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Journal of Central South University Medical Sciences logoLink to Journal of Central South University Medical Sciences
. 2023 Oct 28;48(10):1529–1538. [Article in Chinese] doi: 10.11817/j.issn.1672-7347.2023.230029

SREBP/PCSK9通路与抗精神病药物所致脂代谢紊乱相关性的研究进展

Research progress in the correlation between SREBP/PCSK9 pathway and lipid metabolism disorders induced by antipsychotics

MA Jiashu 1,2, ZHENG Yunshao 2, SUN Fengxia 2, FAN Yunli 2, FAN Yunming 2, SU Xianbiao 2, WANG Zhongbao 3, WENG Ning 2, LI Ranran 2,✉
Editor: 郭 征
PMCID: PMC10929898  PMID: 38432882

Abstract

Antipsychotic medications are commonly used to treat schizophrenia, but they can have negative effects on lipid metabolism, leading to an increased risk of cardiovascular diseases, reduced life expectancy, and difficulties with treatment adherence. The specific mechanisms by which antipsychotics disrupt lipid metabolism are not well understood. Sterol regulatory element-binding proteins (SREBPs) are important transcriptional factors that regulate lipid metabolism. Proprotein convertase subtilisin/kexin type 9 (PCSK9), a gene regulated by SREBPs, plays a critical role in controlling levels of low-density lipoprotein cholesterol (LDL-C) and has become a focus of research on lipid-lowering drugs. Recent studies have shown that antipsychotic drugs can affect lipid metabolism through the SREBP/PCSK9 pathway. A deep understanding of the mechanism for this pathway in antipsychotic drug-related metabolic abnormalities will promote the prevention of lipid metabolism disorders in patients with schizophrenia and the development and application of new drugs.

Keywords: antipsychotics, sterol regulatory element-binding proteins, proprotein convertase subtilisin/kexin type 9, abnormal lipid metabolism

精神分裂症是一种病因复杂、临床异质性高的精神疾病，具有高致残率和高病死率的特点。该疾病导致患者的预期寿命比普通人群缩短约14.5年[1]，心血管疾病是精神分裂症患者过早死亡的主要原因之一[2-3]。血脂异常是引发动脉粥样硬化性心血管疾病的重要危险因素。抗精神病药物是精神分裂症治疗的主要药物，在使用过程中会导致脂代谢紊乱，主要表现为总胆固醇、低密度脂蛋白胆固醇(low-density lipoprotein cholesterol，LDL-C)和甘油三酯升高，以及高密度脂蛋白胆固醇(high-density lipoprotein cholesterol，HDL-C)降低。这显著增加了患者代谢综合征和心血管疾病的发病风险[4-5]，并对其心理健康产生负面影响。更好地理解抗精神病药物引起脂代谢紊乱的分子机制，可以提供新的目标和策略来预防和治疗相关的代谢性疾病。已有研究[6-8]表明，抗精神病药物可广泛上调由固醇调节元件结合蛋白(sterol regulatory element binding protein，SREBP)控制的基因表达水平。最新的研究[9]发现，抗精神病药物奥氮平通过多种途径增强前蛋白转化酶枯草溶菌素9(proprotein convertase subtilisin/kexin type 9，PCSK9)的表达。SREBP/PCSK9信号通路与抗精神病药物引起的脂代谢异常密切相关。阐明SREBP、PCSK9与抗精神病药物引起的血脂异常之间的关系，可为预防和治疗抗精神病药物引起的代谢方面的不良反应提供新的视角。

1. SREBP/PCSK9通路与脂代谢

1.1. 脂代谢

脂质主要包括磷脂、甘油三酯和胆固醇等，广泛分布于细胞器中。它们不仅是细胞膜的基本结构成分，还参与多数生物过程中的代谢和信号调控。脂代谢是指生物体内有关脂质的合成、分解、运输和调控的一系列生化过程，对于维持正常的细胞结构和功能、能量平衡以及细胞信号转导等生理过程至关重要。脂代谢紊乱可导致心血管疾病、脂肪肝和糖尿病等多种代谢性疾病的发展[10]。

