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摘要:
代谢功能障碍相关脂肪性肝病(metabolic dysfunction-associated steatotic liver disease, MASLD) 以肝脏脂质异常沉积为特征, 发病机制与胰岛素抵抗、脂质代谢紊乱、氧化应激及肠肝轴异常等因素密切相关，目前临床尚缺乏有效的治疗手段。沉默信息调节因子2(silent information regulator 2, SIRT2)是一种依赖烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD+) 的去乙酰化酶，通过与不同底物相互作用而发挥多种病理生理功能，如参与改善代谢平衡、缓解肝脏炎症、促进肝脏再生、延缓MASLD进展。本文就SIRT2在MASLD中的作用机制作一综述，以阐述SIRT2作为MASLD治疗靶点的潜在价值。
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关键词:
- 代谢功能障碍相关脂肪性肝病 /
- 沉默信息调节因子2 /
- 胰岛素抵抗 /
- 炎症反应
Abstract:Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by abnormal lipid deposition in the liver and its mechanism is closely related to insulin resistance, lipid metabolism disorders, oxidative stress, and abnormalities of the gut-liver axis. Currently, there is no effective treatment for this disease. Silent information regulator 2 (SIRT2) is a nicotinamide adenine dinucleotide (NAD+)-dependent deacetylase which performs various pathophysiological functions by interacting with different substrates. For example, it is involved in improving metabolic homeostasis, alleviating liver inflammation, promoting liver regeneration, and delaying the progression of MASLD. In this paper, we present a review of the mechanism of action of SIRT2 in MASLD to analyze the potential value of SIRT2 as a therapeutic target in MASLD.
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非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD) 是最常见的慢性肝病，近年来其全球患病率呈逐年增长趋势。NAFLD的主要病变特点为肝脂肪变性，其诊断需排除大量饮酒及其他继发性肝损伤原因[1]。鉴于有学者指出NAFLD的定义不能准确反映肝脂肪变性与全身代谢紊乱的联系，2020年国际专家共识提出“代谢相关脂肪性肝病(metabolic associated fatty liver disease，MAFLD)”的新概念。与NAFLD不同，MAFLD诊断标准中纳入了代谢功能障碍。尽管MAFLD受到一些学者的认可，但更多研究者认为MAFLD的诊断与酒精摄入量无关，可能导致对异质性病因的忽视，且“fatty”一词可能污名化肥胖患者。因此，欧美肝脏协会建议将MAFLD重新命名为代谢功能障碍相关脂肪性肝病(metabolic dysfunction-associated steatotic liver disease, MASLD)。为强调脂肪毒性对肝脏脂肪变性进展的影响，用更准确的术语“steatotic”取代了口语化的“fatty”[2]。学界普遍倾向于用“多重打击”理论解释MASLD的发病机制，即在胰岛素抵抗(insulin resistance, IR)、氧化应激(oxidative stress, OS)、内质网应激(endoplasmic reticulum stress, ERS) 和脂毒性等多种因素的共同作用下诱发MASLD, 并可进一步发展为代谢功能障碍相关脂肪性肝炎(metabolic dysfunction-associated steatohepatitis, MASH)、肝纤维化甚至肝癌[3]。目前，尚缺乏针对MASLD的特效干预手段，临床治疗以生活方式管理为主[4]，因此亟待探寻潜在的分子标志物，以辅助MASLD的早期诊断、疗效评估及预后预测。
