环境空气污染与代谢相关脂肪性肝病及其各代谢组分的关系研究进展

Research Progress on the Relationship between Ambient Air Pollution and Metabolic Associated Fatty Liver Disease and Its Metabolic Components

摘要

代谢相关脂肪性肝病（metabolic associated fatty liver disease，MAFLD，原名非酒精性脂肪性肝病）是一种与代谢功能障碍密切相关的慢性肝病。近年来，环境空气污染（ambient air pollution，AAP）作为一项重要的环境风险因素，其对代谢健康的影响备受关注。本文旨在综述AAP与MAFLD及其相关代谢组分之间关联的研究进展。流行病学证据表明，AAP暴露是MAFLD和代谢综合征（metabolic syndrome，MetS）发生与发展的危险因素。具体而言，AAP与肥胖、2型糖尿病、高血压及脂代谢异常的风险增加均存在关联，这些代谢紊乱可能共同介导了AAP对MAFLD的促进作用。其潜在生物学机制涉及炎症反应、氧化应激、内皮功能障碍、表观遗传学改变以及肠道菌群紊乱等多条途径。综上所述，新的MAFLD命名强调了代谢异常的核心地位，而现有研究证实AAP通过扰乱代谢稳态，显著增加了脂肪肝及相关代谢疾病的群体负担。

Abstract

Nonalcoholic fatty liver disease （NAFLD） is a clinicopathological syndrome characterized by excessive deposition of lipids in liver cells， caused by nonalcoholic factors. It has recently been renamed as metabolic associated fatty liver disease （MAFLD）， which is more closely related to metabolic factors. Ambient air pollution （AAP） has an increasingly significant impact on public health. This article reviews the latest progress in understanding the relationship between AAP and MAFLD and its metabolic components. AAP is a risk factor for the development of fatty liver and metabolic syndrome （MetS）. AAP is also associated with the risk of obesity and weight gain. AAP not only increases the incidence of diabetes， but also promotes the progression and comorbidity of diabetes. Long-term exposure to AAP can lead to an increase of hypertension in patients from different countries and regions. AAP is associated with abnormal lipid metabolism， and dyslipidemia may mediate the association between AAP and MAFLD. Metabolic disorders can also serve as mediating factors between AAP and many metabolic diseases， thereby increasing disease susceptibility. Air pollutants mainly act on the body through pathways such as inflammatory reactions， oxidative stress， endothelial dysfunction， epigenetics， hormone regulation， and gut microbiota. Overall， the new MAFLD nomenclature underscores the importance of metabolic abnormalities. There is considerable epidemiological evidence that indicates AAP increases the risk of fatty liver and MetS. The different metabolic components of MAFLD and MetS are also negatively affected by air pollutants. AAP may continue to bring a significant disease burden to the population.

关键词

空气污染 / 非酒精性脂肪性肝病 / 代谢相关脂肪性肝病 / 代谢综合征 / 肥胖 / 糖尿病 / 高血压 / 血脂异常

Key words

Air pollution / Nonalcoholic fatty liver disease / Metabolic associated fatty liver disease / Metabolic syndrome / Obesity / Diabetes / Hypertension / Dyslipidemia

随着现代经济社会的快速发展，不良饮食习惯和生活方式有关的代谢性疾病日益突出。非酒精性脂肪性肝病（nonalcoholic fatty liver disease,NAFLD）是与代谢紊乱相关的全球性公共卫生健康问题，其患病率急剧上升至约30%，逐渐超越慢性乙型病毒性肝炎成为中国最常见的慢性肝病^[1-2]。国际专家先后提出将NAFLD更名为代谢相关脂肪性肝病（metabolic associated fatty liver disease，MAFLD）、代谢功能障碍相关脂肪性肝病（metabolic dysfunction-associated steatotic liver disease，MASLD），采用肯定性诊断方法，扩大了疾病涵盖范围^[3-5]。脂肪肝常被认为是代谢综合征的肝脏表现，新命名中定义的五个代谢因素与代谢综合征（metabolic syndrome，MetS）的诊断标准不谋而合。新命名提示MAFLD/MASLD是一个有可能通过对代谢障碍进行干预而改善临床结局的肝脏疾病^[6]。伴随新的命名提出，代谢因素在MAFLD/MASLD的诊治过程中占据越来越重要的地位。环境空气污染（ambient air pollution,AAP）是颗粒物（particulate matter,PM）和气态成分的异质性混合物。由于城市工业化的影响，越来越多的证据表明环境空气污染对人类健康造成严重影响^[7-8]。空气污染与代谢性疾病的关系也不容忽视，目前已有诸多研究表明，脂肪肝疾病发生发展可部分归因于空气污染暴露。本文旨在综述AAP与MAFLD/MASLD及其各代谢组分的关系研究进展，为制定减少AAP相关政策和优化MAFLD/MASLD的预防和管理策略提供科学依据。

