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Advances in Clinical Medicine
Vol. 12  No. 05 ( 2022 ), Article ID: 51402 , 11 pages
10.12677/ACM.2022.125610

SREBP-1相关通路为靶点的NAFLD发生机制及治疗进展

朱若岚，宁波

重庆医科大学，重庆

收稿日期：2022年4月18日；录用日期：2022年5月12日；发布日期：2022年5月19日

摘要

非酒精性脂肪肝疾病(NAFLD)是引起肝损伤最常见的原因之一，其特征是肝脏外源性游离脂肪酸增多或内源性从头生成增加，导致肝细胞中甘油三酯的过度积累。甾醇调节元件结合蛋白(SREBPs)是一个转录因子家族，通过调控内源性胆固醇、脂肪酸(FA)、三酰基甘油和磷脂合成所需的一系列酶来调节脂质稳态。SREBP-1是增加肝脏脂肪酸和甘油三酯合成的主要转录因子，本文回顾了近年来以SREBP-1相关通路为靶点NAFLD的研究进展。

关键词

甾醇调节元件结合蛋白-1，非酒精性脂肪性肝病，信号通路，脂质生成

The Pathogenesis and Treatment Progress of NAFLD Targeted by SREBP-1 Related Pathway

Ruolan Zhu, Bo Ning

Chongqing Medical University, Chongqing

Received: Apr. 18th, 2022; accepted: May 12th, 2022; published: May 19th, 2022

ABSTRACT

Nonalcoholic fatty liver disease (NAFLD), one of the most common causes of liver injury, is characterized by an increase in exogenous free fatty acids or endogenous de novogenesis in the liver, resulting in excessive accumulation of triglycerides in liver cells. Sterol regulatory element binding proteins (SREBPs) are a family of transcription factors that regulate lipid homeostasis by regulating a series of enzymes required for the synthesis of endogenous cholesterol, fatty acids (FA), triacylglycerol and phospholipids. SREBP-1 is the major transcription factor that increases hepatic fatty acid and triglyceride synthesis. This paper reviews the research advances in NAFLD targeting SREBP-1 related pathways.

Keywords:Sterol Regulatory Element Binding Protein 1 (SREBP-1), Nonalcoholic Fatty Liver Disease (NAFLD), Signal Transduction, Lipogenesis

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(NAFLD)全世界患病率为16%~23%，并有逐年递增的趋势。它是由肝脏中脂质的积累引起的，这始于单纯的肝脏脂肪变性，可发展为非酒精性脂肪性肝炎(NASH)，如果不加以控制治疗甚至可能进展为肝硬化。NAFLD与代谢紊乱有关的疾病(如糖尿病、肥胖症和高血压)密切相关，随着我国经济水平提高，糖尿病、肥胖症和高血压患病率逐年上升，因此为了控制和预防NAFLD，研究其发生、发展是非常有必要的 [1] [2] [3]。NAFLD发生发展的病理过程中，肝细胞内过多的脂质沉积造成的脂毒性是第一步，而对脂毒性的研究中，最受关注的就是游离脂肪酸对于肝脏的影响。甾醇调节元件结合蛋白(SREBPs)是可以调控所有器官中胆固醇和脂肪酸生物合成过程的转录因子家族，被认为是肝脏中胆固醇生成和脂肪生成的主要调节因子，其中SREBP-1是影响脂肪酸合成的主要调控因子 [4]。本文将综述近年来在非酒精性脂肪性肝病中，以SREBP-1相关通路为靶点的发生机制及治疗进展。

2. SREBP-1的结构与激活

甾醇调节元件结合蛋白(SREBPs)是膜结合的碱性螺旋-环-螺旋亮氨酸拉链(bHLH-LZ)转录因子的一个亚类 [5]。是脂质代谢的主要调节因子，能够调控一些负责脂肪生成、甾醇产生和脂质摄取的基因的表达 [6]。哺乳动物细胞中SREBPs蛋白有三个亚型：SREBP-1a、-1c和-2。SREBP-1编码SREBP-1a和-1c蛋白，-1a蛋白比-1c长24个氨基酸，具有较强的转录活性 [7]。SREBP-1a调节脂肪酸和胆固醇合成以及胆固醇摄取，而SREBP-1c主要控制脂肪酸合成 [8]。SREBF2编码SREBP-2蛋白，并在调节胆固醇合成和摄取中发挥重要作用 [9]。

2.1. SREBPs的结构

SREBPs表达水平和活性由内源性甾醇通过负反馈调节严格的控制，这与SREBPs的结构相关 [10]。SREBPs在膜结合核糖体上合成前体蛋白，其-NH2端的bHLH-Zip结构域和-COOH端一起延伸，面向胞质插入内质网膜中，两个跨膜螺旋被一个由50个氨基酸组成的短环隔开 [11]。甾醇调节元件结合蛋白裂解激活蛋白(SCAP)是一种具有8个跨膜螺旋的内质网蛋白，其中包含一个可直接结合胆固醇的甾感应域，常与SREBPs以复合物的形式存在于细胞中。

2.2. SREBP-1的激活

当甾醇充足时，SCAP-SREBP复合物通过SCAP与一个名为胰岛素调节基因(INSIGs)的内质网蛋白结合而锚定在内质网中 [12]。当缺乏甾醇时，SCAP构象发生变化，与INSIG的亲和力降低，同时暴露了一种特殊的基序，促进辅原子复合物II(COPII)产生特殊的转运囊泡，由SCAP介导将SCAP-SREBP复合物通过囊泡从内质网运输到高尔基体中依次进行两次连续的蛋白裂解 [13] [14]。第一次裂解发生在50个氨基酸的腔内环内，通过位点1蛋白酶(S1P)将SREBP分成两半，-NH2端的一半通过其单一的跨膜螺旋附着在膜上；第二次裂解发生在这个螺旋内，通过位点2蛋白酶(S2P)暴露出bHLH-Zip结构域 [15] [16]，靶向定位于细胞核内，识别固醇调节元件DNA序列，促进SREBPs靶基因的转录，激活脂质合成和摄取 [17] (见图1)。其中SREBP-1的靶基因包括ATP-柠檬酸裂解酶(ACL)、乙酰辅酶a羧化酶(ACC)、硬脂酰辅酶a去饱和酶(SCD)和脂肪酸合酶(FAS)，均是脂肪酸从头生成的关键酶。