沉默信息调节因子2(silent information regulator 2, SIRT2) 是一种依赖烟酰胺腺嘌呤二核苷酸(nicotinamide adenine dinucleotide, NAD+) 的去乙酰化酶[5], 表达于包括肝脏在内的多个器官，广泛参与多种病理生理过程[6-7]。既往针对SIRT2信号通路的研究表明，SIRT2与多种肝脏疾病存在密切关联[8], 且对MASLD具有抑制作用[9]。本文主要针对SIRT2在MASLD发生发展中的可能作用机制作一综述，以期为MASLD分子标志物的遴选提供新思路。
1. SIRT2概述
沉默信息调节因子(sirtuins, SIRTs) 家族是一类在细胞中广泛存在的去乙酰化蛋白, 主要分布在细胞质、细胞核及线粒体，并具有不同的亚细胞定位[10-11], 目前在哺乳动物中发现了7个SIRTs家族成员，其均由约275个氨基酸构成, 具有保守的催化核心结构域和NAD+结合结构域，且N端与C端序列结构域的序列与长度不同，该结构有利于其与细胞骨架蛋白、转录因子和组蛋白等底物相结合, 从而参与调节体内多种生物学过程[12-14]。编码SIRT2蛋白的基因位于染色体19q13.2位点[15]，SIRT2蛋白主要存在于细胞质, 最初认为其在调控基因组稳定与细胞代谢中发挥作用, 被定义为促微管蛋白去乙酰化蛋白[16]。随后研究发现，SIRT2在调节细胞周期、能量代谢、骨代谢及炎症反应中具有显著作用[17-19]。近年来大量研究发现，SIRT2在乙型病毒性肝炎、肝癌及MASLD等肝脏疾病中呈异常表达[20-21], 并通过多条生物代谢途径影响MASLD进程[9, 22]。笔者主要从鸢尾素、糖代谢、脂质代谢、肠道菌群、ERS、炎症反应等方面阐述SIRT2与MASLD之间可能的潜在关联机制。
2. SIRT2与MASLD之间潜在的关联机制
2.1 SIRT2与鸢尾素
鸢尾素是一种经运动刺激后肌肉分泌的氧化物，可由纤连蛋白Ⅲ型结构域蛋白5 (fibronectin type Ⅲ domain containing 5, Fndc5) 中裂解并进入血液循环，通过刺激线粒体解耦连蛋白1(uncoupling protein 1, UCP1) 表达以促进白色脂肪组织(white adipose tissue, WAT) 棕色化。研究发现，血液中鸢尾素水平适度上调可导致机体能量消耗增加，有助于改善肥胖和葡萄糖稳态[23]。AMPK/mTOR是脂肪分解的重要路径，可将细胞质内容物递送至溶酶体以促进脂肪分解，并通过AMPK依赖性途径缓解高脂饮食喂养大鼠的IR程度，改善代谢紊乱状态，该通路异常可能是MASLD的促进因素[24-25]。研究证明，NAD+增强疗法有助于恢复AMPK/mTOR介导的脂肪分解效应，缓解高脂饮食喂养小鼠的MASLD病理特征，其机制与该疗法可刺激SIRT2对Fndc5的去乙酰化作用而抑制Fndc5泛素化降解，继而导致鸢尾素在血液循环中持续释放，稳定分解脂肪相关[26]。
2.2 SIRT2与糖代谢
2.2.1 SIRT2促进胰岛素信号传导
IR是因机体对胰岛素的敏感性下降而造成的葡萄糖利用障碍及其继发的脂质代谢紊乱，大量研究表明，IR可促进WAT分解并激活新生脂肪生成(de novo lipogenesis, DNL)途径, 进而释放大量游离脂肪酸(free fatty acids, FFAs)、合成甘油三酯沉积于肝脏，是MASLD的主要危险因素[27-28]。蛋白激酶B(protein kinase B, Akt) 是胰岛素信号传导的关键下游因子，其表达异常可引起肿瘤、心血管疾病、2型糖尿病及自身免疫性疾病[29]。研究表明, SIRT2过表达可通过增强Akt及其下游因子的效应，以提高机体对胰岛素的敏感性。该过程依赖于AMPK直接或间接磷酸化SIRT2的苏氨酸101位点，促使该位点结构域发生改变并加速SIRT2与Akt的结合[30]。此外，动物实验发现，敲除高脂饮食喂养小鼠的SIRT2基因将导致骨骼肌中Akt磷酸化水平下调和IR的发生，增加MASLD的易感性[31]。
