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非酒精性脂肪性肝病與心血管疾病相關(guān)性研究進(jìn)展與現(xiàn)狀

2020-06-11 09:14
世界華人消化雜志 2020年9期
關(guān)鍵詞:硬化受體動(dòng)脈

池肇春,青島市市立醫(yī)院消化內(nèi)科 山東省青島市 266011

0 引言

據(jù)世界衛(wèi)生組織統(tǒng)計(jì),心血管疾病(cardiovascular disease,CVD)仍然是世界范圍內(nèi)死亡的主要原因,每年約有1800萬(wàn)人死亡.然而,在過(guò)去的幾十年里,全球范圍內(nèi)的代謝性疾病,如2型糖尿病、肥胖癥和非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD),也被認(rèn)為是CVD的常見危險(xiǎn)因素.NAFLD約占慢性肝病的75%,已成為困擾世界的主要疾病之一,同時(shí)也是世界各國(guó)最常見的肝病病因.目前,NAFLD最常見的死亡原因仍然是CVD.通過(guò)多種機(jī)制,包括低級(jí)別的全身炎癥反應(yīng),氧化應(yīng)激,脂肪細(xì)胞因子,內(nèi)質(zhì)網(wǎng)應(yīng)激,脂毒性和微生物群失調(diào),也可能受其他因素,如遺傳和表觀遺傳變異的影響NAFLD與CVD.盡管有這些證據(jù),但NAFLD如何導(dǎo)致CVD的確切機(jī)制還沒有完全闡明,有很多方面還不清楚.此外,目前的文獻(xiàn)支持并有越來(lái)越多的證據(jù)表明NAFLD與一些心血管(cardiovascular,CV)不良事件相關(guān),包括冠狀動(dòng)脈疾病(coronary artery disease,CAD)、亞臨床動(dòng)脈粥樣硬化風(fēng)險(xiǎn)增加、結(jié)構(gòu)改變主要是左心室肥厚、心外膜脂肪厚度(epicardial fat thickness,EFT)增加,瓣膜鈣化包括主動(dòng)脈瓣硬化和二尖瓣環(huán)鈣化,功能性心臟改變主要是舒張功能障礙,此外還有房顫、室性心律失常等心律失常和房室傳導(dǎo)阻滯、束支傳導(dǎo)阻滯等傳導(dǎo)缺陷.因此,對(duì)NAFLD患者應(yīng)進(jìn)行相應(yīng)的評(píng)估和管理,以防止進(jìn)一步的并發(fā)癥發(fā)生.可能的治療方法包括非藥理學(xué)策略,包括生活方式改變、藥理學(xué)治療以及外科治療[1].

一些研究表明[2,3]NAFLD與CVD之間存在著直接的聯(lián)系,提出肝-心軸概念,NALFD應(yīng)被視為一個(gè)重要的獨(dú)立危險(xiǎn)因素,而傳統(tǒng)的CV危險(xiǎn)因素和亞臨床和臨床CVD與代謝綜合征(metabolic syndrome,MetS)則不相關(guān).

目前的文獻(xiàn)表明,NAFLD與CV并發(fā)癥如CAD、亞臨床動(dòng)脈粥樣硬化、心律失常以及傳導(dǎo)、結(jié)構(gòu)和功能改變有關(guān).與NAFLD相關(guān)的額外CVD可進(jìn)一步增加CV發(fā)病率和死亡率[4].與脂肪肝相關(guān)的致病因素是多因素的.其中包括炎癥、脂肪因子、腸道菌群失調(diào)、遺傳學(xué)、氧化應(yīng)激以及心理應(yīng)激,如焦慮和抑郁,這些都是CVD的標(biāo)志物.這表明需要進(jìn)一步的研究和采取措施,以減輕NAFLD造成的負(fù)擔(dān)和不良影響[5,6].

1 NAFLD致CVD研究現(xiàn)狀

1.1 NAFLD引起CAD的流行病學(xué)研究 一些研究評(píng)估了脂肪肝(fatty liver disease,FLD)與CAD之間的關(guān)聯(lián),大多數(shù)研究結(jié)果顯示FLD的存在顯著增加了冠狀動(dòng)脈粥樣硬化的風(fēng)險(xiǎn).冠狀動(dòng)脈鈣化(coronary artery calcium,CAC)是不良CV事件的獨(dú)立標(biāo)志,導(dǎo)致血管順應(yīng)性降低、心肌灌注受損,導(dǎo)致冠心病(coronary heart disease,CHD)發(fā)病風(fēng)險(xiǎn)增加,以及血管運(yùn)動(dòng)異常反應(yīng)和長(zhǎng)期死亡率增加[7].當(dāng)前文獻(xiàn)中大多數(shù)已發(fā)表的研究使用多探測(cè)器計(jì)算機(jī)斷層掃描和計(jì)算CAC評(píng)分來(lái)評(píng)估CHD風(fēng)險(xiǎn),這是一種評(píng)估無(wú)癥狀的中等CV風(fēng)險(xiǎn)受試者的合適方法.另一方面,脂肪肝主要通過(guò)超聲或磁共振成像-質(zhì)子密度脂肪分?jǐn)?shù)(proton density fat fraction,PDFF)進(jìn)行診斷.

Chang等[7]最近進(jìn)行了一項(xiàng)橫斷面研究,評(píng)估了105328名受試者的酒精和非酒精病因的CAC評(píng)分與脂肪性肝病的相關(guān)性.研究表明,酒精性肝病和NAFLD與CAC評(píng)分升高有關(guān).此外,他們還發(fā)現(xiàn),即使在控制了傳統(tǒng)的CV危險(xiǎn)因素、MetS和C-反應(yīng)蛋白(C-reactive protein,CRP)后,胰島素抵抗(insulin resistance,IR)指數(shù)也被證明是一個(gè)穩(wěn)健和獨(dú)立的CAC評(píng)分預(yù)測(cè)因子.此外,Kim等[8]對(duì)來(lái)自Rancho Bernardo研究預(yù)期人群的250名受試者進(jìn)行了橫斷面研究,主要涉及南加州郊區(qū)的白人成年人.表明盡管NAFLD與CAC密切相關(guān),但它并不是絕經(jīng)后婦女冠狀動(dòng)脈粥樣硬化的獨(dú)立因素.

Wolff等[9]評(píng)估了基于人群的Rotterdam研究中的2351名受試者,并證明肝脂肪的比例增加與EFT (epicardial fat thicknee,心外膜脂肪厚度)和CAC的增加相關(guān),獨(dú)立于傳統(tǒng)的CV危險(xiǎn)因素.另一方面,Kim等[10]對(duì)2238名患者進(jìn)行了橫斷面研究,報(bào)告稱盡管CAC與EFT和肝脂肪的增加有關(guān),但與NAFLD相比,EFT與CAC的關(guān)系更為密切.

此外,一項(xiàng)橫斷面研究發(fā)現(xiàn),盡管老年受試者的NAFLD患病率較低,但他們?nèi)匀槐憩F(xiàn)出CAC評(píng)分和內(nèi)臟脂肪組織(visceral adipose tissue,VAT)增加.Lee等[11]研究21335名受試者參加了一個(gè)篩選項(xiàng)目,表明與腹部肥胖相比,NAFLD與CAC的關(guān)系更為顯著.

另一項(xiàng)Jung等[12]旨在研究1218名受試者肝脂肪和血清丙氨酸轉(zhuǎn)氨酶(alanine aminotransferase,ALT)與CAC的關(guān)系的橫斷面研究.結(jié)果提示同時(shí)伴有肝脂肪變性和ALT升高的受試者被發(fā)現(xiàn)與較高的CAC評(píng)分相關(guān).有報(bào)告稱,在NAFLD患者中,較高的CAC評(píng)分與使用瞬時(shí)彈性成像評(píng)估的肝硬度值獨(dú)立相關(guān).

NAFLD患者CAC、高血壓、主動(dòng)脈瓣硬化、舒張功能障礙、動(dòng)脈粥樣硬化斑塊和頸動(dòng)脈內(nèi)膜中層厚度(carotid intima-media thickness,CIMT)增加的發(fā)生率高于非NAFLD患者[13].越來(lái)越多的研究表明NAFLD與CHD之間存在關(guān)系[14].據(jù)估計(jì),癌癥和CVD是NAFLD患者死亡的主要原因.51%的輕度和不明顯冠狀動(dòng)脈狹窄患者和100%的三支受影響冠狀動(dòng)脈患者中觀察到NAFLD.Perera等[15]注意到46.7%的急性冠狀動(dòng)脈綜合征患者存在NAFLD.NAFLD患者鈣化和非鈣化冠狀動(dòng)脈斑塊的患病率明顯高于健康人,而與MetS的發(fā)病率無(wú)關(guān)[16].再次,冠狀動(dòng)脈血流儲(chǔ)備(coronary flow reserve,CFR)在NAFLD患者比健康受試者顯著降低[17].

1.2 NAFLD與頸動(dòng)脈疾病 CIMT與NAFLD、亞臨床動(dòng)脈粥樣硬化、心肌梗死和卒中獨(dú)立相關(guān)[18].CIMT測(cè)量和超聲斑塊負(fù)荷可用于篩查無(wú)癥狀個(gè)體,因?yàn)樗且环N有效且廣泛接受的預(yù)測(cè)CVD的篩查工具.

一項(xiàng)包括27項(xiàng)研究的薈萃分析得出結(jié)論[19],即使調(diào)整了年齡、性別、體重指數(shù)、吸煙、低密度脂蛋白(low-density lipoprotein,LDL)膽固醇、IR和MetS等傳統(tǒng)危險(xiǎn)因素,NAFLD仍與亞臨床動(dòng)脈粥樣硬化獨(dú)立相關(guān).此外,NAFLD患者頸動(dòng)脈斑塊的出現(xiàn)頻率更高.

