趙晨露 周鋮 尚東方 劉素彤 石俊豪 王曉杰 趙文霞
摘要:非酒精性脂肪性肝?。∟AFLD)是由于脂肪代謝功能異常而出現(xiàn)大量脂肪類物質(zhì)在肝細(xì)胞中蓄積的慢性肝病。常規(guī)的抗炎降酶治療效果不佳,恢復(fù)人體脂類物質(zhì)的正常生物合成與代謝是NAFLD的治療關(guān)鍵。棕色脂肪已被證明可通過增強(qiáng)機(jī)體胰島素敏感性、調(diào)節(jié)脂質(zhì)代謝而改善代謝相關(guān)性疾病,促進(jìn)人體白色脂肪棕色化治療NAFLD受到了醫(yī)學(xué)界的廣泛關(guān)注。本文重點(diǎn)綜述了白色脂肪棕色化改善NAFLD的作用機(jī)制,總結(jié)了促進(jìn)白色脂肪棕色化的肝因子,為NAFLD的臨床治療提供新思路。
關(guān)鍵詞:非酒精性脂肪性肝?。?脂肪組織, 白色; 脂肪組織, 棕色; 脂肪組織, 米色
基金項(xiàng)目:國家自然科學(xué)基金面上項(xiàng)目(81473651); 河南省特色骨干學(xué)科中醫(yī)學(xué)學(xué)科建設(shè)項(xiàng)目(STG-ZYXKY-2020024)
Influence of white fat browning on nonalcoholic fatty liver disease
ZHAO Chenlu1, ZHOU Cheng1, SHANG Dongfang2, LIU Sutong2, SHI Junhao1, WANG Xiaojie1, ZHAO Wenxia2. (1. The First Clinical Medical College of Henan University of Chinese Medicine, Zhengzhou 450046, China; 2. Department of Hepatology and Spleen-Stomach, The First Affiliated Hospital of Henan University of Chinese Medicine, Zhengzhou 450000, China)
Corresponding author:
ZHAO Wenxia, zhao-wenxia@163.com (ORCID:0000-0001-6666-9469)
Abstract:
Nonalcoholic fatty liver disease (NAFLD) is a chronic liver disease in which a large amount of fat accumulates in hepatocytes due to lipid metabolism disorders. Conventional anti-inflammatory and transaminase-lowering treatment regimens often have an unsatisfactory therapeutic effect, and restoring the normal biosynthesis and metabolism of lipids is the key to the treatment of NAFLD. Studies have shown that brown adipose tissue can improve metabolic diseases by enhancing insulin sensitivity and regulating lipid metabolism, and the treatment of NAFLD by promoting white fat browning has attracted wide attention in the medical field. This article reviews the mechanism of white fat browning in improving NAFLD and summarizes the hepatokines that can promote white fat browning, so as to provide new ideas for the clinical treatment of NAFLD.
