慢加急性肝衰竭能量代谢紊乱的代谢组学特征及相关靶向治疗策略

Metabolomic features of energy metabolic dysregulation and related targeted therapeutic strategies in acute-on-chronic liver failure

摘要

慢加急性肝衰竭是一种在慢性肝病基础上发生的急性失代偿综合征，以短期高病死率为特征。代谢组学揭示其存在显著能量代谢重编程，表现为糖、脂、氨基酸、线粒体代谢及肠道菌群失调的广泛紊乱状态，并与系统性炎症、免疫失衡密切相关，共同推动病情进展。糖异生抑制及糖酵解亢进、脂肪酸β-氧化受阻、线粒体氧化磷酸化受抑制、氨代谢失衡和肠道菌群失调等构成核心代谢表型。本文整合了近年代谢组学与分子机制研究，系统梳理了五大代谢网络的紊乱特征。针对能量代谢干预，归纳糖代谢调节、脂代谢干预、线粒体靶向保护、肠道菌群再平衡、氨基酸优化等五大策略，并评估其应用价值与未来转化前景，为治疗、缓解甚至逆转疾病进程的思路提供科学依据。

Abstract

Acute-on-chronic liver failure is an acute decompensated syndrome that occurs on the basis of chronic liver disease and is characterized by a high short-term mortality rate. Metabolomics reveals the presence of significant energy metabolic reprogramming， manifesting as extensive dysregulation of glucose/lipid/amino acid metabolism， mitochondrial metabolism， and intestinal flora， and it closely interacts with systemic inflammation and immune imbalance， jointly promoting disease progression. The core metabolic phenotypes include suppressed gluconeogenesis， enhanced glycolysis， impaired β-oxidation， inhibited mitochondrial oxidative phosphorylation， ammonia metabolic imbalance， and gut microbiota dysbiosis. This article analyzes the latest studies on metabolomic and molecular mechanisms and systematically reviews the dysregulation characteristics of the five major metabolic networks. In terms of intervention for energy metabolism， this article summarizes the five strategies of glucose metabolism regulation， lipid metabolism intervention， mitochondria-targeted protection， gut microbiota rebalancing， and amino-acid optimization and assesses their application value and prospects for clinical translation， so as to provide a scientific basis for the treatment， alleviation， and even reversal of disease progression.

Graphical abstract

关键词

慢加急性肝功能衰竭 / 能量代谢 / 代谢组学

Key words

Acute-On-Chronic Liver Failure / Energy Metabolism / Metabolomics

在2025年亚太肝病学会更新的共识中，慢加急性肝衰竭（acute-on-chronic liver failure，ACLF）是指在慢性肝病的基础上，由病毒感染、酒精和药物等因素诱发的一种临床综合征，其典型特征为急性肝功能失代偿（总胆红素>5 mg/dL且国际标准化比值≥1.5），常伴腹水、肝性脑病（hepatic encephalopathy，HE）及多器官衰竭，短期病死率高^［1］。ACLF的发病机制复杂且尚未完全明确，系统性炎症与免疫异常激活被证实是疾病进展的核心驱动力，而代谢组学进一步揭示能量代谢重编程与预后密切相关^［2］。现阶段，ACLF内科治疗以针对基础肝病病因及诱发因素的治疗为主，营养支持作为人体机能恢复的基础，尚缺乏高效精准的干预手段。因此，阐明ACLF能量代谢障碍的机制并寻找可干预靶点，对改善预后具有重要临床意义。

肝脏作为人体最大的消化腺，深度参与体内糖类、脂类和蛋白质的代谢过程，在机体代谢中发挥枢纽作用。当肝脏遭受侵害而丧失代偿功能时，会并发不同程度的能量代谢障碍，表现为氧化应激增强、氨基酸分解代谢增强、脂类合成受阻及肠道菌群失调等^［3］。在ACLF的炎症高代谢状态下，机体能量消耗显著增加；与此同时，代谢重编程过程可进一步激活免疫反应，促进促炎及趋化因子的释放，以清除病原体^［4］，具体机制如下所述。