此外,Kim等[20]研究了FLD中動(dòng)脈粥樣硬化疾病與性別差異的關(guān)系,得出結(jié)論:男性FLD、頸動(dòng)脈斑塊的患病率高于女性.Martínez-Alvarado Mdel等[21]提示IR可能是女性代謝異常和亞臨床動(dòng)脈粥樣硬化的介質(zhì).Li等[22]最近對(duì)1007名絕經(jīng)后婦女進(jìn)行了一項(xiàng)研究.據(jù)報(bào)道,NAFLD與絕經(jīng)后婦女動(dòng)脈僵硬風(fēng)險(xiǎn)增高相關(guān),而與是否存在MetS無(wú)關(guān).最近進(jìn)行的研究發(fā)現(xiàn)[23],NAFLD嚴(yán)重程度和肝功能增加試驗(yàn)顯示對(duì)動(dòng)脈粥樣硬化嚴(yán)重程度有影響.

NAFLD組織學(xué)特征的嚴(yán)重程度也與CIMT升高有關(guān).Bhatia等[24]使用磁共振波譜和肝壞死炎癥標(biāo)記物血清細(xì)胞角蛋白-18評(píng)估的NAFLD嚴(yán)重程度改善與CIMT進(jìn)展減少相關(guān).

1.3 NAFLD患者心臟結(jié)構(gòu)和功能的改變 目前大多數(shù)研究報(bào)告NAFLD與左室功能和結(jié)構(gòu)改變,即使在校正了常見的CV代謝危險(xiǎn)因素后仍有顯著相關(guān)性.在無(wú)病態(tài)肥胖、高血壓和糖尿病的NAFLD患者中,存在輕度改變的左室?guī)缀谓Y(jié)構(gòu)和左室舒張功能障礙的早期特征.無(wú)癥狀NAFLD患者也發(fā)現(xiàn)有亞臨床心功能不全,其因?yàn)樽笫夜δ懿蝗妥笫屹|(zhì)量與IR以及隨后的預(yù)后密切相關(guān).有報(bào)告稱肝脂肪的量與舒張功能障礙和IR之間存在強(qiáng)烈的正相關(guān),這是研究中發(fā)現(xiàn)的與NAFLD相關(guān)的唯一獨(dú)立參數(shù)[25].組織學(xué)評(píng)價(jià)的肝纖維化與超聲心動(dòng)圖評(píng)價(jià)的幾個(gè)心臟參數(shù)有關(guān).Petta等[26]對(duì)147例經(jīng)活檢證實(shí)的NAFLD患者進(jìn)行了評(píng)估肝纖維化和心臟并發(fā)癥嚴(yán)重程度的研究.報(bào)道了幾種心臟結(jié)構(gòu)的改變,如舒張后壁厚度、左室質(zhì)量、相對(duì)壁厚、左房容積以及左室舒張功能障礙、射血分?jǐn)?shù)、下側(cè)組織多普勒成像、舒張?jiān)缙诙獍戥h(huán)的速度峰值(E值)和重力血流峰值比率,由心房收縮引起的舒張?jiān)缙?E波)至舒張晚期(A波)的峰值流速(E/A比值)均與嚴(yán)重肝纖維化有關(guān).通過(guò)評(píng)價(jià)冠狀動(dòng)脈微血管循環(huán)的完整性.他們得出結(jié)論,與健康對(duì)照組相比,即使在校正了肥胖、傳統(tǒng)CV危險(xiǎn)因素和MetS之后NAFLD患者的CFR(coronary flow reserve,冠狀動(dòng)脈血流儲(chǔ)備)仍較低[27].

Mahfouz等[28]最近進(jìn)行的一項(xiàng)研究.有人認(rèn)為NAFLD患者的心房厚度和左房硬度指數(shù)的增加可以解釋房顫發(fā)病率增加的原因.

有幾篇文章描述了EFT與NAFLD之間的重要聯(lián)系.O?uz等[29]進(jìn)行橫斷面研究,得出結(jié)論:NAFLD患者的EFT和骨保護(hù)素水平升高,而使主動(dòng)脈血流傳播速度降低.另一項(xiàng)研究涉及868名受試者,來(lái)自Baragetti等[30]進(jìn)行的PLIC研究.據(jù)報(bào)道,肝脂肪變性和EFT與心外斑塊的發(fā)病率增加有關(guān).

1.4 NAFLD患者心律失常與傳導(dǎo)異常 NAFLD與心律失常風(fēng)險(xiǎn)以及相關(guān)傳導(dǎo)異常的關(guān)系最近引起了醫(yī)學(xué)界的興趣.多項(xiàng)研究評(píng)估了NAFLD與若干心電圖表現(xiàn)之間的關(guān)系,并證明房顫風(fēng)險(xiǎn)增加、QTc間期延長(zhǎng)、束支和房室傳導(dǎo)阻滯.此外,糖尿病合并NAFLD患者出現(xiàn)室性心律失常的風(fēng)險(xiǎn)也增加.

最常見的持續(xù)性心律失常是房顫,它是一個(gè)主要的健康問(wèn)題,因?yàn)榘l(fā)病率和死亡率增加.多項(xiàng)研究評(píng)估了NAFLD與房顫之間的關(guān)系.最近的一項(xiàng)薈萃分析評(píng)估了9項(xiàng)共364919名受試者的橫斷面和縱向研究[31],報(bào)告稱NAFLD與中老年受試者,尤其是2型糖尿病患者房顫風(fēng)險(xiǎn)增加相關(guān).一項(xiàng)橫斷面研究顯示患有NAFLD的老年受試者在調(diào)整年齡、性別、收縮壓、空腹血糖、GGT、高密度脂蛋白(high-density lipoprotein,HDL)膽固醇、三酰甘油、總膽固醇和白蛋白后仍有顯著的房顫患病率.另一方面,Markus等[32]對(duì)3090名受試者進(jìn)行了一項(xiàng)基于人群的博美尼亞健康研究,得出結(jié)論:超聲診斷的患者血清肝酶中度升高而與非肝脂肪變性患者相比,前者有較高的房顫患病率.他們認(rèn)為,這種相關(guān)性背后的一個(gè)可能的致病機(jī)制可能是因促炎、促凝血因子水平升高,以及血清肝酶水平升高相關(guān),導(dǎo)致心房結(jié)構(gòu)和電生理改變,從而導(dǎo)致更高的房顫風(fēng)險(xiǎn)發(fā)生,Mantovani[33]認(rèn)為高尿酸血癥可能在NAFLD和房顫之間的聯(lián)系中起著重要作用,有待進(jìn)一步研究.

1.5 NAFLD與亞臨床動(dòng)脈粥樣硬化 NAFLD加速動(dòng)脈粥樣硬化的發(fā)生和發(fā)展.已有研究表明NAFLD與亞臨床動(dòng)脈粥樣硬化之間存在關(guān)聯(lián).他們中的大多數(shù)人證明這種聯(lián)系獨(dú)立于MetS和傳統(tǒng)CV危險(xiǎn)因素.

CAC是動(dòng)脈粥樣硬化負(fù)荷的替代指標(biāo),也是CHD風(fēng)險(xiǎn)的獨(dú)立指標(biāo).一份研究[34]分析了10153名接受腹部超聲檢查評(píng)估脂肪肝和心臟CT CAC評(píng)分的職業(yè)人群的數(shù)據(jù).脂肪肝與CAC評(píng)分>0相關(guān),與所有MetS特征無(wú)關(guān)(OR=1.21;95%CI:1.01-1.45).對(duì)505名無(wú)糖尿病、無(wú)癥狀、無(wú)已知CHD的男性患者的評(píng)估顯示,超聲診斷的肝脂肪變性與電子束斷層掃描量化的CAC呈正相關(guān).肝脂肪變性患者中CAC的患病率較高(52%vs37%,P=0.001).

另一項(xiàng)研究[35]包括2424名年輕人冠狀動(dòng)脈風(fēng)險(xiǎn)發(fā)展研究的參與者.本研究使用CT來(lái)量化肝臟脂肪、CAC和腹主動(dòng)脈鈣化(calcification of abdominal aorta,AAC).NAFLD患者CAC(37.9%vs26.0%,P<0.001)和AAC(65.1%vs49.9%,P<0.001)的患病率增加.NAFLD與CAC和AAC的關(guān)系在人口統(tǒng)計(jì)學(xué)和健康行為調(diào)整后持續(xù)存在.然而,在調(diào)整VAT (visceral adipose tissue,內(nèi)臟脂肪組織)后,這種關(guān)聯(lián)并沒有達(dá)到統(tǒng)計(jì)學(xué)意義[35].最近的一項(xiàng)研究[36]涉及多民族與動(dòng)脈粥樣硬化相關(guān)性的研究,計(jì)3796名參與者的橫斷面分析.這項(xiàng)研究表明NAFLD與炎癥和CAC的增加有關(guān),而與傳統(tǒng)危險(xiǎn)因素、肥胖和MetS無(wú)關(guān).但NAFLD、肥胖和MetS與炎癥和CAC分級(jí)相關(guān).

超聲測(cè)量CIMT是亞臨床動(dòng)脈粥樣硬化的標(biāo)志.CIMT是預(yù)測(cè)未來(lái)血管事件的有力指標(biāo),與心肌梗死相比,它能更好地預(yù)測(cè)中風(fēng)風(fēng)險(xiǎn).印度人群的橫斷面研究顯示[37],NAFLD患者的平均和最大CIMT高于對(duì)照組.NAFLD的存在是調(diào)整肥胖、MetS、IR和血脂參數(shù)后,具有較高的平均CIMT和高的CIMT獨(dú)立預(yù)測(cè)因子.另一項(xiàng)病例對(duì)照研究[38]將50名從診所招募的患者與40名匹配的健康志愿者進(jìn)行對(duì)比,結(jié)果顯示,在非酒精性脂肪性肝炎(non-alcoholic steatohepatitis,NASH)患者、單純性脂肪變性患者和對(duì)照組之間,CIMT存在統(tǒng)計(jì)學(xué)上的顯著差異.調(diào)整年齡、性別、穩(wěn)態(tài)模型評(píng)估IR評(píng)分和MetS后,各組間的差異具有統(tǒng)計(jì)學(xué)意義.