Figure 1. Sterol-regulated maturation model of SREBPs [80]

图1. 甾醇调节的SREBPs成熟模型 [80]

3. SREBP-1相关通路

3.1. AMPK

AMP活化蛋白激酶(AMPK)是一种丝氨酸/苏氨酸蛋白激酶，由一个具有催化功能的α亚基和具有调节作用的β和γ亚基组成，通过AMP(腺苷一磷酸)与γ亚基的变构结合和通过AMPK激酶对α亚基上Thr172的磷酸化均可导致AMPK的激活，作为肝细胞的能量传感器，从而调节参与糖脂代谢的多种途径 [18] [19]。AMPK介导的SREBP-1前体在Ser372上的磷酸化抑制了其裂解、核易位和转录活性，导致SREBP-1靶基因，如FAS、ACC和SCD等的表达下调。AMPK的激活通过抑制SREBP的活性来减少肝脏中的脂肪生成。相反，抑制AMPK会激活合成代谢途径，抑制分解代谢途径 [20]。大量证据表明，AMPK介导的SREBP信号通路是NAFLD发病的原因之一，因此增强AMPK活性被认为是一种可行的预防NAFLD发生和发展的治疗策略。

肝激酶B1(LKB1)和钙调素依赖性蛋白激酶激酶(CaMKK)是AMPK主要的上游激酶，使LKB1的Ser428位点磷酸化可激活AMPK，通过增加细胞内钙离子激活CaMKK从而激活AMPK [21] [22] [23] (见图2)。可通过促进LKB1、CaMKK与AMPK之间的相互作用调节SREBP转录活性以改善肝脂肪变。有研究发现，松柏醛呈浓度依赖性的降低细胞内的甘油三酯及胆固醇水平，改善细胞脂肪变性。它可以刺激LKB1磷酸化使AMPK激活，进而下调了SREBP-1的mRNA水平及蛋白水平，其靶基因FAS、SCD-1的表达相继减少，最终抑制细胞脂肪变。当使用AMPK抑制剂或者敲低LKB1后，上述变化大多都可被逆转 [24]。另一项研究显示，使用黄芩苷处理NAFLD小鼠模型以及HepG2细胞模型后，黄芩苷通过促进CaMKK磷酸化激活AMPK，抑制SREBP-1表达，FAS、ACC、SCD表达从而降低，最终使小鼠血清和肝脏中的甘油三酯、总胆固醇和游离脂肪酸水平降低，肝脂质积累受抑制 [25]。此外，丁香烯、桦木酸亦被证实可以通过调控CAMKK-AMPK-SREBP1信号通路改善肝脂肪变性 [26] [27]。

Figure 2. AMPK phosphorylation model induced by LKB1 and CaMKK [27]

图2. LKB1和CaMKK致AMPK磷酸化模型 [27]

除了通过激活AMPK上游激酶激活AMPK，最近的食品科学研究发现许多草药或食品的提取物也可以通过磷酸化激活AMPK、抑制SREBP-1表达从而减轻肝脏脂肪变性，如藏红花素、牛樟芝提取物、S-蜂斗菜酯、绿茶多酚、β-丁香烷等 [27] [28] [29] [30] [31]，虽然激活AMPK的具体作用机制尚不明确，但是为NAFLD的治疗及预防提供新的临床思路。

3.2. AKT

AKT，也称为蛋白激酶B(PKB)是一种丝氨酸/苏氨酸激酶，有AKT1、AKT2、AKT3这三种亚型，分别由PKBα、PKBβ和PKBγ编码。AKT1在许多组织中广泛表达；AKT2主要在对胰岛素高敏感的组织(如肝脏、胰腺、肌肉)中表达，在其他组织中表达水平较低；而AKT3仅在大脑和睾丸中表达 [32]。它们具有85%的同源性氨基酸序列以及相似的三维结构，由三个功能域组成：-NH2端的PH结构域可调节蛋白–蛋白和蛋白–脂质相互作用；中心激酶催化结构域与负责酶活性的蛋白激酶A(PKA)和蛋白激酶C(PKC)区域具有高度的同源性，磷酸化该结构域的Tr308是激活AKT的必要条件之一；-COOH端的调控区域包含Ser473，磷酸化该位点也是激活AKT的必要条件之一 [33] [34]。

雷帕霉素靶蛋白(mTOR)也是一种丝氨酸/苏氨酸蛋白激酶，包括mTOR复合物1 (mTORC1)和mTOR复合物2 (mTORC2)。前者对雷帕霉素敏感，由mTOR、Raptor和mLST8组成，主要调节细胞生长和能量代谢；后者对雷帕霉素不敏感，由mTOR、Rictor、Sin1和mLST1组成，主要参与细胞骨架的重建和细胞存活 [35]。AKT可以直接磷酸化mTORC1的Ser2448位点直接激活mTORC1；也可以通过磷酸化结节性硬化症蛋白2 (TSC2)，导致TSC2对Rheb (一种ras相关的GTPase)活性的抑制作用减弱，从而促进非活性的Rheb-GDP变成具有活性的Rheb-GTP间接激活mTORC1。mTORC2可以直接通过磷酸化Ser473来促进AKT的激活，这为与AKT一起募集至细胞膜的磷酸肌醇依赖蛋白激酶1 (PDK1)磷酸化Thr308位点最终使AKT完全活化奠定了基础 [36] (见图3)。mTORC1和mTORC2目前已被确定为SREBP1主要的上游效应因子 [37] [38]。

Figure 3. AKT/mTOR signaling pathway [79]

图3. AKT/mTOR信号通路 [79]

