Advances in Clinical Medicine
Vol.
12
No.
04
(
2022
), Article ID:
50956
,
7
pages
10.12677/ACM.2022.124534
胆固醇代谢途径中相关因子与非酒精性脂肪性肝病的研究
张越1,刘冀2
1青海大学,青海 西宁
2青海大学附属医院,青海 西宁
收稿日期:2022年3月28日;录用日期:2022年4月22日;发布日期:2022年4月29日
摘要
非酒精性脂肪性肝病(非酒精性脂肪性肝炎为其严重的亚型)已为我国最常见的慢性肝脏疾病,其发病率仍逐年增加。目前,关于非酒精性脂肪性肝病的发病机制,被广泛认可的是“多重打击学说”,在该学说中的“胆固醇代谢”也被众多学者所关注。因此,本文结合近几年胆固醇代谢途径中相关因子对非酒精性脂肪性肝病的发病机制进行阐述,以期为该病的临床治疗及研究提供相关参考。
关键词
非酒精性脂肪性肝病,非酒精性脂肪性肝炎,胆固醇,稳态HMGCoArSREBP2,游离胆固醇,ABCA1
Study on the Factors Related to Cholesterol Metabolism Pathway and Non-Alcoholic Fatty Liver Disease
Yue Zhang1, Ji Liu2
1Qinghai University, Xining Qinghai
2Affiliated Hospital of Qinghai University, Xining Qinghai
Received: Mar. 28th, 2022; accepted: Apr. 22nd, 2022; published: Apr. 29th, 2022
ABSTRACT
Non-alcoholic fatty liver disease (non-alcoholic steatohepatitis is its serious subtype) has been the most common chronic liver disease in China, and its incidence is still increasing year by year. At present, the pathogenesis of nonalcoholic fatty liver disease is widely recognized as the “multi-hit theory”, and the “cholesterol metabolism” in this theory has also been concerned by many scholars. Therefore, in this paper, the pathogenesis of nonalcoholic fatty liver disease is described in combination with the relevant factors in the cholesterol metabolic pathway in recent years in order to provide a relevant reference for the clinical treatment and research of the disease.
Keywords:Non-Alcoholic Fatty Liver Disease, Non-Alcoholic Steatohepatitis, Cholesterol, Homeostasis, HMGCoAr, SREBP2Free Cholesterol, ABCA1
Copyright © 2022 by author(s) and Hans Publishers Inc.
This work is licensed under the Creative Commons Attribution International License (CC BY 4.0).
http://creativecommons.org/licenses/by/4.0/
1. 引言