一項(xiàng)上海交通大學(xué)瑞金醫(yī)院的研究報(bào)告[34],針對(duì)8632名參與者的大規(guī)模橫斷面研究顯示,與未患NAFLD的人相比,NAFLD患者CIMT在統(tǒng)計(jì)學(xué)上顯著升高.Logistic回歸分析顯示,與常規(guī)危險(xiǎn)因素和MetS的存在無(wú)關(guān),NAFLD增加了35%的CIMT升高的幾率[39].更大的薈萃分析包括4項(xiàng)研究[40],1947名患者,35.1%的NAFLD患者存在病理性CIMT,而非NAFLD患者為21.8%(P<0.0001).

心踝血管指數(shù)(cardio ankle vascular index,CAVI)表示從主動(dòng)脈到足踝的整個(gè)動(dòng)脈段的硬度.CAVI反映動(dòng)脈硬化的進(jìn)展,與冠狀動(dòng)脈粥樣硬化的嚴(yán)重程度呈正相關(guān).CAVI也預(yù)測(cè)頸動(dòng)脈硬化和中風(fēng).在對(duì)2954名受試者的橫斷面分析中,NAFLD與動(dòng)脈硬化風(fēng)險(xiǎn)增加42%相關(guān).動(dòng)脈僵硬的風(fēng)險(xiǎn)隨著NAFLD的嚴(yán)重程度而增加.在校正了包括體重指數(shù)、腰圍、吸煙狀況、糖尿病和高血壓在內(nèi)的其他危險(xiǎn)因素后,這種相關(guān)性具有統(tǒng)計(jì)學(xué)意義[41].

動(dòng)脈硬度的另一個(gè)測(cè)量指標(biāo)是肱踝脈搏波速度(brachial-ankle pulse wave velocity,baPWV).一項(xiàng)前瞻性研究[42]包括728名無(wú)高血壓和糖尿病的男性和497名女性.隨訪5年.在研究期間,NAFLD組的baPWV變化明顯大于非NAFLD組.多元回歸分析[43]顯示NAFLD是baPWV變化的獨(dú)立且顯著的預(yù)測(cè)因子.另一項(xiàng)針對(duì)中國(guó)人群的橫斷面研究[43]包括1296名接受常規(guī)體檢的非肥胖、非高血壓和非糖尿病青壯年受試者.NAFLD組baPWV水平顯著高于對(duì)照組(1321 cm/s±158 cm/s,1244 cm/s±154 cm/s,P<0.001).baPWV升高組NAFLD患病率高于baPWV正常組(29.3%vs16.9%,P<0.001).多元線性Logistic回歸分析顯示NAFLD與baPWV呈正相關(guān)且獨(dú)立相關(guān)[43].另一項(xiàng)研究還表明[44],與未患NAFLD的受試者相比,患有NAFLD的受試者的baPWV高(1665 cm/s±424 cm/svs1558 cm/s±430 cm/s,P<0.0001).Logistic回歸顯示baPWV升高的幾率增加了30%,獨(dú)立于常規(guī)危險(xiǎn)因素和MetS的存在[44].

1.6 NAFLD與動(dòng)脈粥樣硬化性CVD 多項(xiàng)流行病學(xué)研究表明NAFLD與CVD風(fēng)險(xiǎn)增加有關(guān).NAFLD組動(dòng)脈粥樣硬化性CVD (CHD、缺血性卒中和腦出血)的發(fā)生率高于非NAFLD組.多變量分析表明,NAFLD是CVD的獨(dú)立預(yù)測(cè)因子.

一項(xiàng)對(duì)80名接受冠狀動(dòng)脈造影的MetS患者進(jìn)行的前瞻性研究[44]評(píng)估了NAFLD與CHD嚴(yán)重程度之間的關(guān)系.冠狀動(dòng)脈造影顯示NAFLD患者有更多的血管受累(2.5±0.9vs1.0±1.0,P<0.001)和更嚴(yán)重的CAD嚴(yán)重程度評(píng)分(Gensini評(píng)分,90.2±40.0vs36.4±28.9,P<0.001).在多元回歸分析中,NAFLD是影響CAD嚴(yán)重程度評(píng)分的唯一獨(dú)立因素[44].另一項(xiàng)研究[45]調(diào)查了355名接受冠狀動(dòng)脈造影的患者的橫斷面分析,得出了類似的結(jié)論.單因素分析顯示NAFLD的存在對(duì)CAD有獨(dú)立影響(OR=2.58;P<0.01),對(duì)Gensini評(píng)分也有獨(dú)立影響(OR=2.02;P<0.05)[45].Sun等[46]納入542名計(jì)劃接受冠狀動(dòng)脈造影的患者.冠狀動(dòng)脈造影前進(jìn)行腹部電腦斷層掃描(CT)檢查NAFLD.Logistic回歸分析顯示,NAFLD的存在獨(dú)立地增加了冠狀動(dòng)脈造影顯示CHD的風(fēng)險(xiǎn)(OR=7.585;95%CI:4.617-12.461).CHD嚴(yán)重程度的增加,在NAFLD在患者中更為常見.

Pisto等[47]1991/2009共有988名芬蘭參與者參與了調(diào)查.根據(jù)肝臟脂肪含量將患者分為三組.隨訪期間,13.5%的非脂肪肝患者、24.2%的中度脂肪肝患者和29.2%的重度脂肪肝患者發(fā)生CV事件(P<0.001).當(dāng)根據(jù)年齡、性別和研究組進(jìn)行調(diào)整時(shí),嚴(yán)重肝脂肪含量可預(yù)測(cè)未來(lái)CV事件的風(fēng)險(xiǎn)(HR=1.92;95%CI:1.32-2.80).在進(jìn)一步調(diào)整吸煙、飲酒、LDL膽固醇、體重指數(shù)和收縮壓后,風(fēng)險(xiǎn)仍具有統(tǒng)計(jì)學(xué)意義(HR=1.74,95%CI:1.16-2.63),但在進(jìn)一步調(diào)整定量胰島素敏感性檢查指數(shù)后風(fēng)險(xiǎn)消失.

NAFLD與較高的平均CIMT、最大CIMT和病理CIMT的存在相關(guān)[32,33].CIMT可預(yù)測(cè)包括中風(fēng)在內(nèi)的未來(lái)動(dòng)脈粥樣硬化性CVD的風(fēng)險(xiǎn).然而,有一些不確定的數(shù)據(jù)將NAFLD與中風(fēng)聯(lián)系起來(lái).一項(xiàng)橫斷面研究[48]研究了急性缺血性卒中與NAFLD生化標(biāo)志物的相關(guān)性.以ALT升高≥95%作為炎癥性NAFLD的生化指標(biāo).在校正年齡、性別、當(dāng)前吸煙、當(dāng)前大量飲酒、高血壓病史、房顫、LDL膽固醇、血糖和血清肌酐后,ALT升高患者中風(fēng)的比值比矯正前為3.5(95%CI:1.7-7.6),矯正后為3.3(95%CI:1.3-8.4)[48].調(diào)整年齡和性別后,NAFLD與缺血性卒中顯著相關(guān)(OR=2.15;95%CI:1.25-3.71).

綜上所述,大多數(shù)研究表明NAFLD與CVD有關(guān).NAFLD影響CVD的多個(gè)方面.NAFLD與亞臨床動(dòng)脈粥樣硬化和動(dòng)脈硬化有關(guān).過(guò)去人們普遍認(rèn)為這種聯(lián)系是由肥胖、MetS和糖尿病等共同危險(xiǎn)因素造成的.然而,多項(xiàng)研究已經(jīng)證明這種聯(lián)系獨(dú)立于MetS和傳統(tǒng)的CV危險(xiǎn)因素.一項(xiàng)前瞻性研究還表明[42],NAFLD獨(dú)立且顯著地預(yù)測(cè)了baPWV的變化.

此外,Chung等[41]的研究.也顯示了NAFLD與亞臨床動(dòng)脈粥樣硬化之間的關(guān)系,其嚴(yán)重程度依賴于NAFLD.多變量分析顯示,55歲以下年齡組的NAFLD與動(dòng)脈僵硬(中重度NAFLD:OR=1.97,95%CI:1.28-3.01,趨勢(shì)P=0.002)之間存在嚴(yán)重依賴關(guān)系.流行病學(xué)數(shù)據(jù)存在直接連接到NAFLD的CAD.這些研究表明,與未患NAFLD的受試者相比,患有NAFLD的受試者CHD的發(fā)病率更高,CHD的嚴(yán)重程度更高,未來(lái)CV事件的風(fēng)險(xiǎn)更高,動(dòng)脈粥樣硬化性CVD增加.目前的認(rèn)識(shí)是,IR是胰島素抗脂解作用抵抗的原因,并與NAFLD內(nèi)臟和病理異位脂肪堆積相結(jié)合,導(dǎo)致游離脂肪酸(free fatty acid,FFA)的可用性增加.持續(xù)的慢性亞臨床炎癥、氧化應(yīng)激增加和內(nèi)皮功能障礙增加了FFA的可利用性,從而促進(jìn)動(dòng)脈粥樣硬化和CV功能不良發(fā)生.

2 NAFLD發(fā)生CVD的機(jī)制

最近大量證據(jù)表明,NAFLD患者有患CVD的高風(fēng)險(xiǎn).更嚴(yán)重的肝病與致命和非致命CV事件的風(fēng)險(xiǎn)增加相關(guān)[49].盡管許多證據(jù)表明NAFLD與CVD密切相關(guān),通過(guò)治療NAFLD可減少CVD的發(fā)生,然而其發(fā)病機(jī)制目前知之甚少.