Key words:
Non-alcoholic Fatty Liver Disease; Adipose Tissue, White; Adipose Tissue, Brown; Adipose Tissue, Beige
Research funding:
General Project of National Natural Science Foundation of China (81473651); Subject Construction Project of Traditional Chinese Medicine in Henan Province (STG-ZYXKY-2020024)
非酒精性脂肪性肝?。╪onalcoholic fatty liver disease,NAFLD)是常見的慢性肝病,以脂肪的異位沉積導(dǎo)致肝臟脂肪變?yōu)槌跏际录?,可逐漸發(fā)展為肝纖維化、肝硬化甚至肝細(xì)胞癌[1]。預(yù)計(jì)未來十年NAFLD可能逐漸成為終末期肝病、肝移植的主要病因之一[2]。我國NAFLD總體患病率為29.6%,且與肥胖率的上升趨勢(shì)是平行的[3]。2020年國際專家小組建議將NAFLD更名為代謝相關(guān)脂肪性肝病(Metabolic associated fatty liver disease,MAFLD),將代謝功能障礙明確列為脂肪性肝病的重要病因[4-5]。NAFLD不僅與肝臟脂代謝障礙相關(guān),更與脂肪組織代謝紊亂密切相關(guān)。研究[6]發(fā)現(xiàn)白色脂肪棕色化既可減少脂肪的過度積累,又可增加脂肪的消耗,可從源頭防止NAFLD的發(fā)生,因此促進(jìn)白色脂肪棕色化成為NAFLD研究的新領(lǐng)域。
1 脂肪組織概述
脂肪組織主要分為白色脂肪組織(white adipose tissue,WAT)、棕色脂肪組織(brown adipose tissue,BAT),以及介于他們之間的米色脂肪組織。WAT是脂質(zhì)儲(chǔ)存和動(dòng)員的主要場(chǎng)所,以甘油三酯(TG)的形式儲(chǔ)存葡萄糖和脂肪酸中所含的能量,以游離脂肪酸(free fatty acid,F(xiàn)FA)的形式釋放能量[7]。此外,WAT還參與激素分泌、免疫功能等。BAT主要用于能量消耗并利用化學(xué)能進(jìn)行產(chǎn)熱,棕色脂肪細(xì)胞由多房脂滴和豐富的線粒體組成,其中含有解偶聯(lián)蛋白1(uncoupling protein-1,UCP1)。它位于線粒體內(nèi)膜,能夠?qū)Ⅲw內(nèi)生物能轉(zhuǎn)化為熱能并釋放出來,是產(chǎn)熱過程中重要的調(diào)節(jié)因子[8]。米色脂肪組織的形態(tài)與BAT類似,經(jīng)常在WAT中發(fā)現(xiàn)米色脂肪,很多研究認(rèn)為米色脂肪是WAT演化而來,也被稱作WAT與BAT的過渡組織[9]。
白色脂肪棕色化是指白色脂肪細(xì)胞具有很高的可塑性,在運(yùn)動(dòng)、冷暴露、腎上腺素受體受刺激等因素的刺激下,可轉(zhuǎn)分化為與棕色脂肪細(xì)胞具有許多相似形態(tài)和功能特性的米色脂肪細(xì)胞[10]。由于BAT具有產(chǎn)熱生熱的功能,促進(jìn)TG清除和葡萄糖代謝,因而白色脂肪棕色化是一種促進(jìn)白色脂肪消耗并加快人體新陳代謝的良好方法[11]。
2 白色脂肪棕色化改善胰島素抵抗
NAFLD發(fā)病機(jī)制從經(jīng)典“二次打擊”學(xué)說過渡到“多次打擊”學(xué)說,但胰島素抵抗仍是NAFLD發(fā)生過程中的重要環(huán)節(jié)[12]。胰島素抵抗是指胰島素作用的靶器官(肝臟、脂肪組織、骨骼肌等)對(duì)胰島素的敏感性或反應(yīng)性下降,即正常劑量的胰島素產(chǎn)生低于正常生物學(xué)效應(yīng)的一種狀態(tài)。NAFLD發(fā)生過程中存在肝臟、脂肪組織、骨骼肌胰島素抵抗。研究[13]顯示,白色脂肪棕色化有助于改善全身胰島素抵抗。