1.2. SREBP的结构与功能

SREBP在20世纪90年代发现的一类碱性螺旋-环-螺旋-亮氨酸拉链(basic helix-loop-helix-leucine zipper，bHLH-zip)转录因子[11-12]。内质网中SREBP的非活性前体与SREBP裂解激活蛋白(SREBP cleavage acting protein，SCAP)和胰岛素诱导基因(insulin-induced gene，INSIG)形成复合物。当内质网中胆固醇浓度较低时，INSIG发生泛素化进行降解，并与保持结合状态的SCAP-SREBP复合物分离。SCAP产生构象变化，使其能够结合COPII蛋白并协助将120 kD的前体SREBP转运至高尔基体。前体SREBP在高尔基体中经过蛋白酶(S1P、S2P)的两步蛋白水解切割后被激活，形成具有转录活性的碱性螺旋-环-螺旋(basic helix-loop-helix，bHLH)，bHLH最后进入细胞核中，与相关基因启动子中的固醇调节元件(sterol regulatory element，SRE)结合，调控下游脂代谢基因的表达(图1)[11, 13-14]。

图1.

图1

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SREBP对靶基因的调控

Figure 1 Regulation of target genes by SREBP

When cholesterol levels are low in the endoplasmic reticulum, INSIG (in yellow) undergoes ubiquitination for degradation, leading to the dissociation of the bound SCAP-SREBP (in blue-red) complex. The precursor SREBP is activated in the Golgi apparatus through 2 sequential proteolytic cleavages by proteases (S1P, S2P), releasing the basic helix-loop-helix structure (bHLH), known as nSREBP. Subsequently, nSREBP translocates into the cell nucleus and acts on the SRE (in light blue) regions within the promoters of target genes, thereby regulating downstream gene expression. SREBP: Sterol regulatory element binding protein; INSIG: Insulin-induced gene; SCAP: SREBP cleavage acting protein; SRE: Sterol regulatory element; bHLH: Basic helix-loop-helix; FAS: Fatty acid synthase; ACC: Acetyl-CoA carboxylase; LDLR: Low-density lipoprotein receptor; PCSK9: Proprotein convertase subtilisin/kexin type 9; HMGCR: 3-Hydroxy-3-methylglutaryl-CoA reductase.

SREBP是脂代谢的核心转录因子，控制着与脂质合成和摄取有关基因的表达。SREBP存在3种异构体，即SREBP-1a、SREBP-1c和SREBP-2。SREBP-1a和SREBP-1c都由SREBF-1基因编码，但由不同的启动子转录，因此产生的蛋白质在N-末端区域有所不同。SREBP-1a可以调控胆固醇和脂肪酸生物合成相关基因的表达，SREBP-1c主要调控脂肪酸代谢相关基因，包括脂肪酸合成酶(fatty acid synthase，FAS)、乙酰辅酶A羧化酶(acetyl-CoA carboxylase，ACC)等[15]。SREBP-2主要调控胆固醇代谢相关基因，包括3-羟基-3-甲基戊二酸单酰辅酶A还原酶(3-hydroxy-3-methylglutaryl-CoA reductase，HMGCR)、低密度脂蛋白受体(low-density lipoprotein receptor，LDLR)、PCSK9等[16]。

1.3. PCSK9的结构与功能

PCSK9在2003年被首次报道，是一种主要在肝细胞中产生的丝氨酸蛋白酶[17]。PCSK9由692个氨基酸组成，包含信号肽(氨基酸1~30)、前结构域(氨基酸31~152)、催化结构域(氨基酸152~451)和富含半胱氨酸与组氨酸的C-末端结构域(氨基酸453~692)。PCSK9的信号肽在内质网中被切割后，进行自催化剪切，切断前结构域和催化结构域的共价结合，但二者仍通过非共价结合连接在一起，阻止其他潜在底物进入PCSK9的催化口袋[18]。PCSK9促进LDLR降解的能力与其催化活性无关，而是通过一种伴侣功能与LDLR结合发挥作用，这是一种在丝氨酸蛋白酶中独一无二的作用模式[19]。