2.1 遺傳易感性 遺傳因素似乎在NAFLD的發(fā)展和嚴(yán)重程度中起著關(guān)鍵作用,在高加索人群中遺傳率約為27%.在拉美裔和非裔美國(guó)人中也觀察到類似的結(jié)果,盡管不同人群之間存在一些差異(33%的拉美裔和14%的非裔美國(guó)人)[50].patatin樣磷脂酶結(jié)構(gòu)域蛋白3(patatin-like phospholipase domain-containing protein 3,PNPLA3)基因的patatin樣磷脂酶結(jié)構(gòu)域多態(tài)性被認(rèn)為是NAFLD最相關(guān)的遺傳危險(xiǎn)因素[51].有趣的是,一些證據(jù)表明這種基因變異也可能在CV疾病的易感性中起作用.特別是,意大利的一項(xiàng)研究表明[52],在組織學(xué)診斷為NAFLD的年輕患者中,PNPLA3-GG多態(tài)性與頸動(dòng)脈斑塊和CIMT增厚的患病率高于CC/CG基因型(分別為53% vs 32%,P=0.02;62%vs28%,P<0.001),但在隨訪期間,CIMT增厚也有進(jìn)展.PNPLA3是一種在脂肪細(xì)胞和肝細(xì)胞中高表達(dá)的跨膜水解酶,參與三酰甘油的代謝,其遺傳變異可能促進(jìn)動(dòng)脈粥樣硬化斑塊的發(fā)生和發(fā)展.此外,其他PNPLA3多態(tài)性與內(nèi)皮細(xì)胞的炎癥活性增加有關(guān),特別是rs738409多態(tài)性似乎與內(nèi)皮源性炎癥分子(即細(xì)胞間黏附分子-1,又叫做CD54,屬于黏附分子中免疫球蛋白超家族中的成員,是介導(dǎo)黏附反應(yīng)重要的一個(gè)黏附分子)的異常循環(huán)水平有關(guān).其他基因也與NAFLD的發(fā)生有關(guān),如跨膜6超家族成員2(transmembrane 6 superfamily member 2,TM6SF2)的多態(tài)性,TM6SF2是一種編碼蛋白質(zhì)的基因,其整體功能尚不清楚,但可能與肝臟脂質(zhì)代謝有關(guān).然而,該基因的一些變異體似乎與對(duì)CV系統(tǒng)的不同影響有關(guān)[53,54].其他的遺傳多態(tài)性具有優(yōu)先的有害作用,例如谷氨酸-L-賴氨酸(TM6SF2基因上的一個(gè)異義突變的變異編碼)與較高的心肌梗死風(fēng)險(xiǎn)相關(guān)[55].最后,一些遺傳多態(tài)性NAFLD患者對(duì)CV疾病的高易感性相關(guān).編碼脂聯(lián)素或瘦素受體的基因變異與更嚴(yán)重的肝損傷有關(guān),但也與嚴(yán)重的血脂異常、糖尿病和肥胖有關(guān),證實(shí)NAFLD患者易發(fā)生共同的CV代謝并發(fā)癥[56].

2.1.1 脂肪組織與血脂異常,NAFLD與CVD的聯(lián)系點(diǎn):考慮到MetS、肥胖等代謝性疾病與NAFLD發(fā)生的密切關(guān)系,脂肪組織擴(kuò)張和功能障礙可能是肝臟疾病與CV代謝性并發(fā)癥最重要的共同點(diǎn).事實(shí)上,過(guò)量飲食和卡路里攝入通常是MetS、NAFLD發(fā)病機(jī)制和CV表現(xiàn)的主要決定因素,導(dǎo)致血清FFA水平升高,超過(guò)脂肪組織的儲(chǔ)存能力,從而導(dǎo)致脂肪團(tuán)增大、內(nèi)臟和異位脂肪沉積,也包括肝臟.脂肪組織的異常擴(kuò)張導(dǎo)致脂肪細(xì)胞功能障礙,持續(xù)產(chǎn)生脂肪源性細(xì)胞因子[白細(xì)胞介素(interleukin,IL)-6,腫瘤壞死因子(tumor necrosis factor,TNF)-α]和CRP.持續(xù)性炎癥的存在不僅與IR的發(fā)展有關(guān),還與CVD的直接發(fā)病有關(guān)[57].

此外,由于脂肪團(tuán)增大,脂肪生成增加,導(dǎo)致高循環(huán)水平的FFA、超低密度脂蛋白(very low-density lipoprotein,VLDL)過(guò)多產(chǎn)生,以及進(jìn)一步的脂質(zhì)代謝異常,從而導(dǎo)致顯著的動(dòng)脈粥樣硬化性血脂異常.NAFLD患者的血脂異??赡芫哂懈鼑?yán)重的致動(dòng)脈粥樣硬化潛能,此外,NAFLD患者的脂質(zhì)參數(shù)與肝損傷和炎癥的組織學(xué)嚴(yán)重程度之間存在正相關(guān)[58],證實(shí)了這兩種情況之間的密切關(guān)系.

2.1.2 NAFLD患者微血管損傷、內(nèi)皮功能障礙與CV風(fēng)險(xiǎn):系統(tǒng)性微血管損傷的存在,以及持續(xù)性炎癥引起的內(nèi)皮功能障礙和氧化應(yīng)激可能是增加NAFLD人群CV風(fēng)險(xiǎn)的主要機(jī)制[59].除了脂肪生成增加的直接影響外,動(dòng)脈僵硬的增加還可以增加NAFLD患者的CV風(fēng)險(xiǎn)[60].

此外,有證據(jù)表明[61],不吸煙患者中NAFLD的患病率較高,同時(shí)也有證據(jù)表明[62],NAFLD的嚴(yán)重程度似乎與該人群中動(dòng)脈高血壓的發(fā)病率同時(shí)增加,這支持了一種強(qiáng)烈的雙重關(guān)系.

2.1.3 肝特異性異常與CV系統(tǒng):如上所述,除了動(dòng)脈粥樣硬化性血脂異常、肥胖和動(dòng)脈高壓等對(duì)CV系統(tǒng)的直接影響外,肝病似乎顯著的且可直接地促進(jìn)CV風(fēng)險(xiǎn).肝內(nèi)血管功能受損(竇性變形或微血管形成丟失)和纖維化的存在,本身可導(dǎo)致內(nèi)皮功能障礙,并增加血栓前分子和血管生成因子的產(chǎn)生,這可能涉及系統(tǒng)血管.肝臟中的巨噬細(xì)胞數(shù)量最多,大量細(xì)胞因子(尤其是TNF-α、IL-6、CRP)可慢性釋放到全身循環(huán)中,促進(jìn)慢性炎癥和血栓易感性[63].

NAFLD患者可能有重要的肝血管重塑,可能導(dǎo)致動(dòng)脈功能障礙和CV風(fēng)險(xiǎn).與對(duì)照組相比,NAFLD患者的血清血管內(nèi)皮生長(zhǎng)因子水平升高.血栓前因子的大量產(chǎn)生,特別是因子VIII、IX、XI和XII,與肝脂肪含量呈正相關(guān),因此可能與這些患者的CV風(fēng)險(xiǎn)增加相關(guān).纖溶酶原激活物抑制物-1的釋放增加,通過(guò)抑制組織纖溶酶原激活物與血栓前風(fēng)險(xiǎn)相關(guān),可進(jìn)一步增加CV事件的風(fēng)險(xiǎn)[64].

最近,也有研究表明肝臟組織特異性分子在系統(tǒng)中起作用,它似乎影響多種代謝途徑.這些分子,也被稱為“肝細(xì)胞因子”,可能在NAFLD患者CV并發(fā)癥的發(fā)生中起相關(guān)作用.成纖維細(xì)胞生長(zhǎng)因子-21(fibroblast growth factor-21,FGF-21)是肝臟分泌的一種多肽,參與人體的穩(wěn)態(tài)過(guò)程.它在CV系統(tǒng)中的作用還不完全清楚,但一些研究表明它對(duì)CV系統(tǒng)有負(fù)面影響.血清FGF-21水平的升高與頸動(dòng)脈CIMT增厚、動(dòng)脈粥樣硬化和CAD有關(guān).胎球蛋白-A是由肝臟合成的一種分子,似乎參與胰島素信號(hào)傳導(dǎo).在胎球蛋白A水平較高的糖尿病患者中觀察到對(duì)CV系統(tǒng)的負(fù)面影響,而在非糖尿病患者中觀察到相反的影響[65].

在NAFLD和CV疾病中,如心肌梗死和中風(fēng),人類腸道微生物的狀態(tài)都發(fā)生了改變[66,67].實(shí)驗(yàn)研究表明[68],腸道微生物的變化可能會(huì)影響自然穩(wěn)態(tài),特別是通過(guò)降低能量消耗和胰島素敏感性.在人類中,食物的不正常攝入與肥胖、糖尿病和NAFLD的發(fā)生有關(guān),并影響腸道微生物組成.三聚氰胺N-氧化物是一種由腸道微生物轉(zhuǎn)化為膳食磷脂酰膽堿的分子,與動(dòng)脈粥樣硬化疾病的發(fā)展有關(guān).此外,在動(dòng)脈粥樣硬化斑塊中發(fā)現(xiàn)了大量腸桿菌DNA,如細(xì)菌蛋白[69].這些發(fā)現(xiàn)表明,腸道失調(diào)在飲食、代謝疾病、NAFLD和CV事件的十字路口起著重要作用.圖1顯示了NAFLD與CVD之間的多種聯(lián)系機(jī)制.

2.2 NAFLD作為CVD的危險(xiǎn)因素 肝脂肪堆積可能是NAFLD與動(dòng)脈粥樣硬化關(guān)系的重要決定因素.最近,有人提出脂肪肝本身不是動(dòng)脈粥樣硬化的危險(xiǎn)因素,除非它與代謝紊亂有關(guān).有人認(rèn)為[70],脂肪肝可能有兩種不同的形式:一種主要與代謝異常有關(guān),另一種主要由遺傳因素引起,其特征是有更高的進(jìn)行性肝損傷風(fēng)險(xiǎn).