有研究表明，鞣花酸(EA)可抑制AKT (Thr308)磷酸化，减弱AKT/mTORC1通路下游的效应因子SREBP-1的表达，导致FAS的转录和翻译过程受限，从而减轻了肝脂肪变性模型中脂质的积累 [39]。熊去氧胆酸(UDCA)通过其在肝脏中具有细胞保护作用和抗凋亡活性，被广泛应用于治疗胆汁淤积性肝病(如胆结石和原发性胆汁性肝硬化)的非手术治疗 [40] [41]。另一项研究发现UDCA也可以通过调节AKT/mTOR信号转导来减轻肝脂肪变性。在由OA诱导的肝脂肪变性LO2细胞模型中，脂质积累非常明显；然而予以不同浓度(特别是2 mmol/L)的UDCA可显著地抑制脂质积累、改善ALT、AST、GGT等生化指标，与此同时AKT、mTOR的激活以及SREBP-1的表达明显地受到了抑制 [42]。由此可见，AKT/mTOR通路可作为一个治疗NAFLD及其相关并发症的潜在靶点。

3.3. FXR

法尼酯X受体(FXR)是核受体超家族的一个成员。在哺乳动物中有两种成员：FXRα和FXRβ [43]。FXRα基因编码四种蛋白亚型：FXRα1-α4，在肝脏和回肠中广泛表达，其亚型的相对表达可能具有物种特异性，在小鼠中，四种亚型在肝脏中均有大量表达 [44]，而在人的肝脏中，α1、α2的表达比α3、α4更占优势 [45]。FXRb在人类和灵长类动物中是一种假基因，没有明确的生理意义 [46]。FXR具有典型的核受体结构：A)不依赖配体、可与共调节蛋白相互作用的转录激活域(AF1)；B)高度保守的能够识别特定DNA序列的核心DNA结合域(DBD)；C)作为连接器的铰链区；D)可与配体结合、与共调节蛋白相互作用的-COOH端配体结合域(LBD)；E)依赖配体、能促进不同调控蛋白的相互作用的激活功能域(AF2) [47] [48] [49] [50] (见图4)。FXR通过与配体结合激动，刺激多种基因的转录，调节脂质、葡萄糖和胆汁酸的动态平衡，参与炎症反应 [51] [52]。SREBP-1就是其下游目标基因之一，激活FXR可以下调SREBP-1及其下游靶基因的表达，降低甘油三酯水平，以达到改善NAFLD的目的 [53]。

Figure 4. FXR structure [80]

图4. FXR结构 [80]

棘皮酸(由刺五加中分离出的一种吡二烯二萜)，具有抗炎和肝保护作用，它可以促进FXR表达增加，进而抑制SREBP-1表达，减轻肝脏脂质积累及脂肪酸合成。而当使用FXR的拮抗剂——胃甾酮后，SREBP-1表达增加，肝脏脂质过度堆积 [54]。沙夫托苷是黄芪的一种生物活性化合物，传统上用于治疗肝炎和胆石症。进来，有研究小组用沙夫托苷干预体内、体外的NAFLD模型以及敲除FXR小鼠的原代肝细胞，结果显示：使用沙夫托苷干预后，NAFLD模型中肝细胞的FXR表达下降受到抑制，SREBP-1表达降低，小鼠血清和肝组织中的胆固醇和甘油三酯明显减少。表明沙夫托苷可通过控制FXR-SREBP-1信号通路减少脂质积累来改善NAFLD [55]。因此，调控FXR-SREBP-1信号通路可以减轻肝脏脂肪变性，FXR激动剂在NAFLD的临床应用中具有重要的治疗作用。

3.4. Micro-RNA

microRNAs (miRNAs)是动物中自然发生的、最丰富的一类小的非编码RNA，由19~25个核苷酸组成。在基因组中无处不在，是与环境相关的影响基因表达的重要调控因子 [56]。miRNAs主要与其靶mRNA分子的3'非翻译区(3' UTR)相互作用，调节蛋白质合成，影响多种信号通路：细胞内的大多miRNAs可以通过直接与靶mRNA的3' UTR结合来发挥其功能 [57]；部分miRNAs可以转移到核中调控靶基因的表达 [58]；一些miRNAs还可以被打包进囊泡分泌到细胞外循环中，细胞外囊泡通过受体依赖性或非受体依赖性的方式被其他细胞胞吞，释放miRNAs，调节靶基因基因表达 [59]。除了参与细胞程序性死亡及癌症的调节 [60]，miRNAs还被证实参与了几乎所有代谢稳态过程，包括脂肪发生，脂肪生成和葡萄糖刺激的胰岛素分泌 [61] [62] [63] [64] [65]，进而影响了NAFLD发病机制的代谢途径 [66]，例如：miR-21可通过PPARα通路控制脂质的β-氧化 [67]，miR-206可通过LXRα通路调控脂肪的从头生成 [68]，miR-758可通过作用于ABCA1通路影响胆固醇稳态等 [69]。

miR-122已被证明可以通过靶向SREBP-1来调节脂肪酸代谢：该项研究比较了NASH患者与正常人的474种miRNAs的表达，通过microRNA微阵列分析并用RT-PCR验证，发现miR-122的表达存在差异性，在NASH受试者中，miR-122水平显着降低；然后在体外沉默和过度表达miR-122发现SREBP-1的mRNA水平及蛋白质水平分别相应的增加和降低 [70]。miR-33除了被认为是治疗动脉粥样硬化的潜在治疗靶点外 [71]，也被发现对肥胖和肝脂肪变性具有调节作用。有研究小组通过利用敲除miR-33的小鼠发现缺乏miR-33导致高脂饮食诱导的肥胖和肝脏脂肪变性的显着加重与SREBP-1的表达上调有关，证明了SREBP-1是miR-33的靶点 [72]。可见，miRNAs在脂质代谢中发挥着重要作用，对NAFLD的治疗具有重要的潜力和应用价值。

3.5. 其他

除了上述因子，还有其他通过影响SREBP1转录活性的调控因子可作为NAFLD的治疗靶点。

肝脏X受体(LXR)也属于核受体超家族，参与肝脏脂质生成，LXR-SREBP1通路异常激活是导致NAFLD原因之一 [73]。有研究发现长非编码RNA(lncRNA)Blnc1是诱导SREBP1应答LXR激活的必要条件，它在肥胖和NAFLD小鼠的肝脏中表达明显升高，在肝脏中被特异性灭活可消除高脂肪饮食诱导的肝脂肪变性和胰岛素抵抗 [74]。