PCSK9在调节血浆胆固醇稳态中起重要作用，PCSK9可以通过2条途径诱导LDLR的降解。第1条途径为细胞外途径，分泌到血浆中的PCSK9与细胞表面LDLR的第1个表皮生长因子前体结构域(epidermal growth factor A domain，EGF-A)结合，通过网格蛋白介导的囊泡内吞进入细胞后，再进入核内体，核内体中的酸性环境使PCSK9与LDLR结合更加紧密，阻止LDLR循环至细胞表面，从而一同进入溶酶体中降解。第2条途径为细胞内途径，成熟的PCSK9在分泌前可直接从内质网进入到高尔基体，并与LDLR结合，再从反式高尔基体进入溶酶体，并进行降解(图2)[20]。细胞外途径是肝、小肠和胰腺中PCSK9发挥作用的主要途径[21-22]。这2条途径阻断了LDLR从内体到细胞表面的再循环，使细胞表面LDLR减少，从而导致血液中胆固醇水平上升。

图2.

图2

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PCSK9降解LDLR的2种途径

Figure 2 Two pathways of PCSK9-mediated LDLR degradation

Intracellular pathway (blue line arrows): PCSK9 binds directly to intracellular LDLR before secretion, and together they enter the cell’s lysosome. Extracellular pathway (black line arrows): PCSK9 is secreted into the extracellular space, where it binds to LDLR and enters the cell through endocytosis mediated by clathrin-coated vesicle. Once inside the endosome, PCSK9 forms a tighter complex with LDLR, and together they proceed to the lysosome for degradation. PCSK9: Proprotein convertase subtilisin/kexin type 9; LDLR: Low-density lipoprotein receptor; LDL: Low-density lipoprotein; SRE: Sterol regulatory element; bHLH: Basic helix-loop-helix; SREBP: Sterol regulatory element binding protein.

1.4. SREBP/PCSK9通路的转录调控

PCSK9的合成在转录水平上主要受SREBP-2和SREBP-1c的调控。PCSK9基因的近端启动子包含1个对细胞内胆固醇浓度变化作出反应的SRE。在细胞内胆固醇缺乏时，SREBP-2被激活进入细胞核中，与PCSK9启动子(SRE-1区)相互作用，诱导PCSK9的转录和翻译增加[23-24]。而在高果糖饮食等条件下，SREBP-2正常表达时，主要由SREBP-1c作用于PCSK9启动子SRE区域，上调PCSK9的表达水平[25-26]。

SREBP/PCSK9通路受多种因子调控。AMP活化蛋白激酶(AMP-activated protein kinase，AMPK)是一种重要的细胞内信号转导蛋白激酶，在调节细胞的能量代谢等生理过程中起关键作用，可直接磷酸化SREBP-2，从而影响SREBP-2的蛋白水解加工和转录活性，抑制SREBP介导的PCSK9表达[27]。磷脂酰肌醇3激酶(phosphatidyl inositol 3-kinase，PI3K)/Akt信号通路在细胞生长、调节糖脂代谢中发挥着重要作用。最近的研究[28]表明，PI3K/Akt可以通过SREBP2调节PCSK9的转录调控。此外，肝X受体α(liver X receptor α，LXRα)属于核激活受体家族的成员之一，主要在肝、肠道、脾和脂肪组织中表达，也可以通过SREBP-1c增加PCSK9的表达[29]。

肝细胞核因子1(hepatic nuclear factor-1，HNF-1)由HNF-1α和HNF-1β亚单位组成，可以通过多种途径调控PCSK9表达。一方面，HNF-1α可通过增强miR-122的表达，干扰SREBP-2的成熟，间接抑制PCSK9的表达[30]。另一方面，HNF-1α可以与PCSK9转录起始位点上游第380个碱基对结合，对PCSK9基因的转录具有重要激活和正向调节作用[31]。