2.2.2 SIRT2促进糖酵解
糖尿病是MASLD最重要的代谢危险因素之一，糖尿病患者因IR与糖利用障碍可造成肝脏脂肪异常沉积，而激活糖酵解途径有助于缓解高脂饮食诱导的肥胖及肝脂肪变性[32]。葡萄糖激酶(glucokinase, GK) 是糖酵解的关键酶，经翻译过程后的葡萄糖激酶调节蛋白(glucokinase regulatory protein, GKRP) 可与GK相结合，并使后者停留于细胞核中，继而无法参与细胞胞质中进行的糖酵解，是糖代谢紊乱的促进因素。文献报道，糖尿病小鼠肝脏中存在高度乙酰化的GKRP，从而不利于自身的泛素化降解[33]。日本一项研究表明，SIRT2可促进赖氨酸126位点上的GKRP去乙酰化以改善肥胖合并糖尿病小鼠肝脏葡萄糖摄取受损状态，证明SIRT2可通过抑制GKRP/GK途径以促进糖酵解，可能是2型糖尿病的治疗靶点并有望缓解MASLD病情进展[34]。但也有研究发现, SIRT2通过诱导糖异生关键酶磷酸烯醇式丙酮酸羧激酶1(phosphoenolpyruv-ate carboxykinase 1, PEPCK-1) 去乙酰化而促进糖异生进程[35-36], 而糖异生是糖酵解的相反生物学过程，其异常活化是糖尿病的重要表现。此种相矛盾的生物学现象可能是受细胞微环境与不同实验条件的影响, 提示SIRT2在葡萄糖代谢中具有复杂的调控机制，进一步阐明其作用机理，并根据需要实施精准诱导，有望为糖尿病、MASLD的预防和干预提供新选择。
2.3 SIRT2与脂质代谢
2.3.1 SIRT2促进脂肪酸β氧化
脂肪酸氧化(fatty acid oxidation，FAO)是机体提供能量的重要路径，并可大量消耗循环系统中的FFAs以缓解其对肝脏的脂毒性。既往研究证实，转录共激活因子过氧化物酶体增殖激活受体辅激活因子1α(peroxisome proliferator-activated receptor-coactivator 1α, PGC-1α)可显著促进脂肪组织表达FAO基因，且PGC-1α去乙酰化状态是保持其转录共激活功能的决定性因素[37]。一项针对基因数据库的研究发现，MASH患者肝脏PGC-1α水平显著下调，进一步研究发现SIRT2与PGC-1α相互作用有利于保持后者的去乙酰化状态，敲除SIRT2后可加速甲硫氨酸-胆碱缺乏饮食喂养小鼠的MASH病情进展[38]。Krishnan等[39]发现，SIRT2介导PGC-1α去乙酰化受缺氧诱导因子1α(hypoxia-inducible factor 1α, HIF1α) 的抑制，可能的机制是HIF1α与SIRT2启动子的缺氧反应元件(hypoxia response element, HRE) 相结合后拮抗SIRT2转录, 当使用他莫昔芬特异性灭活脂肪细胞中HIF1α时，高脂饮食喂养小鼠的脂肪组织中SIRT2表达上调，FAO与全身能量消耗速率增加。与一般人群相比，肥胖者WAT中HIF1α表达水平增加并伴SIRT2水平下调[39]，抑制HIF1α以上调SIRT2, 为治疗MASLD的一条非AMPK依赖性途径[24]。另一项动物实验发现，SIRT2水平下调对FAO存在抑制作用, 其机制与SIRT2去乙酰化作用缺失导致FAO的关键酶肉碱棕榈酰转移酶1α(carnitine palmitoyltransferase 1α, CPT-1α) 高度乙酰化，从而降解速率显著加快有关[40]。一项基于STRING数据库中资料进行的研究发现，肝细胞核因子4α(hepatocyte nuclear factor 4α, HNF4α)是脂质和葡萄糖代谢基因表达的主要调节因子，而SIRT2可使赖氨酸458位点上的HNF4α去乙酰化以抑制其降解，并促进HNF4α靶基因表达CPT-1α，最终缓解肝脂肪变性，提示HNF4α有望作为SIRT2的潜在靶点，辅助MASLD的治疗[41]。
2.3.2 SIRT2抑制新生脂肪生成
生理情况下，DNL可将多余的碳水化合物酯化形成甘油三酯并储存在肝细胞中。IR状态下，肝脏中FFAs增多可引起FAO受损和线粒体功能障碍，诱导DNL过度激活并造成肝脏脂质沉积[42]。ATP柠檬酸裂解酶(ATP-citrate lyase, ACLY) 是参与DNL的关键酶之一，在脂肪变性的肝脏中表达水平明显上调, 有研究表明，赖氨酸540 546 554(ACLY-3K) 位点上的ACLY被乙酰化后可拮抗其自身泛素化降解，进而促进肺癌细胞中脂质合成[43]。在经高脂肪/蔗糖(high fat/high sugar, HFS) 喂养的小鼠肝脏中可同样观察到该结果, 且SIRT2对ACLY的去乙酰化作用可逆转此种现象，提示SIRT2可抑制DNL继而减少脂质沉积，对MASLD病情进展具有缓解作用，具有潜在的应用价值[44]。