非酒精性脂肪性肝病(non-alcoholic fatty liver disease, NAFLD)是指在除外在引起肝脏脂肪堆积的继发性原因(酗酒、病毒性肝炎、自身免疫性肝病以及药物等)的基础上,以肝脏脂肪变性为主要特征的临床病理综合征,在临床诊断上主要是通过肝脏影像学或活检。非酒精性脂肪性肝炎(non-alcoholic steatohepatitis, NASH)是NAFLD患者的进行性亚型,并有可能进展为纤维化、肝硬化和肝细胞癌 [1]。现今,NAFLD已成为世界上最常见的肝脏疾病 [1]。在美国,大约25%的成年人在没有摄入过量乙醇的情况下患有该疾病,在日本,每年的健康体检中约三分之一的人被发现,即估计有2000万NAFLD患者 [2]。而在中国,该疾病正以每年0.594%的速度增长,据估计,从2016年的246.33万例增加到2030年的314.58万例 [3]。随着对NAFLD认识的不断深入,发现其不仅可与自身免疫性疾病、病毒性肝炎和酒精性肝病等其他肝病并存,还易促进其他肝病的发生发展。随着动物实验、人类组织活检及流行病学的研究表明,NAFLD的发病机制及进展与胆固醇代谢有关 [4]。因此,在这篇综述中,将简要评述目前胆固醇代谢途径中相关因子与非酒精性脂肪性肝病的研究。
2. 胆固醇结构及胆固醇代谢的定义
胆固醇是一种类脂化合物,系环戊烷多氢菲的衍生物,为无色、蜡状固体,溶解性与脂肪类似,不溶于水,易溶于乙醚、氯仿等有机溶剂,其分子式为C27H46O,早在18世纪人们从胆石中发现了胆固醇,1816年化学家本歇尔将这种具脂类性质的物质命名为胆固醇 [5]。胆固醇广泛存在于动物体内,主要由肝脏产生和代谢,是非必须营养素。动物体内胆固醇合成与转化过程即为胆固醇代谢 [6]。胆固醇稳态的严格调节对于维持正常的生理至关重要,肝脏是其负责胆固醇稳态的中心器官。人类胆固醇的主要来源是新生合成(约70%)和膳食摄入量 [7]。
3. 胆固醇代谢途径中的相关因子
胆固醇的合成涉及复杂的生化过程及众多不同酶的参与,其负反馈调控受到转录和翻译后的介导,以调节细胞胆固醇的水平 [8]。3-羟基-3-甲基戊二酰辅酶A还原酶(3-hydroxy-3-methylpentanoyl-CoA reductase, HMGCoAr)和角鲨烯单加氧酶均为胆固醇生物合成中的限速酶 [9]。起协调作用的转录因子严格调控胆固醇转运和新陈代谢基因的表达。例如,细胞胆固醇水平的降低激活了内质网膜结合转录因子甾醇调节元件结合蛋白亚型2 (Sterol regulatory element-binding protein isoforms 2, SREBP-2),其诱导HMGCoAr和LDLr (低密度脂蛋白受体)的表达 [10]。另一方面,胆固醇外流途径对于预防细胞中胆固醇过度积累至关重要。胆固醇和磷脂外排途径由转运蛋白介导,如三磷酸腺苷(ATP)结合盒转运蛋白A1 (Adenosine triphosphate (ATP)-binding cassette transporter A1, ABCA1) [10];细胞胆固醇的增加会提高含氧胆固醇中间体氧甾醇的水平,其触发肝脏X受体(LXRs)转录因子(可增强ABCA1的表达)以刺激胆固醇流出(主要为胆汁酸代谢),从而增进胆固醇从肝脏中消除 [10]。除了从头合成胆固醇外,肝脏还吸收脂蛋白颗粒携带的过量循环胆固醇,包括低密度脂蛋白,中密度脂蛋白和通过LDLr的乳糜微粒残留物;及通过清道夫受体B型1型的高密度脂蛋白进一步清除 [6]。
4. NAFLD/NASH与胆固醇途径中相关因子的关系
NAFLD的发生发展,其机制具有复杂性、多因素性。二次打击学说中甘油三酯是NAFLD肝脏中积累的主要脂质,作为其发病机制的经典学说被广泛认同,然而,有研究表明,由于从头合成增加或输出减少而导致的甘油三脂增加,不一定是孤立的致病因素,甚至可能对肝损伤有保护作用 [11]。同时随着研究的深入,目前多数学者倾向认为NAFLD是多种因素共同作用的结果,因而提出多重打击学说 [12],其中在该学说中,NAFLD中的胆固醇代谢及代谢途径中的相关因子被越来越广泛的关注。
4.1. HMGCoAr