哺乳动物雷帕霉素靶蛋白复合体1(mammalian target of rapamycin complex 1，mTORC1)由雷帕霉素靶蛋白和辅助因子组成，具有调控蛋白质合成、脂肪生成及自噬的作用。在小鼠中，mTORC1通过激活蛋白激酶C(protein kinase C delta，PKCδ)降低HNF-1α的活性，进而抑制PCSK9的转录[32]。叉头框蛋白3(forkhead box O3，FoxO3)也是PCSK9转录的负调节因子。沉默信息调节因子1(silent information regulator 6，SIRT6)是位于细胞核中的多效赖氨酸脱乙酰酶，在能量代谢、衰老、炎症、应激反应和癌症等多方面发挥重要作用。FoxO3与胰岛素反应元件(insulin response element，IRE)相互作用后，SIRT6与PCSK9启动子结合，使组蛋白H3在赖氨酸9和56位脱乙酰化，导致PCSK9启动活性减弱[33]。FoxO3和SIRT6还可抑制HNF-1α和SREBP-2的转录活性[34-35]。

现阶段已针对PCSK9通路研发出多种降脂药物，目前应用于临床的主要为PCSK9单克隆抗体，其作为一种疗效明确，安全性高的新型降脂药物[36]，可将LDL浓度降低约60%，并大幅降低严重心血管事件的发生风险[37]。但其在精神科应用较少，目前尚未有PCSK9抑制剂与抗精神病药物之间存在相互作用的研究数据。但从机制上看，2种药物之间存在药代动力学或药效学干扰的可能性很小[38]。

综上所述，在脂代谢调节中，转录因子SREBP通过控制内源性胆固醇、脂肪酸、甘油三酯和磷脂合成所需的一系列酶的表达来调节脂质稳态。PCSK9可与LDLR结合，诱导LDLR到溶酶体中降解，影响血液中LDL内吞入肝细胞中清除，进而导致循环中LDL水平升高[39]，其表达受到SREBP、AMPK、PI3K/Akt、LXRα、HNF-1α、mTORC1、FoxO3等的调节(图3)，是近年来降脂药物研究的主要靶点[40]。

图3.

图3

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SREBP/PCSK9通路调控机制

Figure 3 Model of SREBP/PCSK9 pathway regulation

Inline graphicPositive regulation; Inline graphicNegative regulation; Inline graphicNot specified. SREBP: Sterol regulatory element binding protein; PCSK9: Proprotein convertase subtilisin/kexin type 9; mTORC1: Mammalian target of rapamycin complex 1; PKCδ: Protein kinase C delta; HNF-1α: Hepatic nuclear factor-1α; PI3K: Phosphatidyl inositol 3-kinase; AMPK: AMP-activated protein kinase; SIRT6: Silent information regulator 6; FoxO3: Forkhead box O3; LXRα: Liver X receptor α.

2. 抗精神病药物与脂代谢紊乱

抗精神病药物在使用中会引起脂代谢紊乱[41]。不同的抗精神病药物引起脂代谢紊乱的程度不同，Pillinger等[42]对精神分裂症患者使用抗精神病药物的代谢改变进行了系统回顾和荟萃分析，研究纳入18种抗精神病药物，并与安慰剂进行比较，分析患者体重、体重指数和血脂代谢指标的变化。结果显示：奥氮平、氯氮平和佐替平对脂代谢影响最大，氟哌啶醇、阿立哌唑和鲁拉西酮对脂代谢影响最小。

抗精神病药物引起的脂代谢紊乱是药物对中枢和外周器官产生广泛和复杂作用的结果。目前，精神药理学和内分泌学无法准确解释其发生机制。既往研究[43]认为，抗精神病药物通过阻断下丘脑5-羟色胺和组胺受体，干扰机体的饱腹和摄食中心，导致食物摄入量增加，从而引起脂代谢紊乱。但有研究[44]发现，在体重增加之前，抗精神病药物已提高血脂水平并增加胰岛素抵抗，这提示抗精神病药物可以通过直接影响外周器官，引起脂代谢紊乱。随后的多项研究[45-46]显示，抗精神病药物可以直接影响肝、脂肪组织和骨骼肌。在其中，SREBP作为调控细胞胆固醇和脂肪酸生物合成最重要的因子之一发挥重要作用。