1 空气污染与MAFLD/MASLD

近年，新增了一些关于空气污染对脂肪肝影响的流行病学研究证据，主要临床研究归纳如表1所示^[9-16]。一项研究分析显示长期暴露于环境中的PM₁、PM_2.5、PM₁₀和NO₂可能会增加MAFLD患病率，而不健康的生活习惯和中心性肥胖可能会加剧这些影响^[9]。HAN等^[14]发现AAP可能通过血脂的变化导致MAFLD。MATTHIESSEN等^[16]的横断面研究，PM₁₀、PM_2.5、PM_coarse、PM_2.5abs、NO₂和粒子数的年平均暴露量都与NAFLD患病率呈正相关。另外几项研究着重于PM_2.5与脂肪肝的流行病学调查，也得到了一致的结论^[10-13]。LI等^[15]研究认为NAFLD风险与空气污染评分正相关，肝硬化风险也显示了类似趋势，提示空气污染不仅与脂肪肝的发生有关，还协同代谢紊乱等因素促进脂肪肝进展为肝硬化。罗马的一项大型队列研究也观察到长期暴露于研究测试的空气污染物与肝硬化显著相关^[17]。较高的空气污染评分与新发严重肝病的风险增加显著相关^[18]。

由此可见，环境中的空气污染物是脂肪肝疾病发生及病程进展的危险因素的结论较为一致。但是目前尚未检索到以MAFLD/MASLD定义进行的研究，为了明确AAP与MAFLD/MASLD的关系，本文转而进一步探讨环境空气污染对MetS和MAFLD/MASLD的各个代谢组分的影响。

2 空气污染与代谢综合征

代谢综合征是遗传和环境因素（如空气污染）及其复杂相互作用的结果^[19]。MetS的五个组成部分与MAFLD/MASLD诊断标准中的五个代谢组分相同，因此，探讨AAP与MetS的关系对认识AAP对MAFLD/MASLD的影响也至关重要。

空气污染与MetS相关性的流行病学研究数据较充分，主要研究归纳如表2所示^[19-34]。绝对大多数研究都认为AAP增加MetS的患病风险。EZE等^[19]首次观察到了长期暴露于AAP与MetS的患病率呈正相关关系。后续的研究进一步发现AAP不仅增加MetS的发生，还与其各个代谢组分的风险独立相关^{[23, 25, 32]}。MetS还部分介导了长期暴露于PM和心血管疾病之间的关联，PM₁、PM_2.5和PM₁₀的中介效应占比分别为19.3%、12.1%和13.5%^{[23, 30]}。此外，患有MetS和心肺疾病的病人对PM暴露相关炎症更加敏感^[35]。需要进行机制研究来阐明MetS和AP诱导的心血管、肺部疾病的潜在治疗靶点。当然，也有不一致的结论。一项前瞻性研究仅发现了AAP与MetS之间较弱的正相关关系，NO₂的相关性稍强，其OR（95%CI）值为1.12（1.02, 1.24）, PM₁₀、PM_2.5的相关性较弱^[21]。而WANG团队^[31]的研究认为PM₁₀、PM_2.5和O₃ 也许可以增加MetS的风险，但NO₂和SO₂与MetS呈负相关。研究结果的异质性可能与不同地区研究人群的不同特征、污染程度以及暴露评估方法等的不同有关，也可能是由于有限的样本量影响了统计效能。

3 空气污染与肥胖

肥胖是由基因、生活方式、环境因素共同导致的，目前的肥胖流行主要是由环境因素驱动的^[36]，其中空气污染引起了越来越多的讨论^[37]。在一个美国退伍军人群体中，随着PM_2.5浓度的增加，肥胖和体重增加的风险均增大^[38]。中国的全国样本分析也发现长期暴露在PM_2.5环境中会增加成年人肥胖的风险^[39]。PM_2.5与肥胖之间观察到非线性的暴露-反应关系，在PM_2.5浓度小于88 μg/m³时，随着PM_2.5浓度的增加，效应逐渐增强，曲线斜率也逐渐增大，PM_2.5浓度大于88 μg/m³时，效应逐渐减弱^[40]。在校园环境中，与低暴露水平相比，暴露于中等水平的NO₂、PM_2.5或元素碳与儿童超重或肥胖的风险有关^[41]。WANG的团队^[42]发现中国中老年人群暴露于AAP与体重和腰围的增加呈正相关。但是，有研究分析了5 114名韩国健康检查参与者的数据，发现PM₁₀和NO₂年平均浓度的IQR增加与任何肥胖表型无关。同样，在按性别和年龄分层的亚组中，AAP与肥胖特征之间也没有观察到显著关联^[43]。