关于与NAFLD/NASH相关的胆固醇代谢,在NAFLD/NASH患者中,miR-34a水平被证明升高,导致肝脏NAD依赖性去乙酰化酶Sirtuin1 (沉默调节蛋白1抗体)的减少,随后去磷酸化和HMGCoAr增加 [13]。在动物实验中,向小鼠喂食蛋氨酸–胆碱缺乏饮食(MCD) 3周后,miR-29a与HMGCoAr表达之间存在负相关 [14]。该研究阐明,HMGCoAr的3'未翻译区域(3'UTR)被miR-29a靶向,AMP活化蛋白激酶(AMPK)在翻译后修饰水平上通过磷酸化调控HMGCoAr [14]。miR-29a的减少伴随着肝Dicer1酶的减少,这对于microRNA的成熟极其重要。实际上,Dicer1酶的肝脏特异性敲除导致HMGCoAr的增加,与肝脏中游离胆固醇(Free cholesterol, FC)的积累有关 [14]。除了AMPK外,HMGCoAr还在翻译后修饰和降解水平上受到甾醇的相关调控。固醇水平的升高增加了HMGCoAr对内质网膜相关降解的敏感性 [15]。如羟甾醇,被认为可促进HMGCoAr蛋白的泛素化和蛋白酶体降解 [15]。并有学者发现,在NAFLD患者的肝脏以及棕榈酸/油酸处理的HepG2细胞(一种体外NAFLD模型)中,HMGCoArmRNA和蛋白水平显著升高 [13] [16]。最近,Takei等发现HMGCoAr过表达可促使饮食诱导的肥胖小鼠 [17] 的胰岛素抵抗、炎症反应和肝脏脂肪变性。相反,HMGCoAr抑制可减弱高脂饮食诱导的NAFLD [17]。这些发现表明,Dicer1和microRNA在涉及肝脏中胆固醇合成的增加和FC的积累,促进了NAFLD/NASH的发生发展。
4.2. SREBP-2
SREBP-2是一种重要的细胞膜结合转录因子,是肝脏中胆固醇生物合成的主要调节因子 [18]。Mari等人 [19] 在肥胖患者和其他慢性肝病(如丙型肝炎)患者中未发现SREBP2过表达,因而指出SREBP2为NAFLD/NASH相关的特定特征,并发现转录因子SREBP2的表达在NAFLD/NASH患者中增加。应注意肝细胞中FC的积累有望抑制SREBP2的激活 [20]。SREBP2可能在NAFLD/NASH中通过独立于与细胞胆固醇变化相关的规范途径的机制被激活 [21]。然而,有研究发现,在NAFLD/NASH的背景下,尽管细胞内胆固醇和/或脂肪酸水平较高,不过SREBP的调控环仍会受到干扰。在NAFLD患者肝活检发现,即使在肝细胞中,过多的胆固醇积聚使其下调SREBP-2的表达,但是从头胆固醇合成仍然明显增强 [22]。其实,先前的一项研究证实,在C57BL小鼠中注射细胞因子导致肝SREBP2和HMGCoAr表达增加,并且,在将人肝HepG2细胞与细胞因子孵育反应中也有类似的发现 [23]。据报道,miR-122稳定了SREBP2的非活性形式 [24]。有趣的是,miR-122在NASH患者中显着降低,从而为SREBP2的增加提供了潜在的解释 [24]。由胰岛素抵抗增加引起的高胰岛素血症也有可能导致SREBP2活性形式的增加 [25]。总的来说,炎症应激,miR-122的减少和NASH中相关的高胰岛素血症通过抑制负反馈,其调节高水平细胞胆固醇的能力下降,为SREBP2的不断激活提供了合理的依据 [21]。除了肝SREBP2在NAFLD/NASH的病理生理学中的作用外,在SREBP2肠道特异性过度活化的转基因小鼠模型中的研究证明,模型小鼠对严重肝损伤、炎症和纤维化的易感性是增加的 [26]。这些研究阐明,SREBP2不仅在肝脏中激活,而且还在肠道中激活,并在NAFLD/NASH的发展中起着关键作用。
4.3. FC
除了胆固醇合成的增加外,仍需关注在NAFLD/NASH患者中参与胆固醇消除途径的变化,尤其是FC在NASH发病机制中的作用 [19]。事实上,胆固醇代谢失调已被证明会促进FC的积累,从而影响所有肝细胞群,包括肝细胞、肝脏巨噬细胞(KCs)和造血干细胞 [19]。除此之外,胆固醇的促炎作用机制可能与肝细胞中FC晶体的积累有关。据此,肝细胞降解可向KCs提供胆固醇晶体,在KCs中胆固醇晶体可作为损伤相关分子模式,促进NLRP3炎症小体和其他促炎途径的激活 [27]。在这些观察结果中,CYP7A1 (细胞色素P450家族成员7A1)的表达减少与胆固醇中胆汁酸合成的减少有关 [13]。另外,有报道发现,ABCG5/G8 (ATP结合家族亚家族G成员5/8)是负责胆固醇排泄到胆汁中的胆固醇转运蛋白的表达也减少 [13],其FC的氧化可导致羟甾醇的形成。因此,很明显,NAFLD/NASH患者中肝FC的积累是多因素的,具有潜在的胆固醇合成增加及消除的减少。
4.4. ABCA1