1 ACLF能量代谢紊乱的代谢组学特征

1.1 糖代谢紊乱

1.1.1 糖原分解和糖异生抑制

肝脏是机体糖代谢的核心器官，负责糖原合成并通过糖原分解/糖异生以维持血糖稳定。在ACLF的炎症高代谢状态下，下丘脑-垂体-肾上腺轴和交感神经系统被激活，加速糖原分解^［5］。同时，腺苷酸活化蛋白激酶被激活，通过直接磷酸化其底物（环磷腺苷效应元件结合蛋白、环磷腺苷效应元件结合蛋白转录共激活因子2），抑制肝糖异生^［6］。此外，沉默信息调节因子可能与哺乳动物雷帕霉素靶蛋白信号通路相互作用，抑制糖异生限速酶［磷酸烯醇式丙酮酸羧激酶、葡萄糖-6-磷酸酶（glucose-6-phosphatase，G6Pase）］的表达水平^［7］。肝脏功能受损后，可因糖原储备减少、糖异生能力减弱及胰岛素代谢异常等因素，在糖原储备耗竭后，糖原分解无法继续，进而导致低血糖发生风险增加，病死率升高。

1.1.2 糖酵解亢进

糖酵解是将葡萄糖分解为丙酮酸，并产生三磷酸腺苷（adenosine triphosphate，ATP）和还原型烟酰胺腺嘌呤二核苷酸，涉及肝脏糖酵解的关键酶包括己糖激酶、葡萄糖转运蛋白1以及丙酮酸激酶M2型。在炎症刺激下，免疫细胞发生代谢重编程，从氧化磷酸化（oxidative phosphorylation，OXPHOS）转向糖酵解与戊糖磷酸途径（pentose-phosphate pathway，PPP）供能。通常认为ACLF中M1型巨噬细胞糖酵解显著增强。低氧诱导因子-1α（hypoxia-inducible factor-1 alpha，HIF-1α）可驱动免疫细胞（M1巨噬细胞、CD8⁺ T细胞）代谢重编程，上调葡萄糖转运蛋白1、己糖激酶2的表达，促进糖酵解^［8］。而程序性死亡受体-1/程序性死亡配体-1信号进一步抑制T细胞的糖摄取，加重免疫耗竭^［9］。恢复免疫细胞代谢与功能状态可减轻肝损伤并促进肝再生。另外，缺氧时糖酵解增强致乳酸堆积，高乳酸血症与疾病严重程度及不良预后呈正相关^［10］。

1.1.3 PPP激活

PPP是葡萄糖代谢的重要分支，葡萄糖-6-磷酸从糖酵解分支后生成核糖-5-磷酸和还原型烟酰胺腺嘌呤二核苷酸磷酸（reduced nicotinamide adenine dinucleotide phosphate，NADPH）。核糖-5-磷酸可转化为果糖-6-磷酸和甘油醛-3-磷酸，这也是糖酵解途径的中间代谢物。由PPP产生的核糖-5-磷酸进入糖酵解途径并逆向转化为葡萄糖-6-磷酸，如此循环往复直至葡萄糖-6-磷酸完全降解^［11］。尽管NADPH生成增加有助于维持细胞氧化还原平衡，但过量NADPH可导致活性氧（reactive oxygen species，ROS）生成增多，抑制线粒体OXPHOS，加剧细胞损伤^［12］。研究显示，与健康对照组相比，ACLF患者体内糖酵解、PPP、糖异生和糖原分解相关基因表达均上调^［13］。在脂多糖/ATP激活的巨噬细胞中，糖酵解通量增加导致PPP代谢物核糖-5-磷酸累积，其衍生的5-磷酸-α-D-核糖-1-焦磷酸直接促进嘌呤合成；敲低PPP关键酶葡萄糖-6-磷酸脱氢酶或磷酸核糖焦磷酸合成酶，可抑制NOD样受体热蛋白结构域蛋白3炎症小体活化及炎症因子释放^［14］。