2.4 SIRT2与肠道菌群
定植在肠道中的菌群在宿主消化免疫和物质代谢中发挥关键调控作用。有研究证实，肠道菌群失调可诱导代谢紊乱与免疫失衡, 是MASLD发生发展的重要危险因素[45]。不恰当的饮食习惯可改变肠道菌群的分布特征，从而增加MASLD患病风险[46]。我国2023年一项研究发现，敲除SIRT2基因后HFS喂养小鼠的肠道拟杆菌和真杆菌数目及细菌丰富度显著减少, 其肝脏保护性代谢物质(如磷脂酰胆碱和肾上腺素)水平显著下降，促纤维化代谢物质(如L-脯氨酸)水平升高，最终导致MASLD进展为MASH[47]。拟杆菌和真杆菌均有改善肠道菌群紊乱与延缓肝脏脂质沉积的作用, 此外拟杆菌可降低胆固醇水平，真杆菌可显著增强肝脏FAO基因活性，二者又可通过影响肾上腺素释放以调控肝脏中β3受体活性继而促进脂肪分解。L-脯氨酸是参与肝胶原合成的主要氨基酸，其代谢途径可刺激免疫反应产生[48]。提示SIRT2缺乏可引起肠道菌群失调，进而导致代谢紊乱，促进MASLD进展。
2.5 SIRT2与ERS
ERS是病理因素刺激下的细胞自身保护性反应，可通过活化未折叠蛋白反应(unfolded protein response, UPR)以维持蛋白质代谢平衡[49]，但若激活UPR无法缓解内质网压力时, ERS相关促凋亡途径将会启动并促使细胞死亡。研究显示，ERS可影响内质网膜中松散的脂质结构，进而促进脂肪合成, 肥胖啮齿动物的脂肪生成转录因子固醇调节元件结合蛋白1c(sterol regulatory element-binding protein 1c, SREBP1c) 的激活与肝脂肪变性均继发于ERS失调[50]。最新临床研究表明, MASLD患者发展为MASH的过程中存在ERS异常[51]。近年来, 通过SIRT2抑制ERS的生理学功能可能为MASLD的治疗提供了具有潜在应用价值的路径，动物实验证实，在脂质超载条件下SIRT2过表达对棕榈酸酯诱导的ERS具有阻碍作用，而敲除小鼠的SIRT2基因后ERS标志物葡萄糖调节蛋白78(glucose-regulated protein 78, GRP78) 表达增加且该现象不受饮食的影响[9]。这印证了相关毒理学实验：ERS诱导剂毒胡萝卜素可触发人类肝癌细胞中脂质积累，而SIRT2过表达可抵消此种效应[52]。
2.6 SIRT2与炎症反应
炎症反应是以白细胞分泌炎症介质为特征的感染源防御反应, 其过度激活将会对机体产生损害作用[53]。诸多研究表明，SIRT2可通过抑制核因子κB(nuclear factor-κB, NF-κB)和NLR家族pyrin结构域蛋白3(NLR family pyrin domain containing 3, NLRP3) 通路信号传导以缓解炎症反应[54-55]。NF-κB是转录因子家族成员，参与调节炎症和免疫基因表达, 其中以NF-κB p65的作用最为突出。p65通常位于细胞质，在外源性刺激下可转位至细胞核, 从而激活其靶基因表达并启动NF-κB通路依赖性炎症反应。研究表明，肿瘤坏死因子等炎性介质的刺激可促进p65在赖氨酸310位点上的乙酰化，从而增强炎症反应，而SIRT2可通过在相同位点上使p65去乙酰化以抑制NF-κB促炎通路[56]。除作用于NF-κB p65通路外，SIRT2还具有使NLRP3去乙酰化并抑制炎症小体形成的作用, 该机制在动物模型中证实可改善老年小鼠的炎症、IR等MASLD相关病理特征[57]。水飞蓟宾是广泛应用于肝脏疾病治疗的保肝药物，研究发现其作用机制是通过提升肝脏NAD+浓度以促进SIRT2表达，从而抑制上述2条促炎信号通路, 最终缓解肝脏脂肪变性、炎症反应和纤维化[58-59]。
3. 小结
MASLD与机体物质代谢紊乱密切相关[42]。基础研究显示，SIRT2可维持糖脂代谢平衡并改善IR，通过调节PGC-1α、鸢尾素、HNF4α和ACLY等下游因子的活性对MASLD的病理特征具有缓解作用(图 1)。临床研究表明，MASLD患者肝脏中SIRT2水平呈减低状态, 水飞蓟宾与阿卡地新等药物通过上调SIRT2水平可延缓MASLD进展，提示SIRT2有望作为MASLD治疗的新靶点。然而一些研究也报道了SIRT2可诱导加重肝纤维化[22]，表明SIRT2生理作用的复杂性。鉴于目前针对SIRT2在MASLD治疗中作用的研究以动物模型为主，未来需进一步阐明SIRT2在不同环境下的作用机制，并针对特定人群开展临床研究，以期为SIRT2的临床应用提供更多高级别循证医学证据，并促进SIRT2的临床转化，以期为MASLD的干预提供有益参考。