以前的研究表明肾素-血管紧张素系统(RAS)在NAFLD中起着复杂的作用。有研究发现血管紧张素原(AGT)特异性过表达可以抑制SREBP1及其下游分子ACC，FASN的表达，减轻肝脏脂肪变性；当抑制AGT表达时，得到的结果与上述情况相反，证明了AGT可通过SREBP-1通路调控NAFLD的发生与发展 [75]。

与有相同体重指数(BMI)的男性相比，绝经前的女性NAFLD发病率更低 [76]。这种保护作用可能与雌激素限制肝脏脂肪积累的能力有关。激活芳基烃受体(AhR)通路导致雌激素代谢酶细胞色素P450 1A1 (CYP1A1)的过表达，除了参与脂肪酸氧化的过氧化物酶体增殖激活受体(PPARα)的表达显著降低，SREBP-1及其下游生脂基因的表达也明显增加，甘油三酯积累及肝损伤标志物显著升高，17β-雌二醇(E2)对肝脂肪变性的保护作用减弱 [77]。

4. 小结

NAFLD与肥胖、血脂异常及胰岛素抵抗密切相关，肝细胞中的游离脂肪酸及甘油三酯含量增加促进了NAFLD的发生与发展。SREBP-1是介导脂肪生成激活的主要转录因子，阻断SREBP-1的激活可以下调肝细胞脂肪酸和甘油三酯合成所需关键酶的表达，从而抑制脂肪酸的从头合成。因此，抑制SREBP-1表达可以减轻甚至逆转肝脏脂肪变性。大量的系统研究表明，SREBP-1对脂质代谢的分子机制受多因素的调控，而这些因素正在被深入探索和分析，这有可能为NAFLD的治疗策略提供新的思路。

文章引用

朱若岚,宁 波. SREBP-1相关通路为靶点的NAFLD发生机制及治疗进展
The Pathogenesis and Treatment Progress of NAFLD Targeted by SREBP-1 Related Path-way[J]. 临床医学进展, 2022, 12(05): 4210-4220. https://doi.org/10.12677/ACM.2022.125610

参考文献

  1. 1. Calle, E.E. and Kaaks, R. (2004) Overweight, Obesity and Cancer: Epidemiological Evidence and Proposed Mechanisms. Nature Reviews Cancer, 4, 579-591. https://doi.org/10.1038/nrc1408

  2. 2. Racette, S.B., Deusinger, S.S. and De-usinger, R.H. (2003) Obesity: Overview of Prevalence, Etiology, and Treatment. Physical Therapy, 83, 276-288. https://doi.org/10.1093/ptj/83.3.276

  3. 3. Souza, M.R.D.A., Diniz, M.D.F.F.D., Medeiros-Filho, J.E.M.D. and Araújo, M.S.T.D. (2012) Metabolic Syndrome and Risk Factors for Non-Alcoholic Fatty Liver Disease. Arquivos de Gastroenterologia, 49, 89-96. https://doi.org/10.1590/S0004-28032012000100015

  4. 4. Horton, J.D., Shimomura, I., Brown, M.S., Hammer, R.E., Goldstein, J.L. and Shimano, H. (1998) Activation of Cholesterol Synthesis in Preference to Fatty Acid Synthesis in Liver and Adipose Tissue of Transgenic Mice Overproducing Sterol Regulatory Element-Binding Protein-2. Journal of Clinical Investigation, 101, 2331-2339. https://doi.org/10.1172/JCI2961

  5. 5. Hua, X., Yokoyama, C., Wu, J., Briggs, M.R., Brown, M.S., Goldstein, J.L., et al. (1993) SREBP-2, a Second Sic- Helix-Loop-Helix-Leucine Zipper Protein That Stimulates Transcription by Bind-ing to a Sterol Regulatory Element. Proceedings of the National Academy of Sciences of the United States of America, 90, 11603-11607. https://doi.org/10.1073/pnas.90.24.11603

  6. 6. Brown, M.S. and Goldstein, J.L. (1997) The SREBP Pathway: Regulation of Cholesterol Metabolism by Proteolysis of a Membrane-Bound Transcription Factor. Cell, 89, 331-340. https://doi.org/10.1016/S0092-8674(00)80213-5

  7. 7. Shimano, H., Horton, J.D., Shimomura, I., Hammer, R.E., Brown, M.S. and Goldstein, J.L. (1997) Isoform 1c of Sterol Regulatory Element Binding Protein Is Less Active Than Isoform 1a in Livers of Transgenic Mice and in Cultured Cells. Journal of Clinical Investigation, 99, 846-854. https://doi.org/10.1172/JCI119248

  8. 8. Shimomura, I., Shimano, H., Horton, J.D., Goldstein, J.L. and Brown, M.S. (1997) Differential Expression of Exons 1a and 1c in MRNAs for Sterol Regulatory Element Binding Protein-1 in Human and Mouse Organs and Cultured Cells. Journal of Clinical Investigation, 99, 838-845. https://doi.org/10.1172/JCI119247

  9. 9. Horton, J.D., Shah, N.A., Warrington, J.A., Anderson, N.N., Park, S.W., Brown, M.S., et al. (2003) Combined Analysis of Oligonucleotide Microarray Data from Transgenic and Knockout Mice Identifies Direct SREBP Target Genes. Proceedings of the National Academy of Sciences of the United States of America, 100, 12027-12032. https://doi.org/10.1073/pnas.1534923100

  10. 10. Sato, R., Yang, J., Wang, X., Evans, M.J., Ho, Y.K., Goldstein, J.L., et al. (1994) Assignment of the Membrane Attachment, DNA Binding, and Transcriptional Activation Domains of Sterol Regulatory Element-Binding Protein-1 (SREBP-1). THE Journal of Biolcical Chemistry, 269, 17267-17273. https://doi.org/10.1016/S0021-9258(17)32550-4

  11. 11. Wang, X., Sato, R., Brown, M.S., Hua, X. and Goldstein, J.L. (1994) SREBP-1, a Membrane-Bound Transcription Factor Released by Sterol-Regulated Proteolysis. Cell, 77, 53-62. https://doi.org/10.1016/0092-8674(94)90234-8