2.1. 抗精神病药物对SREBP的调节作用

抗精神病药物能激活SREBP通路，调控其下游脂代谢基因的表达。多项细胞实验[47-50]表明，抗精神病药物在肝、脂肪和神经系统细胞系中均能激活SREBP-1c和SREBP-2，进而促进胆固醇和脂肪酸生物合成相关基因的表达，其中包括HMGCR、LDLR、FAS和ACC等基因。为了确定抗精神病药物对脂代谢基因的作用是直接的还是通过SREBP介导的，研究[51]将携带显性负性突变型SREBP的腺病毒转染到大鼠的原代肝细胞中，使SREBP失活。结果显示，奥氮平诱导的脂肪生成相关基因(ACC和FAS)和胆固醇生成相关基因(LDLR和HMGCR)表达水平下降，这表明奥氮平通过SREBP介导了脂代谢相关基因的表达。为了进一步明确奥氮平对SREBP靶基因的转录调控，研究人员构建了含有SRE-1的荧光素酶报告基因腺病毒，并在大鼠原代肝细胞中进行测试。结果显示，在显性负性突变型SREBP腺病毒的作用下，抗精神病药物诱导的SRE-1启动子活性降低3.5倍。上述实验表明，抗精神病药物通过调节SREBP的转录活性来调控脂代谢。

动物实验的结果则显示抗精神病药物对脂代谢的影响与性别有着很大关系[52]。抗精神病药物的性别特异性代谢效应在啮齿类动物中已经得到证实。抗精神病药物可引起雌性小鼠和大鼠食欲增加和体重增加[53-54]，而雄性大鼠给予抗精神病药物后，食欲和体重不增加或增加较少[55-56]。此外，在雌性大鼠中，抗精神病药物可以上调肝和脂肪组织中SREBP靶基因的表达，增加循环中的总甘油三酯[57-58]，但只有少数的研究[59]显示抗精神病药物对雄性大鼠SREBP的表达有影响。在临床研究中，一项荟萃分析[60]表明，在奥氮平和利培酮的短期与中期治疗中，男女性患者间的体重增加的差异并无统计学意义。

不同的抗精神病药物在激活SREBP通路的程度上存在很大差异。研究[61]用6种抗精神病药物(氯丙嗪、氟哌啶醇、氯氮平、奥氮平、利培酮和齐拉西酮)干预GAMG细胞后，检测SREBP-2的激活程度以及SREBP靶基因[3-羟基-3-甲基戊二酰辅酶A合酶1(3-hydroxy-3-methylglutaryl-CoA synthase 1，HMGCS1)、HMGCR、类固醇-C5-脱饱和酶样(sterol-C5-desaturase-like，SC5DL)、LDLR]的表达水平。结果显示，氯丙嗪、氟哌啶醇、氯氮平和奥氮平可显著增强这4个SREBP靶基因的转录，尤其是HMGCS1和HMGCR，而利培酮和齐拉西酮的增强程度非常轻微，同时，SREBP-2的激活程度与SREBP-2靶基因的表达水平平行。另一项研究[62]则证实氯氮平、氟哌啶醇、奥氮平和利培酮可不同程度地激活SREBP-1，表现为参与脂肪酸生物合成的靶基因(SREBP-1、FAS、SCD)和SREBP-1c表达的上调，其中氟哌啶醇、氯氮平和奥氮平显著刺激SREBP-1靶基因的表达，利培酮引起SREBP-1 mRNA表达的显著增加，SREBP-1蛋白质表达呈增加的趋势，并引起下游FAS基因表达的轻微增加，而喹硫平不影响SREBP-1、FAS和SCD1 mRNA的表达，以及SREBP-1蛋白质的表达。这与临床中常见的抗精神病药对脂代谢的影响大小排序相符，即氯氮平、奥氮平>利培酮>喹硫平。

综上，抗精神病药物能广泛激活SREBP通路。关于其中的作用机制，目前研究认为大部分抗精神病药物的分子结构为阳离子两亲化合物，这种结构可以干扰胆固醇从内体/溶酶体外流到内质网，降低内质网中胆固醇浓度，进而激活SREBP的表达[63-64]。但关于其他小部分抗精神病药物对SREBP的影响仍存在一定的争议，还需要进一步的研究阐明。