NAFLD與不良代謝和動(dòng)脈粥樣硬化風(fēng)險(xiǎn)狀況相關(guān).從代謝角度來(lái)看,NAFLD相關(guān)動(dòng)脈粥樣硬化形成的生物學(xué)機(jī)制可能是VAT、腸道、肌肉組織和肝臟之間的串?dāng)_[71].事實(shí)上,擴(kuò)張和炎癥的VAT釋放的分子,如脂肪因子、IL-6和TNF-α,可能參與IR和CVD的發(fā)展[72].此外,飲食中的乳糜微粒和從頭脂肪生成有助于增加肝臟FFA池以及NAFLD的發(fā)生[73].

肝臟中的脂質(zhì)積聚導(dǎo)致亞急性炎癥,隨后通過(guò)核因子κB(nuclear factor-kappa B,NF-κB)途徑產(chǎn)生細(xì)胞因子.尤其是,NF-κB的激活導(dǎo)致一些促炎癥基因的轉(zhuǎn)錄增加,這些基因介導(dǎo)全身和低級(jí)別炎癥的進(jìn)展.脂肪組織的增加和慢性炎癥也會(huì)導(dǎo)致脂肪因子分泌的不平衡,特別是脂聯(lián)素的減少.脂聯(lián)素已被證明具有抗炎和抗纖維化能力(DI Maira等[74],2018),其低水平分別與高脂肪含量和從脂肪變性及CVD到NASH與CV動(dòng)脈粥樣硬化的進(jìn)展有關(guān)[75].NASH通過(guò)系統(tǒng)釋放促動(dòng)脈粥樣硬化介質(zhì)(CRP、IL-6和TNF-α)和纖維蛋白原、因子VII和纖溶酶原激活物抑制物-1介導(dǎo)的高凝和低纖溶可誘導(dǎo)參與動(dòng)脈粥樣硬化形成,通過(guò)這種方式,肝臟成為促動(dòng)脈粥樣硬化分子的來(lái)源,從而放大動(dòng)脈損傷.越來(lái)越多的證據(jù)表明動(dòng)脈粥樣硬化與肝損傷的嚴(yán)重程度成正比[76](圖2).

圖1 非酒精性脂肪性肝病相關(guān)心血管風(fēng)險(xiǎn)的發(fā)病機(jī)制.NAFLD通過(guò)致動(dòng)脈粥樣硬化性血脂異常、肝臟/系統(tǒng)性IR和幾種促炎癥和促凝血介質(zhì)的分泌增加,導(dǎo)致動(dòng)脈粥樣硬化血栓形成的風(fēng)險(xiǎn)更高.FFA:游離脂肪酸;PNPLA3:patatin樣磷脂酶結(jié)構(gòu)域蛋白3;TM6SF2:跨膜6超家族成員2;Glu-L-67Lys:谷氨酸-L-賴氨酸.

圖2 非酒精性脂肪性肝病相關(guān)動(dòng)脈粥樣硬化的關(guān)鍵機(jī)制示意圖.非酒精性脂肪性肝病通過(guò)致動(dòng)脈粥樣硬化性血脂異常、肝臟/系統(tǒng)性胰島素抵抗和幾種促炎癥和促凝血介質(zhì)的分泌增加,導(dǎo)致動(dòng)脈粥樣硬化血栓形成的風(fēng)險(xiǎn)更高.NAFLD:非酒精性脂肪性肝病;FFA:游離脂肪酸;LDL:低密度脂蛋白.

MerTK顯示出清除凋亡小體的顯著能力.已經(jīng)證明M2c極化與MerTK上調(diào)密切相關(guān),檢測(cè)M2c受體可預(yù)測(cè)MerTK的表達(dá)[77].此外,M2c巨噬細(xì)胞能夠釋放Gas-6,而Gas-6又可以通過(guò)MerTK信號(hào)以自分泌方式放大IL-10的分泌[77].

2.3 MerTK在動(dòng)脈粥樣硬化過(guò)程中的作用機(jī)制 MerTK是巨噬細(xì)胞表面的一類蛋白質(zhì),它能夠調(diào)節(jié)炎癥修復(fù),效應(yīng)細(xì)胞增生.通過(guò)與凋亡細(xì)胞表面翻轉(zhuǎn)的磷酯酰絲氨酸結(jié)合,能夠發(fā)生吞噬作用.此外,巨噬細(xì)胞還能夠抑制NF-κB信號(hào)通路.有研究表明[70],MerTK信號(hào)能夠促進(jìn)SPM(炎癥損傷修復(fù)過(guò)程依賴于特定的調(diào)節(jié)因子)的合成.MerTKGIP 還可調(diào)節(jié)巨噬細(xì)胞活化,促進(jìn)凋亡細(xì)胞的吞噬,幫助血小板聚集,并維持體內(nèi)血塊的穩(wěn)定.MerTK是酪氨酸-3、Axl和Mer(TAM)受體酪氨酸激酶家族的第二個(gè)成員.這些受體的特征是細(xì)胞外區(qū)域的黏附分子樣結(jié)構(gòu)域,模擬了細(xì)胞-細(xì)胞接觸中重要的神經(jīng)細(xì)胞黏附分子的結(jié)構(gòu),其中包含五個(gè)Ig結(jié)構(gòu)域和兩個(gè)纖維連接蛋白Ⅲ型結(jié)構(gòu)域,研究最多的MerTK配體是Vit-K修飾的Gas-6和蛋白S.

MerTK通常在單核細(xì)胞/巨噬細(xì)胞、樹突狀細(xì)胞、自然殺傷細(xì)胞、自然殺傷T細(xì)胞、肝星狀細(xì)胞(hepatic stellate cell,HSC)、巨核細(xì)胞、血小板、上皮組織和生殖組織中表達(dá)[78].M2c巨噬細(xì)胞高水平表達(dá).巨噬細(xì)胞極化是調(diào)節(jié)炎癥反應(yīng)的重要機(jī)制,它受核受體超家族成員過(guò)氧化物酶體增殖物激活受體(peroxisome proliferatorsactivated receptors,PPAR) (α,β,δ,γ等位型)和肝X受體(liver X receptor,LXRs) (LXRα和LXRβ)的控制[79].這些轉(zhuǎn)錄因子與維甲酸X受體(α和β等型)形成異二聚體,在結(jié)合脂質(zhì)或合成配體時(shí),通過(guò)反式激活介導(dǎo)基因表達(dá).核受體在巨噬細(xì)胞功能的調(diào)節(jié)中起著重要作用.它們的配體影響調(diào)節(jié)脂質(zhì)穩(wěn)態(tài)、促炎癥細(xì)胞因子產(chǎn)生、炎癥分解和促進(jìn)組織愈合的介質(zhì)合成的基因轉(zhuǎn)錄[80].PPARγ激活通過(guò)清道夫受體CD36引起脂質(zhì)攝取,脂肪酸β氧化與巨噬細(xì)胞極化成M2a細(xì)胞有關(guān).PPARγ和LXR (肝X受體α和β)活性是相互協(xié)調(diào)的,PPARγ實(shí)際上能激活LXRs,但在一定條件下,PPARγ和LXRS發(fā)揮相反的作用.在M2a巨噬細(xì)胞中,IL-4刺激PPARγ表達(dá)和LXR-α下調(diào)[81].

巨噬細(xì)胞中過(guò)量脂蛋白衍生膽固醇的積累激活LXR,進(jìn)而觸發(fā)ABC轉(zhuǎn)運(yùn)體的誘導(dǎo),介導(dǎo)膽固醇外流以及小鼠(A-Gonzalez)和人類[77]中MerTK的上調(diào).證明指出,吞噬凋亡細(xì)胞激活LXRs,可能是通過(guò)膜源性膽固醇的積累.LXRs反過(guò)來(lái)激活MerTK的轉(zhuǎn)錄,產(chǎn)生正反饋以促進(jìn)進(jìn)一步的傳出細(xì)胞,該過(guò)程介導(dǎo)ABC轉(zhuǎn)運(yùn)體基因(如ABCA-1和ABCG-1)的增加表達(dá),參與過(guò)量膽固醇的流出和免疫抑制.這些結(jié)果表明,MerTK的LXR依賴性調(diào)節(jié)對(duì)正常的免疫內(nèi)穩(wěn)態(tài)具有重要意義.MerTK-/-和LXRs-DKO小鼠具有一系列特征,包括炎癥反應(yīng)增強(qiáng)和對(duì)自身免疫和動(dòng)脈粥樣硬化的易感性增加[82].

MerTK通過(guò)不同的機(jī)制,包括效應(yīng)細(xì)胞作用,維持中樞和外周耐受.事實(shí)上,在全基因組相關(guān)研究中,有報(bào)道稱[83],MerTK位點(diǎn)rs4374383 G>A與肝臟MerTK表達(dá)減少相關(guān),從而保護(hù)慢性丙型肝炎和NAFLD患者免受肝纖維化的影響.同樣的G>A變異被發(fā)現(xiàn)與心臟代謝紊亂和營(yíng)養(yǎng)性炎癥有關(guān),并可能以這種方式導(dǎo)致肝臟和心臟代謝疾病[83].此外,研究表明[78],在人類NAFLD標(biāo)本中,MerTK主要在巨噬細(xì)胞和炎癥灶內(nèi)松散聚集的HSC中表達(dá).