  12. 12. Adams, C.M., Reitz, J., De Brabander, J.K., Feramisco, J.D., Li, L., Brown, M.S. and Goldstein, J.L. (2004) Cholesterol and 25-Hydroxycholesterol Inhibit Activation of SREBPs by Different Mechanisms, Both Involving SCAP and Insigs. Journal of Biological Chemistry, 279, 52772-52780. https://doi.org/10.1074/jbc.M410302200

  13. 13. Yang, T., Espenshade, P.J., Wright, M.E., Yabe, D., Gong, Y., Aebersold, R., Goldstein, J.L. and Brown, M.S. (2002) Crucial Step in Cholesterol Homeostasis: Sterols Promote Binding of SCAP to INSIG-1, a Membrane Protein That Facilitates Retention of SREBPs in ER. Cell, 110, 489-500. https://doi.org/10.1016/S0092-8674(02)00872-3

  14. 14. Miller, E.A. and Schekman, R. (2013) COPII—A Flexible Vesicle Formation System. Current Opinion in Cell Biology, 25, 420-427. https://doi.org/10.1016/j.ceb.2013.04.005

  15. 15. Rawson, R.B., Zelenski, N.G., Nijhawan, D., Ye, J., Sakai, J., et al. (1997) Complementation Cloning of S2P, a Gene Encoding a Putative Metalloprotease Required for Intramembrane Cleavage of SREBPs. Molecular Cell, 1, 47-57. https://doi.org/10.1016/S1097-2765(00)80006-4

  16. 16. Sakai, J., Rawson, R.B., Espenshade, P.J., Cheng, D., Seegmiller, A.C., et al. (1998) Molecular Identification of the Sterol-Regulated Luminal Protease That Cleaves SREBPs and Controls Lipid Composition of Animal Cells. Molecular Cell, 2, 505-514. https://doi.org/10.1016/S1097-2765(00)80150-1

  17. 17. Horton, J.D., Goldstein, J.L. and Brown, M.S. (2002) SREBPs: Activators of the Complete Program of Cholesterol and Fatty Acid Synthesis in the Liver. Journal of Clinical Investigation, 109, 1125-1131. https://doi.org/10.1172/JCI0215593

  18. 18. Long, Y.C. and Zierath, J.R. (2006) AMP-Activated Protein Kinase Sig-naling in Metabolic Regulation. Journal of Clinical Investigation, 116, 1776-1783. https://doi.org/10.1172/JCI29044

  19. 19. Garcia, D. and Shaw, R.J. (2017) AMPK: Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance. Molecular Cell, 66, 789-800. https://doi.org/10.1016/j.molcel.2017.05.032

  20. 20. Li, Y., Xu, S., Mihaylova, M. M., Zheng, B., Hou, X., Jiang, B., et al. (2011) AMPK Phosphorylates and Inhibits SREBP Activity to Attenuate Hepatic Steatosis and Atherosclerosis in Diet-Induced Insulinresistant Mice. Molecular Cell, 13, 376-388. https://doi.org/10.1016/j.cmet.2011.03.009

  21. 21. Gowans, G.J., Hawley, S.A., Ross, F.A. and Hardie, D.G. (2013) AMP Is a True Physiological Regulator of AMP-Activated Protein Kinase by Both Allosteric Activation and Enhancing Net Phosphorylation. Cell Metabolism, 18, 556-566. https://doi.org/10.1016/j.cmet.2013.08.019

  22. 22. Li, N., Wang, Y., Neri, S., Zhen, Y., Fong, L.W.R. and Qiao, S.H. (2019).Tankyrase Disrupts Metabolic Homeostasis and Promotes Tumorigenesis by Inhibiting LKB1-AMPK Signalling. Nature Communications, 10, Article No. 4363. https://doi.org/10.1038/s41467-019-12377-1

  23. 23. Day, E.A., Ford, R.J. and Steinberg, G.R. (2017) AMPK as a Therapeutic Target for Treating Metabolic Diseases. Trends in Endocrinology and Metabolism, 28, 545-560. https://doi.org/10.1016/j.tem.2017.05.004

  24. 24. Gai, H., Zhou, F., Zhang, Y., Ai, J., Zhan, J., You, Y., et al. (2020) Coniferaldehyde Ameliorates the Lipid and Glucose Metabolism in Palmitic Acid‐induced HepG2 Cells via the LKB1/AMPK Signaling Pathway. Journal of Food Science, 85, 4050-4060. https://doi.org/10.1111/1750-3841.15482

  25. 25. Chen, Q., Liu, M., Yu, H., Li, J., Wang, S., Zhang, Y., et al. (2018) Scutellaria Baicalensis Regulates FFA Metabolism to Ameliorate NAFLD through the AMPK-Mediated SREBP Signal-ing Pathway. Journal of Natural Medicines, 72, 655-666. https://doi.org/10.1007/s11418-018-1199-5

  26. 26. Hai, Y.Q., Kim, D.Y., Kim, S.J., Jo, H.K., Kim, G.W. and Chung, S.H. (2013) Betulinic Acid Alleviates Non-Alcoholic Fatty Liver by Inhibiting SREBP1 Activity via the AMPK-mTOR-SREBP Signaling Pathway. Biochemical Pharmacology, 85, 1330-1340. https://doi.org/10.1016/j.bcp.2013.02.007

  27. 27. Kamikubo, R., Kai, K., Tsuji-Naito, K. and Akagawa, M. (2016) β-Caryophyllene Attenuates Palmitate-induced Lipid Accumulation through AMPK Signaling by Activating CB2 Receptor in Human HepG2 Hepatocytes. Molecular Nutrition & Food Research, 60, 2228-2242. https://doi.org/10.1002/mnfr.201600197

  28. 28. Luo, L., Fang, K., Dan, X. and Gu, M. (2019) Crocin Ameliorates Hepatic Steatosis through Activation of AMPK Signaling in Db/db Mice. Lipids in Health and Disease, 18, Article No. 11. https://doi.org/10.1186/s12944-018-0955-6