超重或肥胖个体常存在代谢紊乱、内分泌失调、炎症反应、心血管负担增加等问题，可介导AAP与许多疾病之间的关联，增加疾病易感或严重程度。因此，需要注意遭受严重空气污染的人群的体重状况，因为超重/肥胖使他们更容易遭受疾病风险。

4 空气污染与糖尿病

糖尿病和遗传、环境、生活方式等多种因素相关，许多文献已经报道了空气污染和糖尿病之间的关联^[44]。PM暴露导致的T2D负担在不断上升，2019年，全球约20%的T2D负担归因于PM_2.5暴露^[45]。暴露于AAP可能会对血糖稳态产生不利影响，从而增加中国成人患T2D的风险，其中暴露于PM₁₀和NO₂与T2D风险的关联最强 ^[46]。一项基于中国69 210名无糖尿病病史成年人的研究发现，PM_2.5暴露与糖尿病呈正相关^[47]。LAO等^[48]的前瞻性研究也发现与暴露在PM_2.5第一百分位的参与者相比，暴露在PM_2.5第二、第三和第四百分位的参与者的T2D发病率分别增加28%、27%和16%。PM_2.5及其主要成分的长期暴露均与T2D发病率呈正相关，其中黑碳可能是主要介导因素之一^[49]。除了环境PM，其他污染物的长期暴露也是T2D的风险因素。基于13 548名成年人的研究表明，年平均O₃浓度每增加10 μg/m³，T2D发病风险增加5.7% ^[50]。另一项横断面研究发现，长期暴露于NO₂可能会导致T2D和血脂异常的发展, 这种关联独立于O₃和PM_2.5^[51]。

AAP不仅增加T2D的发病，还促进其进展或共病风险^[52]。减少空气污染暴露、增强体育锻炼、增加绿地面积等^[53]在减轻T2D引起的全球疾病负担方面发挥重要作用，可纳入健康促进策略，以减少共病负担。

5 空气污染与高血压

空气污染造成的死亡和发病率中占比最大的是心血管疾病（cardiovascular disease,CVD）。高血压是常见CVD的一个强大而常见的风险因素。已有诸多研究一致表明，长期暴露于空气污染，尤其是PM_2.5，可导致高血压患病率增加^[54-55]。来自21个国家的数据，表明室外PM_2.5为（3～97） µg/m³时，暴露量每增加10 µg/m³，高血压患病率增加4% ^[56]。在中国，城市空气污染程度与高血压患病率呈正相关，城市绿化与高血压患病呈负相关^[57]。LI等^[58]发现PM_2.5每增加10 µg/m³，高血压的多变量校正风险增加6%。西班牙的一项研究中PM₁₀和PM_2.5浓度每增加5 µg/m³，高血压风险增加分别高达22%和39%^[59]。在一些特殊人群中也有类似的研究结论。例如，AAP暴露与儿童和青少年血压升高和高血压患病率增加有关^[60]。长期暴露于PM_2.5及其特定成分，与中国儿童和青少年的血压升高和高血压患病率升高显著相关^[61]。一项系统评价的数据表明PM和NO₂与妊娠期高血压和先兆子痫呈正相关^[62]。

空气污染对高血压疾病进展的影响也较为显著。空气污染物是从健康状态到突发疾病、多发病和死亡的不同转变中的一个重要决定因素^[63]。PM_2.5每增加一个IQR，从高血压前期向高血压、心血管疾病和死亡进展的风险分别增加11%、5%和9%^[64]。总之，空气污染对各个地区的不同人群的高血压发病都发挥了促进作用，并持续不断地影响着心血管疾病发展的全过程。