動(dòng)脈粥樣硬化病變?cè)谂R床上是無(wú)癥狀的,急性CV事件可能是由壞死斑塊演變而來(lái).首先,凋亡細(xì)胞被鄰近的巨噬細(xì)胞有效清除,以限制整個(gè)損傷細(xì)胞的數(shù)量.在這里,傳出細(xì)胞增生迅速,沒有炎癥.在生理?xiàng)l件下,凋亡細(xì)胞在吞噬體中被吞噬和降解,巨噬細(xì)胞被大分子成分和膽固醇超載.在晚期動(dòng)脈粥樣硬化中,慢性炎癥刺激的持續(xù)存在促進(jìn)了病變的不穩(wěn)定性和對(duì)心臟病發(fā)作和中風(fēng)的易感性.炎癥在促進(jìn)動(dòng)脈粥樣硬化中的作用已被充分證明.在晚期斑塊中,由慢性內(nèi)質(zhì)網(wǎng)應(yīng)激誘導(dǎo)的凋亡泡沫細(xì)胞引起炎癥反應(yīng)[84].此外,內(nèi)質(zhì)網(wǎng)應(yīng)激與斑塊破裂密切相關(guān).兩個(gè)過(guò)程有助于凋亡后壞死和有缺陷的傳出細(xì)胞增多,并損害了炎癥反應(yīng)的解決.在最后一個(gè)階段,傳出細(xì)胞功能受損,有缺陷的MerTK至少部分地促進(jìn)壞死斑塊的擴(kuò)張.在這方面,有證據(jù)表明缺乏MerTK的小鼠表現(xiàn)出了有效細(xì)胞增生的缺陷,這與斑塊內(nèi)炎癥和壞死的增加有關(guān).此外,人類動(dòng)脈粥樣硬化壞死核心附近的巨噬細(xì)胞顯示,MerTK表達(dá)低于周圍病變[85].最后,在晚期動(dòng)脈粥樣硬化中,脂質(zhì)和ROS的積累增加了氧化磷脂的水平.這些脂質(zhì)可與清道夫受體結(jié)合,并可能競(jìng)爭(zhēng)凋亡細(xì)胞識(shí)別,損害有效細(xì)胞增生機(jī)制.最近的一項(xiàng)研究表明[86],在病變中,死亡細(xì)胞攝取的預(yù)防是通過(guò)一些凋亡細(xì)胞介導(dǎo)的,這些細(xì)胞顯示一種叫做CD47的分子,這種分子通常在凋亡過(guò)程中丟失.

在某些炎癥條件下,MerTK的失活可能會(huì)損害傳出細(xì)胞.氧化LDL可誘導(dǎo)Toll樣受體(Toll-like receptor,TLR)4的表達(dá),增加TNF-α和IL-1β等促動(dòng)脈粥樣硬化細(xì)胞因子的分泌,減少TGF-β和IL-10的分泌[87].這種促炎性環(huán)境損害了巨噬細(xì)胞的傳出細(xì)胞,促進(jìn)了脂質(zhì)攝取的增加,從而增強(qiáng)了吞噬作用,降低了巨噬細(xì)胞表面的MerTK表達(dá)水平.MerTK表達(dá)的減少與解除整合素金屬蛋白酶17 (Disintegrin metalloproteinase 17,ADAM17)的裂解有關(guān).在人類動(dòng)脈粥樣硬化中,壞死核心附近的巨噬細(xì)胞比周圍病變中的巨噬細(xì)胞具有更高的ADAM17[85].多種動(dòng)脈粥樣硬化炎性刺激,如氧化應(yīng)激、缺氧和氧化配體,能夠促進(jìn)ADAM17活性[88].通過(guò)破壞受體和產(chǎn)生可溶性Mer (sol-Mer,溶膠聚合GAS-6物),抑制競(jìng)爭(zhēng)性細(xì)胞增多癥,其競(jìng)爭(zhēng)結(jié)合分子Gas-6和蛋白S.有趣的是,氧化LDLs促進(jìn)MerTK裂解和有缺陷的吞噬細(xì)胞增多,可以激活高級(jí)斑塊內(nèi)的壞死通路.有利于壞死核的發(fā)育[88].在最近的研究中[89],已經(jīng)證明,氧化LDL能夠增加sol-Mer水平并降低野生型巨噬細(xì)胞表面的MerTK表達(dá).

3 腸道微生物群在動(dòng)脈粥樣硬化和高血壓中的作用

CVD是全世界,特別是發(fā)達(dá)國(guó)家的主要死因,包括動(dòng)脈粥樣硬化、高血壓、中風(fēng)和心力衰竭等多種疾病[90].越來(lái)越多證據(jù)表明NAFLD 時(shí)有菌群失調(diào),引起細(xì)菌易位、內(nèi)毒素血癥、腸道屏障功能障礙和繼發(fā)先天和適應(yīng)性免疫異常等是CVD發(fā)生的主要危險(xiǎn)因素.Wang等[91]報(bào)告了CVD的腸道微生物依賴機(jī)制,強(qiáng)調(diào)了腸道微生物與CVD之間錯(cuò)綜復(fù)雜的關(guān)系.最近,腸道微生物失調(diào)被認(rèn)為是導(dǎo)致動(dòng)脈粥樣硬化和高血壓發(fā)展的重要因素,動(dòng)脈粥樣硬化和高血壓是CVD的兩個(gè)主要危險(xiǎn)因素[92].

3.1 腸道菌群與動(dòng)脈粥樣硬化 動(dòng)脈粥樣硬化是CVD的主要危險(xiǎn)因素,其特征是膽固醇積聚和巨噬細(xì)胞進(jìn)入動(dòng)脈壁,從而導(dǎo)致動(dòng)脈粥樣硬化斑塊的形成.最近的研究表明[93],腸道菌群失調(diào)也有助于動(dòng)脈粥樣硬化的發(fā)展.通過(guò)對(duì)有或無(wú)動(dòng)脈粥樣硬化癥狀的患者的腸道基因組進(jìn)行測(cè)序發(fā)現(xiàn),與健康對(duì)照組相比,動(dòng)脈粥樣硬化患者的羅氏菌屬和真細(xì)菌的相對(duì)豐度較低,而柯林斯氏菌較高.此外,研究發(fā)現(xiàn)[94],艾克曼菌能夠改善腸道屏障功能,并對(duì)動(dòng)脈粥樣硬化起到保護(hù)作用.盡管薈萃分析顯示,抗生素治療對(duì)CHD患者沒有明顯的益處,但是,越來(lái)越多的證據(jù)表明,腸道微生物群通過(guò)調(diào)節(jié)炎癥和微生物代謝產(chǎn)物的產(chǎn)生在動(dòng)脈粥樣硬化中起到了病因作用[95].

3.1.1 動(dòng)脈粥樣硬化中的腸道微生物失調(diào)和炎癥:炎癥通常與許多疾病有關(guān),包括動(dòng)脈粥樣硬化,這是一種典型的慢性炎癥疾病.腸道上皮是宿主的第一道屏障,可防止病原體入侵.鑒于其在防止腸道內(nèi)容物(主要是細(xì)菌成分)易位方面的關(guān)鍵作用,腸道屏障的完整性對(duì)于維持宿主的健康至關(guān)重要.腸道通透性與緊密連接蛋白(包括胞質(zhì)小帶閉塞蛋白1、緊密連接蛋白和閉塞蛋白的表達(dá)減少以及腸上皮細(xì)胞死亡和再生之間的不平衡有關(guān)[96].如果腸上皮屏障受損,病原體相關(guān)分子模式(pathogenic molecular model,PAMPs)的入侵會(huì)驅(qū)動(dòng)免疫反應(yīng),并導(dǎo)致全身和組織特異性炎癥.因此,由腸道微生物失調(diào)引起的腸道屏障完整性損害被認(rèn)為是各種疾病慢性炎癥的危險(xiǎn)因素.值得注意的是,脂多糖(lipopolysacchride,LPS)和肽聚糖(peptidoglycan,PG)是公認(rèn)的CVD危險(xiǎn)因素.

LPS是革蘭陰性細(xì)菌的細(xì)胞壁成分,因其是參與CVD風(fēng)險(xiǎn)的PAMPs之一而被廣泛研究.在一項(xiàng)研究中得出結(jié)論,循環(huán)內(nèi)毒素血癥水平在CVD負(fù)擔(dān)最高的患者中最為顯著.Cani等[97]發(fā)現(xiàn)腸道微生物失調(diào)抑制緊密連接蛋白的表達(dá),導(dǎo)致腸道通透性增加,隨后LPS轉(zhuǎn)移到血液中.腸道菌群失調(diào)衍生的LPS可能通過(guò)調(diào)節(jié)TLR及其下游靶點(diǎn)發(fā)揮重要作用[98].作為模式識(shí)別受體家族的一部分,TLRs可以識(shí)別細(xì)菌產(chǎn)物并調(diào)節(jié)宿主免疫系統(tǒng).采用TLR4和LDL受體雙基因敲除小鼠,Ding等[99]發(fā)現(xiàn)TLR4缺乏可減少動(dòng)脈粥樣硬化,但對(duì)炎癥無(wú)影響.一直以來(lái),臨床研究表明,TLRs的上調(diào)與人類動(dòng)脈粥樣硬化的炎癥激活有關(guān),并促進(jìn)動(dòng)脈粥樣硬化.然而,2012年Zhang等[100]的薈萃分析表明Asp299Gly (TLR4基因),一種TLR4多態(tài)性,在動(dòng)脈粥樣硬化的發(fā)展中沒有明顯的作用.此外,LPS與TLR4的結(jié)合激活了其下游途徑,包括MyD88和NF-κB,促進(jìn)了促炎性細(xì)胞因子如IL-6、IL-1、IL-27和TNF-α的產(chǎn)生,從而增加了發(fā)生CVD的風(fēng)險(xiǎn)[101],缺乏MyD88可通過(guò)減少巨噬細(xì)胞募集而減少動(dòng)脈粥樣硬化.腸道微生物群與炎癥之間的主要相互作用如圖3所示.