2.1 白色脂肪棕色化改善胰島β細(xì)胞功能 BAT是對(duì)胰島素最敏感的組織之一,尤其是在交感神經(jīng)激活狀態(tài)下[13]。BAT葡萄糖攝取率接近于觀察到的人類癌旁組織,BAT對(duì)胰島素的高敏感性使葡萄糖攝取增加5倍,而在冷暴露條件下,大量BAT激活產(chǎn)熱增加,葡萄糖攝取增加12倍[14]。臨床通過FDG-PET/CT檢測(cè)證實(shí)有BAT個(gè)體的空腹血糖水平低于無BAT個(gè)體[15]?;A(chǔ)研究[16]發(fā)現(xiàn),活化的BAT可吸收、利用葡萄糖和脂質(zhì),從而改善胰島β細(xì)胞功能,減少胰島β細(xì)胞對(duì)胰島素分泌的需求。除了經(jīng)典的BAT激活能夠調(diào)節(jié)胰島素分泌和葡萄糖穩(wěn)態(tài)外,白色脂肪棕色化在控制體質(zhì)量、調(diào)節(jié)能量平衡和改善糖代謝方面也發(fā)揮著重要作用。白色脂肪發(fā)生棕色化后加速循環(huán)葡萄糖和脂質(zhì)的吸收,增加能量消耗和產(chǎn)熱,間接地提高了葡萄糖耐量、胰島素敏感性和β細(xì)胞功能[17]。
2.2 白色脂肪棕色化提高代謝組織胰島素敏感性 多項(xiàng)研究[18-19]均表明,內(nèi)源性及外源性因子激活不同的信號(hào)通路促進(jìn)BAT激活或白色脂肪棕色化,進(jìn)而提高葡萄糖耐量和脂肪組織、骨骼肌的胰島素敏感性。如成纖維細(xì)胞生長因子21(fibroblast growth factor 21, FGF21)通過肝臟內(nèi)分泌和脂肪組織自分泌形式促進(jìn)白色脂肪棕色化,促進(jìn)脂肪細(xì)胞葡萄糖轉(zhuǎn)運(yùn)蛋白1(glucose transporter 1,GLUT1)和GLUT4表達(dá),加速葡萄糖向細(xì)胞內(nèi)轉(zhuǎn)運(yùn),降低血糖水平[20]。冷暴露活化β3-腎上腺素能受體促進(jìn)白色脂肪棕色化,激活BAT,增加葡萄糖氧化和進(jìn)入線粒體三羧酸循環(huán)的葡萄糖通量,調(diào)節(jié)全身血糖平衡[21]。
3 白色脂肪棕色化減少肝臟脂質(zhì)沉積
肝臟是脂肪吸收、合成、分解與運(yùn)輸?shù)闹行膱?chǎng)所。經(jīng)腸道消化的脂質(zhì)以甘油和FFA形式由門靜脈到達(dá)肝臟,在肝細(xì)胞胞漿內(nèi)合成TG,并以TG-VLDL形式輸出肝外供其他組織利用[22]。脂肪組織是人體儲(chǔ)存脂肪和脂肪動(dòng)員的重要器官。隨著飲食結(jié)構(gòu)改變,機(jī)體常常處于能量過剩狀態(tài),大量脂質(zhì)輸送至脂肪組織[23]。脂肪細(xì)胞雖然發(fā)生肥大或增生,但血管生成不足,引起缺氧和炎癥反應(yīng),造成脂肪組織功能障礙[24]。主要表現(xiàn)為:(1)儲(chǔ)脂能力下降,多余的脂質(zhì)經(jīng)由門靜脈重新導(dǎo)向肝臟,造成脂肪在肝臟的過量堆積[25];(2)胰島素敏感性下降,脂肪分解增加,產(chǎn)生的FFA大量涌入肝臟,研究[26]發(fā)現(xiàn)脂肪組織分解來源的FFA占肝臟FFA通量的59%,加重肝臟脂代謝負(fù)擔(dān);(3)分泌功能下降,脂肪因子分泌減少,其促進(jìn)肝臟脂代謝作用下降[27]。當(dāng)大量FFA超出肝臟合成、運(yùn)輸及氧化分解能力時(shí),造成FFA、TG堆積,導(dǎo)致NAFLD發(fā)生。同時(shí)FFA產(chǎn)生的脂毒性破壞線粒體功能,發(fā)生氧化應(yīng)激和脂質(zhì)過氧化[28],誘導(dǎo)炎性因子生成增加,使脂肪變性的肝臟呈現(xiàn)瀑布型炎癥反應(yīng),誘發(fā)細(xì)胞死亡,加重NAFLD發(fā)展。