6 空气污染与血脂代谢

血脂异常是动脉粥样硬化和随之而来的心血管疾病发展的关键因素。大量证据表明空气污染与血脂代谢受损之间存在关联。一项meta分析发现，在长期暴露的情况下，PM₁₀每增加10 µg/m³，甘油三酯水平就会增加3.14%，NO₂每增加10 µg/m³，甘油三酯水平会增加4.24%^[65]。极端空气污染事件和中等PM_2.5暴露也具有独立的代谢后果，这些暴露导致脂质水平升高，增加心血管疾病风险^[66]。在韩国年轻人中，PM_2.5暴露导致总胆固醇升高，NO₂导致甘油三酯升高和高密度脂蛋白胆固醇降低，O₃导致高密度脂蛋白胆固醇降低^[67]。在丹麦的队列研究中，短期暴露于PM_2.5、超细颗粒物、元素碳和NO₂与高密度脂蛋白降低、非高密度脂蛋白升高相关^[68]。妊娠期间的AAP暴露将影响脐带血脂水平，妊娠期间暴露于空气污染PM_2.5和PM₁₀浓度越高，脐带血样品中甘油三酯、总胆固醇、低密度脂蛋白胆固醇水平越高^[69]。血脂异常可能是AAP和MAFLD之间的重要介质。一项研究分析得出AAP可能通过血脂的变化导致MAFLD^[14]。动物实验证实了PM_2.5诱导代谢功能障碍相关的脂毒性^[70]。与对照组小鼠相比，暴露于环境PM_2.5的小鼠的肝脏甘油三酯、游离脂肪酸和胆固醇水平增加^[71]。

7 环境空气污染影响脂肪肝和代谢的机制

AAP影响脂肪肝和代谢过程的潜在生物学机制尚未阐明，近年的实验研究提出了一些可能的生物学途径来解释这种复杂的联系。首先，长期暴露于空气污染，可通过增加参与先天免疫的炎症细胞，如巨噬细胞和自然杀伤细胞等^[72]，使血液中促炎性生物标志物浓度升高，抗炎性生物标志物浓度降低^[73]。环境空气污染还会诱导机体的肝脏、心脏和其他组织的线粒体损伤，当线粒体功能障碍影响脂质代谢的稳态时，组织脂质供应增加，脂质氧化不完全又将作用于线粒体，影响能量代谢^[74]。空气污染也增加ROS产生，导致氧化还原稳态失衡，加重氧化损伤^[75-76]。总之，空气污染物可能通过直接炎症反应和氧化应激，促进肝脏脂质积聚，导致肝损伤^[77]。其次，空气污染物可导致阻力血管内皮功能障碍，引起动脉硬化和后负荷的变化，转化为持续性高血压，加速动脉粥样硬化^[78]。再者，环境压力源还会引发信号级联的不利遗传变化。例如，暴露于环境PM可以通过ABO基因多态性来改变血脂水平^[79]。DNA甲基化可以介导空气污染对MetS的影响^[80]。空气污染可能通过改变微小RNA谱的表达而导致不良脂质谱和NAFLD风险^[81]。此外，下丘脑-垂体-肾上腺轴相关的激素调节效应^[71]、肠道微生物群^[82] 等也被提出可能导致空气污染诱导的代谢功能障碍。

近年研究表明，空气污染可能通过多种途径与病毒感染产生协同作用，共同促进MAFLD/MASLD的发生发展。首先，空气污染物可直接携带病原体或破坏呼吸道屏障功能，增加病毒感染风险。例如，PM_2.5可携带内毒素^[83]，而NO₂暴露可破坏呼吸道上皮屏障^[84]，从而增加病毒入侵的机会。其次，空气污染可通过干扰抗病毒免疫应答，加重病毒相关代谢损伤。研究表明，臭氧暴露可抑制干扰素的产生^[85]，而PM_2.5可通过TLR4/NF-κB通路激活巨噬细胞，导致慢性炎症^[86]。此外，某些病毒本身具有直接的代谢干扰作用。例如，丙型肝炎病毒（hepatitis c virus,HCV）可通过上调SREBP-1c通路诱导肝脂肪变^[87]。这些研究表明，空气污染可能通过“感染-免疫-代谢”轴，与病毒感染协同作用，共同促进MAFLD/MASLD的发生发展。

8 小结与展望

最新提出的MAFLD/MASLD概念强调了代谢异常的重要性，已有较多流行病学证据表明AAP增加了脂肪肝和MetS的疾病风险。MAFLD/MASLD和MetS的代谢组分受到空气污染物的负面影响，代谢紊乱作为中介因素介导了AAP与许多代谢疾病的关联，增加疾病的易感性。空气污染物成分中PM是最主要的致病原，尤其是PM_2.5促进代谢性疾病的证据最充分，其他PM、NO_X、SO₂、O₃等成分也显示出了类似的较强相关性。AAP可能是通过炎症反应、氧化应激、内皮功能障碍、表观遗传、激素调节和肠道微生物群等途径作用于机体，导致代谢性疾病的发生和进展。尽管AAP只是代谢性疾病的众多诱因之一，但由于其无处不在的性质，可造成全生命周期健康的不利影响。因此，它可能会继续带来大量人口的疾病负担。我们呼吁制定改善空气质量战略，建设健康城市，最大限度地提高公共健康效益，以减少、降低各相关疾病的发生与进展，实现健康中国的宏伟目标。

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基金资助

自贡市卫生健康科研课题(22zd011)