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图 1 SIRT2在MASLD中的作用机制示意图NAD+(nicotinamide adenine dinucleotide): 烟酰胺腺嘌呤二核苷酸; SIRT2(silent information regulator 2)：沉默信息调节因子2;AICAR(5-aminoimidazole-4-carboxamide)：5-氨基咪唑-4-甲酰胺核糖核苷酸；silybin：水飞蓟宾；Fndc5(fibronectin type Ⅲ domain containing 5): 纤连蛋白Ⅲ型结构域蛋白5；Irisin：鸢尾素；PGC-1α(peroxisome proliferator-activated receptor-coactivator 1α)：过氧化物酶体增殖激活受体辅激活因子1α；mitochondrial metabolism：线粒体代谢；HNF4α(hypoxia-inducible factor 1α): 肝细胞核因子4α；FAO(fatty acid oxidation)；脂肪酸β氧化；DNL(de novo lipogenesis)：新生脂肪生成；ACLY(ATP-citrate lyase)：ATP柠檬酸裂解酶；p65(nuclear factor-κB p65)：核因子κB 65；NLRP3(NLR family pyrin domain containing 3)：NLR家族pyrin结构域蛋白3；inflammation response：炎症反应；Intestinal flora disorders：肠道菌群紊乱；MASLD (metabolic dysfunction-associated steatotic liver disease)：代谢功能障碍相关脂肪性肝病；deacetylation：去乙酰化Figure 1. Schematic diagram of the mechanism of action of SIRT2 in MASLD作者贡献：董凯旋负责文献检索和论文撰写；郑亚、王玉平、郭庆红负责论文修订。利益冲突：所有作者均声明不存在利益冲突 -
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图 1 SIRT2在MASLD中的作用机制示意图
NAD+(nicotinamide adenine dinucleotide): 烟酰胺腺嘌呤二核苷酸; SIRT2(silent information regulator 2)：沉默信息调节因子2;AICAR(5-aminoimidazole-4-carboxamide)：5-氨基咪唑-4-甲酰胺核糖核苷酸；silybin：水飞蓟宾；Fndc5(fibronectin type Ⅲ domain containing 5): 纤连蛋白Ⅲ型结构域蛋白5；Irisin：鸢尾素；PGC-1α(peroxisome proliferator-activated receptor-coactivator 1α)：过氧化物酶体增殖激活受体辅激活因子1α；mitochondrial metabolism：线粒体代谢；HNF4α(hypoxia-inducible factor 1α): 肝细胞核因子4α；FAO(fatty acid oxidation)；脂肪酸β氧化；DNL(de novo lipogenesis)：新生脂肪生成；ACLY(ATP-citrate lyase)：ATP柠檬酸裂解酶；p65(nuclear factor-κB p65)：核因子κB 65；NLRP3(NLR family pyrin domain containing 3)：NLR家族pyrin结构域蛋白3；inflammation response：炎症反应；Intestinal flora disorders：肠道菌群紊乱；MASLD (metabolic dysfunction-associated steatotic liver disease)：代谢功能障碍相关脂肪性肝病；deacetylation：去乙酰化
Figure 1. Schematic diagram of the mechanism of action of SIRT2 in MASLD
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