  29. 29. Peng, C.H., Yang, M.Y., Yang, Y.S., Yu, C.C. and Wang, C.J. (2017) Antrodia Cinnamomea Prevents Obesity, Dyslipidemia, and the Derived Fatty Liver via Regulating AMPK and SREBP Signaling. The American Journal of Chinese Medicine, 45, 67-83. https://doi.org/10.1142/S0192415X17500069

  30. 30. Guo, L., Kang, J.S., Park, Y.H., Je, B.I., Lee, Y.J., Kang, N.J., et al. (2020) S-Petasin Inhibits Lipid Accumulation in Oleic Acid-Induced HepG2 Cells through Activation of the AMPK Signaling Pathway. Food & Function, 11, 5664-5673. https://doi.org/10.1039/D0FO00594K

  31. 31. Yi, T., Jane, K., Jing, C., Ong, M., Lao, W.G., Jin, X.L., et al. (2017) Green Tea Polyphenols Ameliorate Non-Alcoholic Fatty Liver Disease through Upregulating AMPK Activation in High Fat Fed Zucker Fatty Rats. World Journal of Gastroenterology, 23, 3805-3814. https://doi.org/10.3748/wjg.v23.i21.3805

  32. 32. Dummler, B. and Hemmings, B.A. (2007) Physiological Roles of PKB/Akt Isoforms in Development and Disease. Biochemical Society Transactions, 35, 231-235. https://doi.org/10.1042/BST0350231

  33. 33. Szymonowicz, K., Oeck, S., Malewicz, N.M. and Jendrossek, V. (2018) New Insights into Protein Kinase B/Akt Signaling: Role of Localized Akt Activation and Compartment-Specific Target Proteins for the Cellular Radiation Response. Cancers, 10, Article No. 78. https://doi.org/10.3390/cancers10030078

  34. 34. Wadhwa, B., Makhdoomi, U., Vishwakarma, R. and Malik, F. (2017) Protein Kinase B: Emerging Mechanisms of Isoform-Specific Regulation of Cellular Signaling in Cancer. An-ti-Cancer Drugs, 28, 569-580. https://doi.org/10.1097/CAD.0000000000000496

  35. 35. Kim, J. and Guan, K.L. (2019) MTOR as a Central Hub of Nutrient Signalling and Cell Growth. Nature Cell Biology, 21, 63-71. https://doi.org/10.1038/s41556-018-0205-1

  36. 36. Lim, W., Mayer, B. and Pawson, T. (2015) Cell Signaling: Princi-ples and Mechanisms. Garland Science, New York. https://doi.org/10.1201/9780429258893

  37. 37. Porstmann, T., Santos, C.R., Griffiths, B., Cully, M., Wu, M., Leevers, S., Griffiths, J.R., et al. (2008) SREBP Activity Is Regulated by MTORC1 and Contributes to Akt-Dependent Cell Growth. Cell Metabolism, 8, 224-236. https://doi.org/10.1016/j.cmet.2008.07.007

  38. 38. Hagiwara, A., Cornu, M., Cybulski, N., Polak, P., Betz, C., Trapa-ni, F., et al. (2012) Hepatic MTORC2 Activates Glycolysis and Lipogenesis through Akt, Glucokinase, and SREBP1c. Cell Metabolism, 15, 725-738. https://doi.org/10.1016/j.cmet.2012.03.015

  39. 39. Zhang, C., Hu, J., Sheng, L., Yuan, M., Wu, Y., Chen, L., et al. (2019) Ellagic Acid Ameliorates AKT-Driven Hepatic Steatosis in Mice by Suppressing De Novo Lipogenesis via the AKT/SREBP-1/FASN Pathway. Food & Function, 10, 3410-3420. https://doi.org/10.1039/C9FO00284G

  40. 40. Lim, S.C., Duong, H.Q., Parajuli, K.R. and Han, S.I. (2012) Pro-Apoptotic Role of the MEK/ERK Pathway in Ursodeoxycholic Acid-Induced Apoptosis in SNU601 Gastric Cancer Cells. Oncology Reports, 28, 1429-1434. https://doi.org/10.3892/or.2012.1918

  41. 41. Tonin, F. and Arends, I.W.C.E. (2018) Latest Development in the Syn-thesis of Ursodeoxycholic Acid (UDCA): A Critical Review. Beilstein Journal of Organic Chemistry, 14, 470-483. https://doi.org/10.3762/bjoc.14.33

  42. 42. Hu, J., Hong, W., Yao, K.N., Zhu, X.H., Chen, Z.Y. and Ye, L. (2019) Ursodeoxycholic Acid Ameliorates Hepatic Lipid Metabolism in LO2 Cells by Regulating the AKT/mTOR/SREBP-1 Signaling Pathway. World Journal of Gastroenterology, 25, 1492-1501. https://doi.org/10.3748/wjg.v25.i12.1492

  43. 43. Lee, F.Y., Lee, H., Hubbert, M.L., Edwards, P.A. and Zhang, Y. (2006) FXR, a Multipurpose Nuclear Receptor. Trends in Biochemical Sciences, 31, 572-580. https://doi.org/10.1016/j.tibs.2006.08.002

  44. 44. Zhang, Y., Kast-Woelbern, H.R. and Edwards, P.A. (2003) Natural Structural Variants of the Nuclear Receptor Farnesoid X Receptor Affect Transcriptional Activation. Journal of Biologi-cal Chemistry, 278, 104-110. https://doi.org/10.1074/jbc.M209505200

  45. 45. Huber, R.M., Murphy, K., Miao, B., Link, J.R., Cunningham, M.R., Rupar, M.J., et al. (2002) Generation of Multiple Farnesoid-X-Receptor Isoforms through the Use of Alternative Pro-moters. Gene, 290, 35-43. https://doi.org/10.1016/S0378-1119(02)00557-7

  46. 46. Otte, K., Kranz, H., Kober, I., Thompson, P., Hoefer, M., Haubold, B., et al. (2003) Identification of Farnesoid X Receptor Beta as a Novel Mammalian Nuclear Receptor Sensing Lanosterol. Molecular and Cellular Biology, 23, 864-872. https://doi.org/10.1128/MCB.23.3.864-872.2003