1.2 脂代谢紊乱

肝脏是脂肪代谢的主要器官，参与脂肪酸氧化、甘油三酯合成、胆固醇代谢以及脂蛋白合成和分泌。ACLF的脂质代谢呈“β-氧化受阻、脂蛋白合成减少、胆汁酸循环紊乱”三联征。肉碱棕榈酰转移酶1是线粒体脂肪酸氧化的关键限速酶，肝细胞坏死及线粒体损伤使其活性下降，长链脂酰-辅酶A无法转入线粒体，进而造成酰基肉碱堆积，ATP生成减少^［15］。同时，肝合成载脂蛋白A、B能力下降，导致高密度脂蛋白水平与低密度脂蛋白水平降低^［16］。研究显示，血浆载脂蛋白A-Ⅴ、载脂蛋白A-Ⅰ的同步下降对1年病死率具有预测价值（载脂蛋白A-Ⅴ<480 ng/mL，阴性预测值为92.23%）^［17-18］。胆汁酸是胆汁的关键成分，主要存在于肠-肝循环系统，并通过再循环维持代谢稳态。研究证实，胆汁酸淤积可通过法尼酯X受体/过氧化物酶体增殖物激活受体α信号通路下调肉碱棕榈酰转移酶1A与酰基辅酶A氧化酶1的表达，导致脂肪酸β氧化受阻，脂肪酰肉碱堆积，肠腔内乳化作用减弱^［19］。

1.3 线粒体代谢紊乱

线粒体作为细胞的 “能量工厂”，主要通过OXPHOS过程产生ATP，同时也是ROS的主要产生场所。OXPHOS是ACLF能量危机的核心环节。锌指同源盒蛋白2是OXPHOS的负调控因子，其通过促进F-box/WD重复结构域蛋白7介导的泛素化降解过氧化物酶体增殖物激活受体γ共激活因子1α，下调线粒体电子传递链基因的表达，导致线粒体质量减少、ATP产出下降^［20］。在急性肝衰竭炎症环境下，线粒体苹果酸脱氢酶1活性下降，导致乳酸和葡萄糖堆积^［21］。血清代谢组学证实，OXPHOS受抑制、脂肪酸β氧化减弱、乳酸堆积与疾病进展呈正相关^［22］。ROS过度释放进一步损伤呼吸链复合物，引发质子漏，形成“ROS升高-OXPHOS降低”的恶性循环，持续加剧能量缺陷与器官损伤^［23］。

1.4 肠道菌群代谢失调

肠道菌群是指寄居于人类胃肠道内的微生物群落，涵盖多种菌群，ACLF患者的肠道菌群呈现多样性减少、有益菌数量下降和致病菌数量升高的趋势，且紊乱幅度与肝损伤及28天/90天病死率呈正相关^［24］。炎症因子可下调紧密连接蛋白表达^［25］，破坏肠屏障功能，导致粪便肠道短链脂肪酸减少，脂多糖易位增加，加剧全身炎症反应^［26］。肝脏合成的胆汁酸池及其各组分参与肠道细菌酶的活性调节。次级胆汁酸可经TGR5-NO/H₂S双通路扩张肝窦及外周血管，降低平均动脉压，该病理过程持续加重门静脉高压与肠道菌群失调^［27］。此外，芳香氨基酸、支链氨基酸（branched-chain amino acids，BCAA）等菌群相关代谢物可进一步放大神经毒性与促炎信号，构成“菌群-代谢-炎症”网络，驱动疾病进展^［25］。

1.5 氨基酸代谢紊乱

ACLF患者常伴随营养缺乏与代谢稳态失衡。病原相关分子模式/损伤相关分子模式可激活Toll样受体4/核因子κB信号通路，诱发细胞因子风暴，促使下丘脑-垂体-肾上腺轴和交感神经系统兴奋，加速骨骼肌蛋白水解，导致氨基酸（尤其是芳香族与含硫氨基酸）在血浆内蓄积^［28］。ACLF患者血浆中缬氨酸、谷氨酸和天冬氨酸水平下降，而芳香族氨基酸（如苯丙氨酸、酪氨酸）水平升高，其异常变化与炎症因子表达相关^［29］。核心成员之一的BCAA在HE中扮演双重角色：BCAA虽可与谷氨酸结合生成谷氨酰胺发挥暂时性解毒效应，但在肝衰竭时，谷氨酰胺被肠道细菌重新分解为氨，形成“氨生成-解毒-再生成”的恶性循环，反而加重高氨血症与HE^［30］。门静脉高压及肠屏障破坏可导致革兰氏阴性菌过度生长，其尿素酶、氨基酸脱羧酶活性增加，进一步提高肠腔氨的产生，导致肠源性氨负荷增加^［31］。此外，犬尿氨酸途径活性随炎症水平升高而上调，提示该途径的激活参与了ACLF的发病机制^［28］。上述五大代谢紊乱相互关联，形成复杂的代谢网络（图1）。