2.2. 抗精神病药物对SREBP/PCSK9通路的调节作用

由于PCSK9具有通过降解LDLR显著调节血脂代谢的功能，研究人员开始关注抗精神病药物对PCSK9表达的影响。抗精神病药物奥氮平可上调PCSK9的表达。小鼠给予奥氮平处理后，RT-qPCR和蛋白质印迹法结果显示肝组织中PCSK9 mRNA和蛋白质的表达均显著上调，免疫荧光染色结果也证实肝组织中PCSK9的表达增加，油红O(oil red O，ORO)染色显示PCSK9的过表达显著增加肝细胞内脂滴的数量和大小；此外，敲除体外培养的HepG2细胞和AML12细胞中的PCSK9基因后，奥氮平诱导的细胞内脂质积聚得到有效改善[65]。这项研究表明奥氮平在体外和体内均上调PCSK9的表达，从而导致脂代谢紊乱。靶向PCSK9的药物可能有助于改善奥氮平诱导的肝脏脂肪变性和LDL的升高。该研究还发现奥氮平上调LXRα的表达，在拮抗LXRα和过表达LXRα处理后，分别导致PCSK9表达减少和增加。这表明奥氮平对PCSK9的调控可能是通过LXRα介导的。LXRα对SREBP-1c有重要的调控作用[66-67]，而SREBP-1c可以直接调控PCSK9，LXRα对PCSK9的作用机制有待进一步明确。

奥氮平治疗后患者血浆中PCSK9的水平显著升高，且与LDL-C水平的升高呈正相关；体外实验发现，奥氮平处理后的小鼠肝组织中PCSK9表达增加，且先于LDL-C的异常；此外，还发现低剂量奥氮平处理组小鼠肝组织的SREBP-2与SREBP-1c表达均升高，而高剂量处理组小鼠肝组织的SREBP-2表达降低，SREBP-1c表达升高[9]。这些研究结果提示奥氮平可通过SREBP-2与SREBP-1c调节PCSK9的表达，进而导致LDL-C的升高；且低剂量的奥氮平可能通过SREBP-2与SREBP-1c介导PCSK9的升高，而在高剂量的奥氮平影响下，SREBP-1c占主导作用。抗精神病药物对SREBP/PCSK9通路的影响包含多种机制，但在不同的样本与药物剂量下结果也有所差异，其中的作用机制有待进一步研究分析。

3. 展 望

抗精神病药物引起的脂代谢紊乱对个体健康造成严重危害，由于其作用机制尚不明确，现临床治疗手段局限，效果欠佳。SREBP/PCSK9通路作为调节脂代谢的关键通路，可被抗精神病药物广泛激活，日益受到研究者的关注。然而，现有研究主要集中在动物实验和细胞实验中，研究结果多表明抗精神病药物对SREBP/PCSK9通路有激活作用。对该通路具体机制的探讨相对有限，缺乏前瞻性、大样本的临床实验。目前已有针对该通路的降脂药物应用于临床，如PCSK9抑制剂，但其在精神科的应用十分罕见。因此，需要进行更全面、深入和细致的临床和基础研究，以深入了解该通路在抗精神药物相关代谢异常中的作用机制。这将有助于揭示其潜在的治疗靶点，促进精神分裂症患者脂代谢紊乱的预防和新药的研发应用。

基金资助

国家自然科学基金(82101580)；山东省中医药科技发展计划项目(2019-0528)。

This work was supported by the National Natural Science Foundation (82101580) and the Traditional Chinese Medicine Science and Technology Development Project of Shandong Province (2019-0528), China.

利益冲突声明

作者声称无任何利益冲突。

作者贡献

马家树 论文构思与撰写；郑云哨、李然然 论文指导与修改；孙丰霞、樊运莉 论文审阅与修改；范允明、苏现彪、翁柠 文献查阅与整理；王忠宝 图片制作。所有作者阅读并同意最终的文本。

原文网址

http://xbyxb.csu.edu.cn/xbwk/fileup/PDF/2023101529.pdf

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