  47. 47. Weikum, E.R., Liu, X. and Ortlund, E.A. (2018) The Nucle-ar Receptor Superfamily: A Structural Perspective. Protein Science, 27, 1876-1892. https://doi.org/10.1002/pro.3496

  48. 48. Devarakonda, S., Harp, J.M., Kim, Y., Ozyhar, A. and Rastinejad, F. (2003) Structure of the Heterodimeric Ecdysone Receptor DNA-Binding Complex. The EMBO Journal, 22, 5827-5840. https://doi.org/10.1093/emboj/cdg569

  49. 49. Wang, N., Zou, Q., Xu, J., Zhang, J. and Liu, J. (2018) Ligand Binding and Heterodimerization with Retinoid X Receptor a (RXRa) Induce Farnesoid X Receptor (FXR) Conformational Changes Affecting Coactivator Binding. Journal of Biological Chemistry, 293, 18180-18191. https://doi.org/10.1074/jbc.RA118.004652

  50. 50. Laffitte, B.A., Kast, H.R., Nguyen, C.M., Zavacki, A.M., Moore, D.D., et al. (2000) Identification of the DNA Binding Specificity and Potential Target Genes for the Farnesoid Xactivated Receptor. Journal of Biological Chemistry, 275, 10638-10647. https://doi.org/10.1074/jbc.275.14.10638

  51. 51. Jia, W., Xie, G. and Jia, W. (2018) Bile Acid-Microbiota Crosstalk in Gastrointestinal Inflammation and Carcinogenesis. Nature Reviews Gastroenterology & Hepatology, 15, 111-128. https://doi.org/10.1038/nrgastro.2017.119

  52. 52. Massafra, V., Milona, A., Vos, H.R., Ramos, R.J.J., Gerrits, J., Willemsen, E.C.L., Ramos Pittol, J.M., Ijssennagger, N., Houweling, M., Prinsen, H., Verhoeven-Duif, N.M., Burgering, B.M.T. and Van Mil, S.W.C. (2017) Farnesoid X Receptor Activation Promotes Hepatic Amino Acid Catabolism and Ammonium Clearance in Mice. Gastroenterology, 152, 1462-1476. https://doi.org/10.1053/j.gastro.2017.01.014

  53. 53. Watanabe, M., Houten, S.M., Wang, L., Moschetta, A., Man-gelsdorf, D.J., Heyman, R.A., et al. (2004) Bile Acids Lower Triglyceride Levels Via a Pathway Involving FXR, SHP, and SREBP-1c. Journal of Clinical Investigation, 113, 1408-1418. https://doi.org/10.1172/JCI21025

  54. 54. Han, X., Cui, Z.-Y., Song, J., Piao, H.-Q., Lian, L.-H., Hou, L.-S., et al. (2019) Acanthoic Acid Modulates Lipogenesis in Non-alcoholic Fatty Liver Disease via FXR/LXRs-Dependent Manner. Chemico-Biological Interactions, 311, Article ID: 108794. https://doi.org/10.1016/j.cbi.2019.108794

  55. 55. Liu, M., Zhang, G., Wu, S., Song, M., Wang, J., Cai, W., et al. (2020) Schaftoside Alleviates HFD-Induced Hepatic Lipid Accumulation in Mice Via Upregulating Farnesoid X Receptor. Journal of Ethnopharmacology, 255, Article ID: 112776. https://doi.org/10.1016/j.jep.2020.112776

  56. 56. Yi, L., Ding, D., Huang, Q., Oda, Y., Takagi, S., Fukami, T., et al. (2017) Downregulation of MiR-192 Causes Hepatic Steatosis and Lipid Accumulation by Inducing SREBF1: Novel Mechanism for Bisphenol A-Triggered Non-Alcoholic Fatty Liver Disease. Biochimica et Biophysica Acta (BBA): Mo-lecular and Cell Biology of Lipids, 1862, 869-882. https://doi.org/10.1016/j.bbalip.2017.05.001

  57. 57. Selbach, M., Schwanhausser, B., Thierfelder, N., Fang, Z., Khanin, R. and Rajewsky, N. (2008) Widespread Changes in Protein Synthesis Induced by MicroRNAs. Nature, 455, 58-63. https://doi.org/10.1038/nature07228

  58. 58. Meister, G., Landthaler, M., Patkaniowska, A., Dorsett, Y., Teng, G. and Tuschl, T. (2004) Human Argonaute2 Mediates RNA Cleavage Targeted by MiRNAs and SiRNAs. Molecular Cell, 15, 185-197. https://doi.org/10.1016/j.molcel.2004.07.007

  59. 59. van Niel, G., D’Angelo, G. and Raposo, G. (2018) Shedding Light on the Cell Biology of Extracellular Vesicles. Nature Reviews Molecular Cell Biology, 19, 213-228. https://doi.org/10.1038/nrm.2017.125

  60. 60. Pan, J.H., Abernathy, B., Kim, Y.J., Lee, J.H., Kim, J.H., Shin, E.C. and Kim, J.K. (2017) Cruciferous Vegetables and Colorectal Cancer Prevention through MicroRNA Regulation: A Re-view. Critical Reviews in Food Science and Nutrition, 58, 2026-2038. https://doi.org/10.1080/10408398.2017.1300134

  61. 61. Shen, L., Zhang, Y., Du, J., Chen, L., Luo, J., Li, X., Li, M., Tang, G., Zhang, S. and Zhu, L. (2016) MicroRNA-23a Regulates 3T3-L1 Adipocyte Differentiation. Gene, 575, 761-764. https://doi.org/10.1016/j.gene.2015.09.060

  62. 62. Song, G., Xu, G., Ji, C., Shi, C., Shen, Y., Chen, L., Zhu, L., Yang, L., Zhao, Y. and Guo, X. (2014) The Role of MicroRNA-26b in Human Adipocyte Differentiation and Prolif-eration. Gene, 533, 481-487. https://doi.org/10.1016/j.gene.2013.10.011

  63. 63. Lie, S., Morrison, J.L., Williams-Wyss, O., Suter, C.M., Hum-phreys, D.T., Ozanne, S.E., Zhang, S., MacLaughlin, S.M., Kleemann, D.O., Walker, S.K., et al. (2016) Impact of Ma-ternal Undernutrition Around the Time of Conception on Factors Regulating Hepatic Lipid Metabolism and MicroRNAs in Singleton and Twin Fetuses. American Journal of Physiology-Endocrinology and Metabolism, 310, e148-e159. https://doi.org/10.1152/ajpendo.00600.2014