2 靶向能量代谢的治疗策略

2.1 糖代谢调节

针对上述代谢紊乱，可采取多靶点干预策略（图2）。ACLF糖代谢的核心矛盾是“低糖危险+高糖炎症”，推荐将目标血糖维持在6.1～10 mmol/L^［32］。床旁干预策略主要包括：（1）持续泵注葡萄糖+夜间加餐，并补充BCAA以预防低血糖发生^［33］；（2）对于高血糖，首选胰岛素治疗；（3）通过代谢重编程进行干预：Lon蛋白酶-1过表达有助于恢复糖异生酶葡萄糖-6-磷酸酶、磷酸烯醇式丙酮酸羧激酶1的活性^［34］。尽管糖原分解及糖异生在ACLF代谢紊乱中发挥重要作用，但目前尚无相应特异性抑制剂应用于临床。当前研究多集中于整体代谢重编程策略，例如通过抑制脂肪酸氧化以加强糖酵解，而非直接干预糖原分解。实验研究发现，曲美他嗪可部分抑制脂肪酸氧化，增强糖酵解，提高低氧/高氨环境下肝细胞的存活率^［35］。糖酵解抑制剂2-脱氧-D-葡萄糖可减少中性粒细胞胞外诱捕网的形成，通过抑制糖酵解逆转中性粒细胞功能障碍，进而减少炎症反应^［36］。中医药在调节糖酵解方面亦显示出独特作用。中药复方赤芍-附子可通过下调HIF-1α表达，抑制糖酵解关键酶活性，减少乳酸生成，从而减轻免疫炎症损伤^［37］。四逆汤加人参汤则通过抑制哺乳动物雷帕霉素靶蛋白/HIF-1α信号轴改善巨噬细胞极化，间接调节葡萄糖代谢重编程^［8］，实现“代谢-免疫”双重调控。尽管PPP的激活被证实与氧化应激相关，但目前仍缺乏针对其特异性酶靶点的干预手段，相关研究尚处于探索阶段。

2.2 脂代谢干预

ACLF患者处于“急性消耗-肌肉分解”的高代谢状态，此时干预的核心是“快速补充，减轻肝脏负担”。早期（终末期肝病模型评分≤30分）建议采用高碳水、低脂饮食，睡前碳水加餐可抑制夜间脂解、降低呼吸商^［38］。静脉补充ω-3脂肪乳剂有助于减少内毒素及脓毒症的发生^［39］。曲美他嗪单用或联合L-精氨酸和L-天冬氨酸可通过抑制脂肪酸氧化、增强糖酵解、改善肝细胞能量代谢并提高肝细胞再生能力，进而改善乙型肝炎病毒相关ACLF患者的预后^［35］。二十烷酸（如前列腺素E2）可促进M2型巨噬细胞极化^［40］，而5-脂氧合酶/5-脂氧合酶激活蛋白抑制剂则通过抑制5-脂氧合酶或5-脂氧合酶激活蛋白来减少白三烯生成^［41］，二者均具有额外的抗炎作用。

2.3 线粒体保护

线粒体功能障碍可导致ATP生成减少，进而激活炎症信号通路，加剧肝脏炎症反应和氧化应激损伤。研究表明，大豆异黄酮可通过多途径抑制HIF-1α，减少线粒体通透性转换孔的开放，提升ATP水平、二磷酸腺苷/氧比值和呼吸控制比，从而保护肝脏免受侵害^［42］。NO供体型他汀能抑制Ras同源基因家族成员A/Rho相关卷曲螺旋形成蛋白激酶信号轴，减少线粒体ROS生成、恢复线粒体膜电位，并额外释放NO，可协同改善肝窦内皮功能，在降低门静脉压的同时避免了肌毒性^［43］。中药截断逆挽方通过抑制过度线粒体自噬、稳定线粒体融合/分裂动力学，维持线粒体数量与功能^［2］。“赤芍-附片”复方能降低肿瘤坏死因子α含量，减轻线粒体氧化应激反应，保护肝细胞^［44］。总体而言，线粒体靶向策略仍处临床前研究阶段，亟需推进其安全性验证及Ⅱ期临床转化研究。