近期研究表明,ABCA1在NAFLD/NASH中具有保护作用 [28],因ABCA1可增进肝脏胆固醇和磷脂的过度转运,减少肝脏脂质积累,抑制内质网应激 [29]。Vega-Badillo等的一项临床研究显示,NAFLD受试者的ABCA1水平明显低于非NAFLD受试者 [30]。发现ABCA1过表达导致胆固醇外排增加,肝细胞内脂质积累减少,从而改善高脂肪-高胆固醇(HFC)诱导的NAFLD [30],相反则加重NAFLD。此外,有报道称ABCA1突变或其变异与NAFLD相关的危险因素如2型糖尿病、肥胖、代谢综合征等密切相关 [28] [31]。在肝脏内,ABCA1的表达受到多种转录因子的密切调控。肝X受体(LXRα和LXRβ)是重要的转录因子,它们与视黄素X受体相互作用形成异源二聚体,然后与ABCA1基因启动子中的DR4元件结合 [32]。细胞中胆固醇衍生的氧化甾醇水平升高可促进LXR的转录活性,从而增强ABCA1的表达 [32],促进胆固醇的反向运输,将其转化为肝脏中的胆汁酸,增加外排作用,预防或减缓NAFLD/NASH的发生发展。
再者,在首次全国健康和营养检查调查中发现,膳食胆固醇是肝硬化和肝癌的独立危险因素 [33]。并为动物模型观察中得到的实验结果提供了支持,证明了胆固醇在诱导肝损伤中的作用 [34]。得到了胆固醇摄入量的增加与NAFLD的风险和严重程度有关 [33] [35] [36]。我们知道,膳食胆固醇是通过乳糜微粒途径吸收,所以肝胆固醇摄取的增加最有可能由肝脏中残留颗粒的清除增加或高密度脂蛋白胆固醇的吸收来介导 [37]。此外,有研究指出,膳食胆固醇不仅在炎症中起着决定性的独立作用,因饮食中的脂肪酸饱和度几乎不影响肝脏脂肪变性或炎症,而且性别特别是在雌性小鼠中,被描述为包括肝脂肪变性和炎症在内的各种肝脏疾病结局的重要因素,因为饮食中的脂肪酸饱和度几乎不影响肝脏脂肪变性或炎症,所以调节膳食胆固醇可能对女性非常有益 [38]。虽然膳食胆固醇仅占肠腔内吸收胆固醇总量的一小部分,但胆固醇吸收效率与NAFLD/NASH的肝脏疾病的发展仍不容忽视。
5. 降胆固醇药物在NAFLD/NASH管理中的应用
先前研究发现体重减轻5%和7%~10%可分别减轻脂肪变性和脂肪性肝炎 [39]。然而饮食和运动疗法有时很难达到并保持10%的减肥效果。根据目前的研究现状发现,他汀类药物是广泛使用的降低血浆胆固醇的药物,为HMGCoAr的抑制剂。但使用他汀类药物可能升高血清转氨酶的水平,特别是在NAFLD/NASH患者中。不过在近1200名欧洲患者的队列研究中证明了,他汀类药物在肝活检评估的脂肪变性、脂肪性肝炎和纤维化方面的有益作用 [40]。另外,在动物实验中发现,胆固醇吸收抑制剂–依折麦布可降低血浆胆固醇,缓解了高脂肪饮食喂养的小鼠的肝脏脂肪变性,并可减缓NAFLD/NASH的进展 [41]。可是依折麦布在NAFLD/NASH患者中的疗效受益有着互相矛盾的结局 [42],进一步对比发现,可能是因为样本量小且为有限的临床试验 [42]。目前,奥贝胆酸,处于Ⅲ期临床试验,是一种有效的FXRs激动剂,在大规模FLINT NASH患者的试验中证实,在没有加重肝纤维化的情况下改善了坏死性炎症,需同时应注意此药物会使血中甘油三酯和低密度脂蛋白胆固醇水平明显升高 [43]。总之,在NAFLD/NASH的研究中,以胆固醇代谢机制为切点作为其靶点,为该疾病的治疗提供了研究方向。
6. 小结与展望
随着NAFLD发病率的逐年增加,人们对NAFLD及其进行性亚型-NASH所带来的危害性越发重视,多种研究发现胆固醇代谢途径中相关因子与NAFLD的发生发展相关,如HMGCoAr增加、SREBP2过表达、FC积累、ABCA1减少等,此外,膳食胆固醇也有助于该疾病的进展。另外,胆固醇管理治疗似乎是NAFLD的一种很有前途的治疗方法。因此探索NAFLD的具体发病机制以便为临床提供有效的治疗靶点至关重要,但目前仍存在有些机制尚不完全清楚,还需进一步探索。
文章引用
张 越,刘 冀. 胆固醇代谢途径中相关因子与非酒精性脂肪性肝病的研究
Study on the Factors Related to Cholesterol Metabolism Pathway and Non-Alcoholic Fatty Liver Disease[J]. 临床医学进展, 2022, 12(04): 3703-3709. https://doi.org/10.12677/ACM.2022.124534
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