研究[29]表明,BAT移植能夠防止肥胖小鼠體質(zhì)量增加、降低總脂肪重量并增加耗氧量,從而改善胰島素抵抗和肝臟脂肪變性。而且BAT移植可提高循環(huán)脂聯(lián)素水平,增加WAT中β-腎上腺素能受體和脂肪酸氧化相關(guān)基因的表達(dá),降低循環(huán)FFA、TG水平[30]。多種因素促進(jìn)白色脂肪棕色化后均能抑制高脂飲食誘導(dǎo)的肝臟脂肪沉積,降低體質(zhì)量。如大黃素促進(jìn)皮下白色脂肪棕色化,降低了高脂飲食誘導(dǎo)的肥胖小鼠的體質(zhì)量和攝食量,提高糖耐量,降低血脂[31]。鳶尾素激活的米色脂肪細(xì)胞通過快速消耗葡萄糖和脂肪來增加產(chǎn)熱,從而促進(jìn)體質(zhì)量下降[32]。以上表明,白色脂肪棕色化或者BAT激活主要通過消耗脂肪促使產(chǎn)熱增加,減少白色脂肪體積和重量,達(dá)到降低體質(zhì)量目的;同時(shí)脂肪消耗減少循環(huán)FFA水平,肝臟攝取的FFA減少,在一定程度上阻止了肝臟的脂肪沉積。
4 促進(jìn)白色脂肪棕色化的肝因子
肝細(xì)胞因子是肝臟通過自分泌、旁分泌和內(nèi)分泌途徑分泌的蛋白質(zhì),在肝臟、脂肪組織代謝中起重要作用。FGF21、骨形態(tài)發(fā)生蛋白(bone morphogenetic protein, BMP)9、中腦星形膠質(zhì)細(xì)胞源性神經(jīng)營養(yǎng)因子(mesencephalic astrocyte-derived neurotrophic factor,Manf)、激活素E(Activin E)等均可促進(jìn)白色脂肪棕色化,已成為肝臟和脂肪組織對(duì)話關(guān)系的橋梁。
4.1 FGF21 FGF21是FGF家族成員之一,主要由肝臟分泌,并在脂肪組織和其他組織中表達(dá)[33]。FGF21需要與位于細(xì)胞膜上的輔助受體β-klotho結(jié)合,共同激活成纖維細(xì)胞因子受體1(fibroblast growth factor receptor 1,F(xiàn)GFR1),F(xiàn)GF21的C端與β-klotho相結(jié)合,N端與FGFR1相結(jié)合,進(jìn)而形成穩(wěn)定FGF21/β-klotho/FGFR1復(fù)合體[34],共同激活下游絲裂原激活的蛋白激酶/MAP激酶(mitogen-activated protein kinase,MAPK)、PR結(jié)構(gòu)域蛋白16(PR domain-containing 16,PRDM16)、過氧化物酶體增殖物激活受體γ共激活劑1α(peroxisome proliferator-activated receptor gamma coactivator 1α,PGC1α)、過氧化物酶體增殖物激活受體γ(peroxisome proliferator-activated receptor-γ,PPARγ)途徑,進(jìn)而刺激UCP1表達(dá),激活BAT活性和WAT褐變[35]。臨床研究[36]顯示,F(xiàn)GF21類似物L(fēng)Y2405319可改善肥胖的2型糖尿病患者的血脂水平及體質(zhì)量。