此外,另一種細(xì)菌PAMP,PG(peptidoglycan,肽聚糖)也被發(fā)現(xiàn)通過(guò)損害腸上皮屏障與CVD風(fēng)險(xiǎn)相關(guān).PG是革蘭陰性細(xì)菌的一個(gè)次要細(xì)胞壁成分,但也是革蘭陽(yáng)性細(xì)菌的一個(gè)主要成分.利用亞基因組測(cè)序發(fā)現(xiàn)動(dòng)脈粥樣硬化患者富含編碼PG合成的基因[102].事實(shí)上,在動(dòng)脈粥樣硬化動(dòng)脈中觀察到促炎性細(xì)菌PG,并與易損斑塊相關(guān).通過(guò)PG識(shí)別,核苷酸結(jié)合寡聚結(jié)構(gòu)域(nucleotide binding oligomeric domain,NOD)蛋白NOD1和NOD2通過(guò)涉及NF-κB和絲裂原活化蛋白激酶信號(hào)途徑的程序.促進(jìn)細(xì)胞內(nèi)細(xì)菌清除[103].對(duì)NOD2缺陷小鼠的研究表明,NOD2是腸道細(xì)菌免疫的關(guān)鍵調(diào)節(jié)因子,有助于維持腸道屏障的完整性.近年來(lái),科學(xué)家利用NOD1基因敲除小鼠研究了NOD1在動(dòng)脈粥樣硬化中的潛在作用.數(shù)據(jù)顯示,小鼠載脂蛋白E和NOD1基因敲除顯著減少動(dòng)脈粥樣硬化病變的發(fā)展[104].此外,還有其他PAMP可以通過(guò)參與宿主模式識(shí)別受體來(lái)促進(jìn)炎癥過(guò)程,如CpG(胞嘧啶-鳥嘧啶二核苷酸)寡核苷酸鞭毛蛋白、脂肽等[105].

3.1.2 TMAO與動(dòng)脈粥樣硬化:膳食磷脂酰膽堿或左旋肉堿在腸道內(nèi)由腸道微生物群代謝為三甲胺(trimethylamine,TMA).它是氧化三甲胺(trimethylamine oxide,TMAO)的前體,TMA被轉(zhuǎn)運(yùn)到肝臟并被含黃素單氧化酶(flavin-containing monooxygenase 3,FMO)3氧化,這是肝臟FMO酶家族的一個(gè)成員,導(dǎo)致TMAO的產(chǎn)生[106].使用反義寡核苷酸的小鼠肝臟中FMO3的敲除通過(guò)刺激基礎(chǔ)代謝和激活巨噬細(xì)胞反向膽固醇轉(zhuǎn)運(yùn)降低了循環(huán)TMAO水平并減輕動(dòng)脈粥樣硬化[107].同時(shí)Chen等[108]還發(fā)現(xiàn),腸道微生物膳食磷脂酰膽堿代謝物的血漿水平和產(chǎn)生相關(guān)分子(左旋肉堿和γ-丁基甜菜堿)的TMAO水平與CVD風(fēng)險(xiǎn)相關(guān).血漿TMAO水平的升高與動(dòng)脈粥樣硬化形成和動(dòng)脈粥樣硬化斑塊面積的范圍相關(guān).對(duì)有或無(wú)慢性心力衰竭患者的前瞻性和觀察性臨床研究表明[109],血漿TMAO水平與慢性心力衰竭風(fēng)險(xiǎn)呈正相關(guān).提示循環(huán)中TMAO水平是CVD發(fā)病的重要危險(xiǎn)因素.

為了探討TMAO促進(jìn)動(dòng)脈粥樣硬化的可能機(jī)制,Ma等[93]給ApoE-/-小鼠補(bǔ)充了一種膳食膽堿,測(cè)定了與動(dòng)脈粥樣硬化有關(guān)的兩種巨噬細(xì)胞清除劑受體CD36(脂肪酸轉(zhuǎn)運(yùn)蛋白,屬于B類清道夫受體家族)和類固醇受體核糖核酸激活劑A1類清道夫受體(scavenger receptor class A1,SR-A1)的表達(dá).結(jié)果顯示,與正常對(duì)照組相比,TMAO治療小鼠的巨噬細(xì)胞中CD36和SR-A1水平升高.TMAO可通過(guò)抑制RCT和調(diào)節(jié)巨噬細(xì)胞中膽固醇轉(zhuǎn)運(yùn)蛋白的活性而導(dǎo)致動(dòng)脈粥樣硬化.此外,TMAO可抑制肝膽汁酸(bile acid,BA)合成酶(Cyp7a1和Cyp27a1)和BA轉(zhuǎn)運(yùn)蛋白(Oatp1、Oatp4、Mrp2和Ntcp)的水平,導(dǎo)致BA相關(guān)通路和動(dòng)脈粥樣硬化的發(fā)生[110],提示TMAO促進(jìn)動(dòng)脈粥樣硬化的作用也與BA代謝的變化有關(guān).法尼酯衍生物X受體(famesoid X receptor,FXR)是控制BA代謝的重要核受體,它還可以調(diào)節(jié)肝臟FMO3的表達(dá),從而改變TMAO的產(chǎn)生.FXR激動(dòng)劑抑制ApoE-/-小鼠中的CYP7A1和CYP8B1的表達(dá),并保護(hù)小鼠免受動(dòng)脈粥樣硬化[107].最近,發(fā)現(xiàn)TMAO上調(diào)血管細(xì)胞黏附分子-1、活化蛋白激酶C和NF-κB的表達(dá)[93],提示TMAO可能通過(guò)誘導(dǎo)內(nèi)皮細(xì)胞功能障礙和增加單核細(xì)胞黏附而加速動(dòng)脈粥樣硬化的發(fā)展.此外,血小板直接暴露于TMAO可通過(guò)提高細(xì)胞內(nèi)存儲(chǔ)的Ca2+釋放,增加刺激依賴性血小板激活,從而增加血栓形成和斑塊不穩(wěn)定的風(fēng)險(xiǎn)[111].總的來(lái)說(shuō),TMAO通過(guò)促進(jìn)膽固醇內(nèi)流、抑制膽固醇外流、阻斷BA途徑和/或引起血小板過(guò)度激活來(lái)加速動(dòng)脈粥樣硬化的發(fā)展.所有這些發(fā)現(xiàn)都證實(shí)TMAO是CVD風(fēng)險(xiǎn)的生物標(biāo)記物和動(dòng)脈粥樣硬化疾病的啟動(dòng)子[112].TMAO被認(rèn)為是最有前途的代謝產(chǎn)物之一,在大量實(shí)驗(yàn)和臨床資料的基礎(chǔ)上,TMAO不僅可能是CVD的獨(dú)立危險(xiǎn)因素,而且可能是CVD的潛在治療靶點(diǎn).然而,也觀察到不一致的結(jié)果.值得注意的是,由不同國(guó)家進(jìn)行的幾項(xiàng)大規(guī)模人群研究表明[113,114],飲食中膽堿和甜菜堿的攝入與CVD的發(fā)病無(wú)關(guān).因此,需要更多的研究來(lái)證實(shí)TMAO在動(dòng)脈粥樣硬化中的確切作用,以及通過(guò)靶向TMAO產(chǎn)生菌或酶來(lái)驗(yàn)證其治療潛力.

圖3 腸道菌群和脂多糖誘導(dǎo)動(dòng)脈粥樣硬化炎癥反應(yīng).LPS:脂多糖;ZO-1:小帶閉塞蛋白-1;CD14:單核細(xì)胞分化抗原;TLR:Toll樣受體;LXR:肝X受體;MyD88:髓樣分化初級(jí)反應(yīng)基因88;NF-κB:核因子kappa B;IL:白細(xì)胞介素;TNF-α:腫瘤壞死因子α;PG:肽聚糖;NODs:核苷酸結(jié)合寡聚結(jié)構(gòu)域蛋白.

3.1.3 BA與動(dòng)脈粥樣硬化:BA是另一組與各種代謝疾病有關(guān)的腸道微生物衍生代謝物,這些代謝物儲(chǔ)存在膽囊中并釋放到腸道中,以促進(jìn)膳食脂質(zhì)和脂溶性維生素的吸收.Zheng等[115]研究發(fā)現(xiàn),抑制肝BA生物合成可抑制HFD誘導(dǎo)的腸道微生物群改變,這凸顯了肝-腸-腸道微生物群落代謝軸.因此,腸道微生物群與BA代謝之間存在雙向關(guān)系.

BA也是調(diào)節(jié)宿主代謝和能量消耗過(guò)程的重要信號(hào)分子[116].膽汁鹽可以通過(guò)腸道微生物群在富含膽汁鹽的微環(huán)境中生存,從而分化為具有生物活性的物種.腸道微生物群介導(dǎo)的腦血管病中的BA代謝最近受到廣泛關(guān)注[117].然而,到目前為止,BAs在CVD發(fā)展中的作用仍不清楚.眾所周知,BAs主要通過(guò)膽鹽水解酶(bile salt hydrolase,BSH)和BA受體促進(jìn)動(dòng)脈粥樣硬化的發(fā)展.細(xì)菌介導(dǎo)的BSH活性可通過(guò)增加膽固醇積聚、泡沫細(xì)胞形成和動(dòng)脈粥樣硬化斑塊的大小而影響動(dòng)脈粥樣硬化發(fā)病的潛在過(guò)程.BSH存在于多種細(xì)菌中,如甲烷桿菌、梭菌、腸球菌等[118].