  64. 64. Massart, J., Katayama, M. and Krook, A. (2016) MicroManaging Glucose and Lipid Metabolism in Skeletal Muscle: Role of MicroRNAs. Biochimica et Biophysica Acta (BBA) - Molecu-lar and Cell Biology of Lipids, 1861, 2130-2138. https://doi.org/10.1016/j.bbalip.2016.05.006

  65. 65. Baffy, G. (2015) MicroRNAs in Nonalcoholic Fatty Liver Dis-ease. Journal of Clinical Medicine, 4, 1977-1988. https://doi.org/10.3390/jcm4121953

  66. 66. Tessitore, A., Cicciarelli, G., Del Vecchio, F., Gaggiano, A., Verzella, D., Fischietti, M., Mastroiaco, V., Vetuschi, A., Sferra, R., Barnabei, R., et al. (2016) MicroRNA Expression Analysis in High Fat Diet-Induced NAFLD-NASH-HCC Progression: Study on C57BL/6J Mice. BMC Cancer, 16, Article No. 3. https://doi.org/10.1186/s12885-015-2007-1

  67. 67. Kida, K., Nakajima, M., Mohri, T., Oda, Y., Takagi, S., Fukami, T., et al. (2011) PPARα Is Regulated by MiR-21 and MiR-27b in Human Liver. Pharmaceutical Research, 28, 2467-2476. https://doi.org/10.1007/s11095-011-0473-y

  68. 68. Zhong, D., Huang, G., Zhang, Y., Rajeev, K.G., Tuschl, T., Manoharan, M., et al. (2013) MicroRNA-1 and MicroRNA-206 Suppress LXRα-Induced Lipogenesis in Hepatocytes. Cellular Signalling, 25, 1429-1437. https://doi.org/10.1016/j.cellsig.2013.03.003

  69. 69. Krützfeldt, J., Rajewsky, N., Braich, R., Rajeev, K.G., Tuschl, T., Manoharan, M., et al. (2005) Silencing of MicroRNAs in Vivo with ‘Antagomirs’. Nature, 438, 685-689. https://doi.org/10.1038/nature04303

  70. 70. Cheung, O., Puri, P., Eicken, C., Contos, M.J., Mirshahi, F., Maher, J.W., et al. (2010) Nonalcoholic Steatohepatitis Is Associated with Altered Hepatic MicroRNA Expression. Hepatology, 48, 1810-1820. https://doi.org/10.1002/hep.22569

  71. 71. Horie, T., Baba, O., Kuwabara, Y., Chujo, Y., Watanabe, S., Kinoshita, M., et al. (2012) MicroRNA-33 Deficiency Reduces the Progression of Atherosclerotic Plaque in ApoE/ Mice. Journal of the American Heart Association Cardiovascular & Cerebrovascular Disease, 1, Article ID: e003376. https://doi.org/10.1161/JAHA.112.003376

  72. 72. Horie, T., Nishino, T., Baba, O., Kuwabara, Y., Nakao, T., Nishi-ga, M., et al. (2013) MicroRNA-33 Regulates Sterol Regulatory Element-Binding Protein 1 Expression in Mice. Nature Communications, 4, Article No. 2883. https://doi.org/10.1038/ncomms3883

  73. 73. Calkin, A.C. and Tontonoz, P. (2012) Transcriptional Integration of Me-tabolism by the Nuclear Sterol-Activated Receptors LXR and FXR. Nature Reviews Molecular Cell Biology, 13, 213-224. https://doi.org/10.1038/nrm3312

  74. 74. Zhao, X.-Y., Xiong, X., Liu, T., Mi, L., Peng, X., Rui, C., Guo, L., et al. (2018) Long Noncoding RNA Licensing of Obesity-Linked Hepatic Lipogenesis and NAFLD Pathogenesis. Nature Communications, 9, Article No. 2986. https://doi.org/10.1038/s41467-018-05383-2

  75. 75. Tao, X. and Rong, J. (2019) Angiotensinogen in Hepatocytes Contributes to Western Diet-Induced Liver Steatosis. SSRN Electronic Journal. https://doi.org/10.2139/ssrn.3335005

  76. 76. Miele, L., Dall’Armi, V., Cefalo, C., Nedovic, B., Arzani, D., Amore, R., et al. (2014) A Case-Control Study on the Effect of Metabolic Gene Polymorphisms, Nutrition, and Their Interaction on the Risk of Non-Alcoholic Fatty Liver Disease. Genes & Nutrition, 9, Article No. 383. https://doi.org/10.1007/s12263-013-0383-1

  77. 77. Xyzab, C., Hgxab, C., Zhwab, C., Li, B., Jiang, H.Y., Li, D.L., et al. (2020) In Vitro and in Vivo Approaches for Identifying the Role of Aryl Hydrocarbon Receptor in the Development of Nonalcoholic Fatty Liver Disease. Toxicology Letters, 319, 85-94. https://doi.org/10.1016/j.toxlet.2019.10.010

  78. 78. Guo, D., Bell, E.H., Mischel, P. and Chakravarti, A. (2014) Tar-geting SREBP-1-Driven Lipid Metabolism to Treat Cancer. Current Pharmaceutical Design, 20, 2619-2626. https://doi.org/10.2174/13816128113199990486

  79. 79. Ediriweera, M.K., Tennekoon, K.H. and Samarakoon, S.R. (2019) Role of the PI3K/AKT/mTOR Signaling Pathway in Ovarian Cancer: Biological and Therapeutic Significance. Seminars in Cancer Biology, 59, 147-160. https://doi.org/10.1016/j.semcancer.2019.05.012

  80. 80. Jiang, L., Zhang, H., Xiao, D., Wei, H. and Chen, Y. (2021) Farnesoid X Receptor (FXR): Structures and Ligands. Computational and Structural Biotechnology Journal, 19, 2148-2159. https://doi.org/10.1016/j.csbj.2021.04.029

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