4.2 BMP9 BMP9屬于TGFβ超家族成員。BMP9是肝臟分泌的蛋白,以自分泌或旁分泌形式通過血液到達(dá)全身發(fā)揮多種生理功能[37]。葡萄糖、胰島素是上調(diào)肝臟BMP9表達(dá)的主要調(diào)控因子,胰島素抵抗模型大鼠肝臟BMP9表達(dá)明顯降低[38]。BMP9主要通過Smad依賴型通路和非Smad依賴型通路(如ERK1/2、ERK5、JNKs和p38MAPK通路)調(diào)控靶基因的轉(zhuǎn)錄和表達(dá)[39]。小鼠腹腔注射外源性BMP9重組衍生物(200 mg·kg-1·周-1)能降低高脂飲食誘導(dǎo)的肥胖小鼠的體質(zhì)量[40]。BMP9不僅能減少白色脂肪細(xì)胞的大小,阻礙脂肪質(zhì)量增加,而且能夠誘導(dǎo)皮下WAT發(fā)生褐變,抑制高脂飲食小鼠肥胖的發(fā)生[41]。肥胖小鼠皮下注射外源性BMP9重組衍生物可提高脂肪組織中UCP1 mRNA和CD137 mRNA的表達(dá)[40]。前者與WAT線粒體功能相關(guān),后者與糖耐量相關(guān)。BMP9能夠在體外促進(jìn)棕色脂肪細(xì)胞的生成,其機(jī)制與Smad依賴型通路激活密切相關(guān)[37]。
4.3 Manf Manf是一種分泌蛋白,其N端結(jié)構(gòu)域和saposin樣蛋白同源,含有21個(gè)氨基酸的分泌信號(hào)肽序列,可與脂質(zhì)和細(xì)胞膜相結(jié)合,C端結(jié)構(gòu)域與SAP蛋白超家族同源[42]。臨床研究[43]表明,血清Manf水平與BMI、體脂百分比、胰島素抵抗穩(wěn)態(tài)模型評(píng)估呈負(fù)相關(guān)。肝臟過表達(dá)Manf可減少高脂飲食誘導(dǎo)的肥胖,其附睪、腹股溝處WAT重量明顯低于野生型小鼠,且脂肪細(xì)胞的大小更?。?4]。進(jìn)一步研究[45]發(fā)現(xiàn),肝臟過表達(dá)Manf小鼠耗氧量、能量消耗持續(xù)增加,WAT中UCP1、PGC1α mRNA和蛋白表達(dá)顯著增加。體外研究[44]證實(shí),Manf通過p38 MAPK/ATF2通路促進(jìn)下游UCP1、PGC1α、CIDEA表達(dá),誘導(dǎo)原代脂肪細(xì)胞發(fā)生棕色化。
4.4 Activin E Activin E是由TGFβ超家族成員βE抑制素基因編碼的肽,其分泌水平受機(jī)體營養(yǎng)狀況調(diào)控。攝入高脂肪飲食會(huì)增加抑制素βE mRNA表達(dá),從而促進(jìn)Activin E分泌[45]。體內(nèi)研究[46]顯示,肝臟過表達(dá)Activin E小鼠的腹股溝WAT、腸系膜WAT中的線粒體密度增加,UCP1、FGF21和BMP8b表達(dá)明顯高于對(duì)照組小鼠。其中BMP8b在成熟的棕色脂肪細(xì)胞中表達(dá),能夠放大棕色脂肪組織中的產(chǎn)熱反應(yīng)。此外,體外研究[46]表明Activin E可直接上調(diào)UCP1和FGF21表達(dá),促進(jìn)白色脂肪細(xì)胞向棕色脂肪細(xì)胞分化。
5 小結(jié)與展望
白色脂肪棕色化對(duì)全身糖脂代謝、維持機(jī)體能量平衡方面具有重要作用,目前對(duì)其研究重點(diǎn)關(guān)注了促進(jìn)白色脂肪棕色化的各種因素,直接或間接探討其對(duì)肥胖和2型糖尿病的防治作用。白色脂肪棕色化不僅僅是脂肪組織本身的代謝變化,更與肝臟、胰腺、心血管、肌肉等組織存在串?dāng)_關(guān)系。肝因子作為促進(jìn)白色脂肪的重要因素,逐漸成為該領(lǐng)域的研究熱點(diǎn),但肝因子在肝臟的亞細(xì)胞表達(dá)位點(diǎn)有待深入研究。未來應(yīng)該更加關(guān)注白色脂肪棕色化和其他代謝組織之間的相互作用,闡明其具體機(jī)制,加強(qiáng)脂肪組織和肝臟等其他組織之間的關(guān)系,為包括NAFLD在內(nèi)代謝性疾病的臨床治療提供更多的實(shí)驗(yàn)依據(jù)。
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收稿日期:
2022-08-02;錄用日期:2022-09-29
本文編輯:林姣