现25例NASH患者、36例慢性丙型肝炎(CHC)患者的肝穿刺组织中VDR表达与NASH和CHC患者的肝组织学严重程度呈负相关，血清25(OH)D3水平与活检证实的NASH患者的肝细胞损伤程度成反比, NASH患者胆管细胞VDR表达与脂肪变性严重程度、小叶炎症、NAS评分呈负相关。VDD不仅体现在成年NAFLD患者中，有研究[29]还发现了儿童NAFLD患者的血清低维生素D水平。Manco M等[30]发现64例NAFLD患儿中伴随纤维化的血清25-(OH)D3水平更低，发现肝组织纤维化及炎症程度与血清25-(OH)D3水平相关(P＜0.01)。Kim H S等[31]筛选了1988—1994年4 015例确诊NAFLD的患者并进行长达19年的随访，发现维生素D水平与肝脏脂肪变性程度呈显著负相关(P < 0.01), 并提出VDD增大了NAFLD患者糖尿病和阿尔兹海默症的相关死亡风险。
3. 1, 25-(OH)2D3对NAFLD治疗作用
3.1 NAFLD的发病机制
1998年由DAY最早提出的“二次打击”学说，被广大学者所认可[32]。第一次打击是高脂饮食、肥胖和胰岛素抵抗等导致的肝脏脂质积聚。NAFLD最直接的病因是肝脏脂代谢异常，大量游离脂肪酸及甘油三酯在肝细胞内蓄积。体内正常脂质代谢有以下4种途径: ①膳食脂质吸收[33]; ②脂肪动员; ③肝脏从头合成; ④脂肪酸β氧化。第二次打击是活性氧激发肝实质细胞的炎症级联反应和纤维化。随着研究深度及广度的拓展，“多重打击学说”认为除“二次打击”外，环境、遗传因素和肠道微生物的变化共同作用于遗传易感者诱导NAFLD, 肠道菌群改变导致肠内脂肪酸进一步产生，激活炎症途径和释放促炎因子，炎症细胞因子加重肝脏炎症反应及脂质蓄积，形成肠道-肝脏轴恶性循环[34]。因此，以上任何一个途径出现问题都会导致NAFLD的发生和发展，且这些问题通常是共同存在的。
3.2 1, 25-(OH)2D3改善NAFLD的基础研究
在脂质代谢方面，对高脂饮食(HFD)建立的NAFLD小鼠的研究[35]发现，其肝脏过氧化物酶体增殖剂激活受体(PPAR)-α的表达减少平行于PPAR-γ的表达增加。Borges C C等[36]在喂养HFD及VDD的小鼠肝脏中发现PPAR-γ、甾醇调节元件结合蛋白1(SREBP1c)、碳水化合物反应元件结合蛋白(ChREBP)和脂肪酸合成酶(FAS)增加以及β-氧化减少，这些都是导致肝脏脂肪堆积的重要因素，而1, 25-(OH)2D3剂量依赖性地抑制3T3-L1前脂肪细胞分化后细胞内脂滴的形成，抑制分化早期转录因子PPAR-γ、转录因子α(C/EBPα)[37]、脂蛋白脂酶(LPL)、SREBP1c和FAS的表达[38]。
在氧化应激及炎症反应方面，中国学者[39]以HFD及HFD+VDD构建小鼠NAFLD模型，并连续6周进行5 ng/g的1, 25-(OH)2D3肌注，发现1, 25-(OH)2D3可降低模型鼠的肝甘油三酯、炎症因子TNF-α、IL-6的水平。有研究[40]发现, 1, 25-(OH)2D3通过降低丙二醛(MDA)减弱氧化应激，诱导转录因子NRF2核转位和上调编码抗氧化酶的基因的表达来保护免受HFD诱导的NAFLD。Jahn D等[41]在高脂高糖饮食的小鼠饲料中加入不同剂量的维生素D，发现高剂量(10 000 IU维生素D3)的维生素D可明显改善肝脏脂质堆积情况，降低炎症基因趋化因子(CCL2)的表达，同时发现维生素D治疗后回肠TLR4、TNF-α和IL-1β促炎基因的下调。一项对胆碱缺乏饮食诱导的NASH大鼠的研究[42]发现，补充1, 25-(OH)2D3提高了大鼠血清中25-(OH)D3的水平，降低了谷草转氨酶(AST)、ALT的表达量，并且提高肝脏VDR的表达，提示活性维生素D3对NASH的缓解作用。
3.3 1, 25-(OH)2D3改善NAFLD的临床研究
大量基于人群的临床试验也支持维生素D对NAFLD的治疗作用。Foroughi等[43]研究表明，维生素D补充治疗可降低NAFLD患者空腹血糖，减轻NAFLD患者胰岛素抵抗(IR)程度，增强胰岛素敏感性。Sharifi N等[44]发现改善NAFLD患者维生素D状态可改善血清高敏C反应蛋白和MDA水平。Kitson M T等[45]对12例经活检证实无肝纤维化的NASH患者给予大剂量维生素D(25 000 IU/周)口服24周，发现肝组织学及血清肝酶指标差异无统计学意义，但同时提出，在人群治疗中，维生素D效果体现可能24周时间相对较短。因此，国外学者[46]对48例组织学确定为NASH的患者进行了一项双盲随机对照实验，发现给予2 100 IU维生素D治疗48周后，治疗组血清ALT水平较安慰剂组显著改善。
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