2.4 肠道菌群再平衡

ACLF患者的肠道菌群结构失衡、细菌易位以及菌群代谢物改变等与疾病严重程度密切相关，因此肠道菌群再平衡成为重要治疗方向。《肝衰竭诊治指南（2024年版）》^［45］推荐使用双歧杆菌、乳酸杆菌等益生菌/合生元改善肠屏障功能、降低感染风险。尽管肝脏相关疾病是益生菌治疗的主要目标人群，但目前仍缺乏聚焦ACLF患者的临床研究。抗生素具有“双刃剑”效应，长期使用会破坏ACLF相关菌群-免疫-肝轴，而短期、靶向、窄谱抗生素联合微生态调节剂则可能对疾病产生积极作用。利福昔明是一种肠道局部作用的抗生素，短期应用可在不降低多样性的前提下抑制致病菌生长^［46］，但仍需开展随机、双盲、对照临床试验加以验证。4α-葡聚糖基转移酶通过产生潘糖，与溶质载体家族7成员11蛋白相互作用，提高上皮细胞中谷胱甘肽水平，从而限制细菌扩散^［47］。粪菌移植能重建肠道微生态，研究显示其可降低ACLF患者30天与90天的病死率^［48］。中医药在以肠道菌群干预调节为核心的研究领域也取得一定进展。中药复方如防风通圣散、凉血解毒方可增加双歧杆菌数量、降低肠杆菌数量及内毒素水平，调节胆汁酸代谢，恢复菌群多样性^［49-50］。

2.5 氨基酸治疗

氨部分来源于肠道细菌对蛋白质的分解，目前国内外指南和共识均不再推荐对合并HE的ACLF患者常规采用低蛋白饮食。当患者存在HE时，可给予适量蛋白质补充（1.2～1.5 g・kg⁻¹・d⁻¹），但并不推荐高蛋白摄入，以减少肠道产氨^［51］。静脉输注BCAA联合乳果糖治疗ACLF合并HE，虽能够暂时改善患者的意识状态，但无法持续逆转病情且未降低短期病死率^［52］。ACLF患者血浆犬尿氨酸/色氨酸比值与疾病预后密切相关，但相关干预实验尚未开展。其他单一氨基酸或靶向代谢通路（谷氨酰胺、精氨酸等）治疗仍处于机制研究或早期转化阶段，除试验外暂不建议常规应用于临床。

3 小结及展望

本研究系统梳理了基于代谢组学视角的ACLF能量代谢重编程的五大核心紊乱状况，包括糖代谢紊乱、脂肪酸β-氧化受阻、线粒体OXPHOS受抑制、氨基酸代谢失衡及肠道菌群失调。这些代谢网络与系统性炎症、免疫失衡形成正反馈，共同推动疾病进展。上述代谢紊乱并非孤立事件，而是彼此协同放大。糖酵解亢进加重乳酸堆积，抑制线粒体功能；脂代谢受阻减少ATP供应，迫使氨基酸分解，并升高血氨水平；肠道菌群失调则通过内毒素-炎症轴进一步抑制肝再生。鉴于单一靶点干预难以打破这一恶性循环，未来的治疗需转向“代谢-免疫-微生态”多维联动策略，从传统的“纠正单一代谢缺陷”转为“重塑整体代谢生态”。本文综述并评估了“糖代谢调节、脂干预、线粒体保护、菌群再平衡及氨基酸优化”五大策略的临床前及早期临床证据，为后续试验提供了参考方向。现有证据多为横断面或小样本研究，缺乏纵向验证；干预研究多在动物实验或早期临床阶段，缺乏大规模随机对照试验；此外，代谢生物标志物尚未形成统一标准。未来需建立国际多中心ACLF代谢队列，整合多组学与实时能量监测技术，开发基于人工智能的疾病预警系统；同时应推动相关药物进入Ⅱ/Ⅲ期临床试验，探索“代谢-免疫”双靶点联合方案，最终实现从“代谢支持”到“代谢逆转”的治疗理念突破。

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基金资助

广西壮族自治区自然基金项目(2023GXNSFAA026380)