除BA自身外,FXR是一種最重要且研究得很好的BA受體,通過(guò)影響參與初級(jí)BA合成的基因轉(zhuǎn)錄來(lái)調(diào)節(jié)葡萄糖和脂質(zhì)代謝[119].與野生型小鼠相比,FXR-/-小鼠血漿HDL膽固醇、非HDL膽固醇和三酰甘油水平升高,說(shuō)明FXR在調(diào)節(jié)膽固醇代謝中的關(guān)鍵作用.在先前的一項(xiàng)研究中[120],載脂蛋白E缺乏(ApoE-/-)小鼠(動(dòng)脈粥樣硬化小鼠模型)的功能性FXR缺失可導(dǎo)致更嚴(yán)重的脂質(zhì)代謝缺陷和主動(dòng)脈斑塊形成增強(qiáng).此外,FXR缺乏可導(dǎo)致血漿LDL膽固醇和巨噬細(xì)胞CD36表達(dá)減少,導(dǎo)致LDLR基因敲除(LDLR-/-)小鼠動(dòng)脈粥樣硬化風(fēng)險(xiǎn)降低.另一方面,研究表明在LDLR-/-和ApoE-/-小鼠中,用激動(dòng)劑激活FXR可以保護(hù)動(dòng)脈粥樣硬化,這可能與抑制參與BAs合成的基因有關(guān).G蛋白偶聯(lián)的膽汁酸受體(G proteincoupled bile receptor,TGR)5,是另一種對(duì)BAs敏感的重要宿主BA受體.最近的研究表明[121],激活TGR5可以抑制動(dòng)脈粥樣硬化的形成,TGR5的激活也有助于提高能量消耗和改善血糖控制.孕烷X受體(pregnane X-receptor,PXR)是另一種核激素受體,調(diào)節(jié)參與BAs生物合成、運(yùn)輸和代謝的基因表達(dá),也可被石膽酸(lithocholic acid,LCA)等次級(jí)BAs激活.PXR的缺失會(huì)減弱PXR和apoE雙基因敲除(PXR-/-和apoE-/-)小鼠動(dòng)脈粥樣硬化的發(fā)展,這可能與減少巨噬細(xì)胞CD36表達(dá)和脂質(zhì)攝取有關(guān).據(jù)報(bào)道[122],PXR激動(dòng)劑激活PXR可增加致動(dòng)脈粥樣硬化脂蛋白VLDL和LDL的水平,PXR激活可加速ApoE-/-小鼠的動(dòng)脈粥樣硬化.此外,維生素D3受體(Vitamin D3 receptor,VDR3)是細(xì)菌誘導(dǎo)的BA的傳感器,它比其他核受體對(duì)LCA及其代謝物(3-oxo-LCA)更敏感.已經(jīng)發(fā)現(xiàn)巨噬細(xì)胞VDR3信號(hào)通過(guò)抑制局部腎素-血管緊張素系統(tǒng)部分地減輕小鼠動(dòng)脈粥樣硬化.最后,鞘氨醇-1-磷酸酯受體2 (sphingosine-1-phosphatereceptor 2,S1PR2)可被各種結(jié)合的BAs激活,然后通過(guò)調(diào)節(jié)巨噬細(xì)胞滯留和炎性細(xì)胞因子分泌促進(jìn)動(dòng)脈粥樣硬化,而S1PR2基因敲除可減輕ApoE-/-小鼠的動(dòng)脈粥樣硬化[123].

總之,腸道菌群衍生的次級(jí)BAs通過(guò)調(diào)節(jié)各種BA受體,如FXR、PXR、TGR5、VDR和S1PR2在動(dòng)脈粥樣硬化的發(fā)生發(fā)展中發(fā)揮重要作用.這一發(fā)現(xiàn)凸顯了以腸道微生物群為靶點(diǎn)的新型動(dòng)脈粥樣硬化治療的巨大潛力.

3.2 腸道菌群與高血壓 高血壓是遺傳易感性和環(huán)境因素共同誘發(fā)的CVD的另一個(gè)重要風(fēng)險(xiǎn).鑒于人們?cè)絹?lái)越認(rèn)識(shí)到腸道菌群在代謝性疾病中的作用[124],近年來(lái)也對(duì)腸道菌群與高血壓的關(guān)系進(jìn)行了評(píng)估.在自發(fā)性高血壓大鼠中,Yang等[125]發(fā)現(xiàn)微生物豐度和多樣性顯著降低,硬壁菌/類桿菌比例增加.在另一項(xiàng)研究中,與常規(guī)飼養(yǎng)小鼠相比,注射血管緊張素2 (angiot6ensin II,AngII)的小鼠顯示,對(duì)AngII的血壓升高反應(yīng)減弱,表明腸道微生物群促進(jìn)了AngII誘導(dǎo)的血管功能障礙和高血壓.因此,腸道微生物群可能與高血壓的發(fā)生有關(guān).雖然腸道菌群和高血壓的關(guān)系和機(jī)制尚未完全闡明,現(xiàn)有的證據(jù)突出了臨界脂肪酸和氧化LDL (OX-LDL)在高血壓中的關(guān)鍵作用.

3.2.1 短鏈脂肪酸與高血壓:來(lái)自膳食纖維(主要是多糖)的短鏈脂肪酸(如乙酸、丙酸和丁酸)在維持腸道微生物群的穩(wěn)態(tài)和宿主免疫方面發(fā)揮著關(guān)鍵作用[126].有趣的是,將多糖代謝成不同類型短鏈脂肪酸(short-chain fatty acids,SCFAs)的細(xì)菌是特殊的.例如,主要的產(chǎn)醋酸細(xì)菌是鏈球菌屬、普雷沃菌屬、雙歧桿菌屬、梭菌屬、嗜粘桿菌屬等[127].丙酸鹽是由擬桿菌屬、沙門氏菌屬、二烯鏈球菌屬、維氏菌屬、菊苣苔蘚菌屬、卡氏黃連菌屬、闌尾菌屬等的碳水化合物發(fā)酵產(chǎn)生的[128],而丁酸鹽則是由藍(lán)螺旋菌科、瘤胃球菌科和酸性氨基球菌科產(chǎn)生的.最近的一項(xiàng)研究發(fā)現(xiàn)[129],補(bǔ)充纖維和醋酸鹽改善了腸道菌群失調(diào),與嗜酸類桿菌增多有關(guān),這可能在高血壓小鼠的高血壓和心力衰竭中起到保護(hù)作用.

迄今為止,至少有三個(gè)宿主G蛋白偶聯(lián)受體受SCFA監(jiān)管,包括G蛋白偶聯(lián)受體(G protein-coupled receptors,GPR) 41、GPR43和GPR109A.SCFAs可以刺激宿主GPCRs調(diào)節(jié)的途徑,導(dǎo)致腎素分泌,從而影響血壓,SCFAs通過(guò)調(diào)節(jié)內(nèi)皮細(xì)胞GPR41來(lái)降低血壓[130].嗅覺受體78 (olfactory receptor 78,Olfr78)是另一種在腎臟中表達(dá)的GPCR,它也可以被SCFAs如醋酸鹽和丙酸鹽調(diào)節(jié).此外,Olfr78和GPR41均在小阻力血管的平滑肌細(xì)胞中表達(dá).丙酸鹽可通過(guò)調(diào)節(jié)Olfr78和GPR41活性誘導(dǎo)小鼠血管舒張并產(chǎn)生急性低血壓反應(yīng)[131].另一方面,刺激GPR41可導(dǎo)致低血壓反應(yīng)降低,而刺激Olfr78可對(duì)抗這種效應(yīng)[132].總之,雖然所有這些發(fā)現(xiàn)都揭示了腸道微生物群可能通過(guò)產(chǎn)生微生物SCFAs在調(diào)節(jié)宿主血壓方面發(fā)揮重要作用,但SCFAs作為CVD治療靶點(diǎn)的潛力需要在未來(lái)的進(jìn)一步研究中得到證實(shí).

3.2.2 OX-LDL與高血壓:一般來(lái)說(shuō),血壓的調(diào)節(jié)除了各種受體的調(diào)節(jié)外,腸道疾病也通過(guò)氧化LDL介導(dǎo)的血管收縮參與高血壓的發(fā)生.腸道微生物失調(diào)可以促進(jìn)促炎性細(xì)胞因子的表達(dá),并誘導(dǎo)氧化應(yīng)激,這可以刺激OXLDL,較高水平的OX-LDL通過(guò)抑制NO和內(nèi)皮素的產(chǎn)生而有助于高血壓.NO是通過(guò)NO合成酶氧化L-精氨酸而產(chǎn)生的良好的血管擴(kuò)張劑.OX-LDL降低NO的生成,降低血管舒張的程度.此外,內(nèi)皮素-1在維持基本血管張力和CV系統(tǒng)穩(wěn)態(tài)方面起著關(guān)鍵作用.內(nèi)皮素-1通過(guò)激活內(nèi)皮受體B和促進(jìn)NO的產(chǎn)生,在低濃度時(shí)產(chǎn)生血管舒張作用,但在高濃度時(shí)通過(guò)增加斑塊中OX-LDL的產(chǎn)生和激活內(nèi)皮受體A[93].

盡管腸道菌群失調(diào)與高血壓之間的因果關(guān)系已經(jīng)得到證實(shí)[104,133],但腸道菌群在介導(dǎo)高血壓中的確切作用仍需進(jìn)一步廣泛研究.與腸道微生物群和高血壓相關(guān)的主要機(jī)制如圖4.

4 結(jié)論

大量臨床證據(jù)表明NAFLD可能先于和/或促進(jìn)T2D、高血壓和動(dòng)脈粥樣硬化/CVD的發(fā)展.發(fā)生這些CV代謝疾病的風(fēng)險(xiǎn)與NAFLD的潛在嚴(yán)重程度相似[134].越來(lái)越多的證據(jù)表明NAFLD的存在和嚴(yán)重程度與T2D和高血壓的發(fā)病風(fēng)險(xiǎn)增加有關(guān),就其相關(guān)機(jī)制、臨床的聯(lián)系和治療的探索有待進(jìn)一步作深入的研究,通過(guò)不懈的努力,提供治療的新策略,為改善NAFLD和CVD的預(yù)后提供新途徑,是今后幾年研究的中心環(huán)節(jié).

圖4 腸道菌群與高血壓的主要機(jī)制. SCFAs:短鏈脂肪酸;GPRs;G-蛋白偶聯(lián)受體;Olfr78:嗅覺受體78;ox-LDL:氧化低密度脂蛋白;ETA:內(nèi)皮素受體A;L-arginine:L-精氨酸.

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