俞媛潔，譚詩云

武漢大學(xué)人民醫(yī)院消化內(nèi)科，湖北 武漢 430060

姜黃素對非酒精性脂肪性肝病的作用研究

俞媛潔，譚詩云

武漢大學(xué)人民醫(yī)院消化內(nèi)科，湖北 武漢 430060

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)是最常見的慢性肝病之一，包括單純性脂肪肝、非酒精性脂肪性肝炎(NASH)、肝纖維化、肝硬化及肝細(xì)胞癌。NAFLD的發(fā)病機(jī)制復(fù)雜，胰島素抵抗(IR)與氧化應(yīng)激共同參與了NAFLD的發(fā)生與發(fā)展，NF-κB信號通路的激活可能是NAFLD重要的發(fā)病機(jī)制之一。近年來，由于姜黃素具有調(diào)脂、抗氧化、抗炎、護(hù)肝等功能，越來越受到學(xué)界的重視，極有可能成為NAFLD潛在的治療藥物。本文就姜黃素對NAFLD的研究進(jìn)展作一概述。

非酒精性脂肪性肝病；NF-κB；姜黃素

非酒精性脂肪性肝病(non-alcoholic fatty liver disease，NAFLD)是一種與基因、環(huán)境、代謝、應(yīng)激等多因素相關(guān)的臨床病理綜合征，也是代謝綜合征(metabolic syndrome)的肝臟表現(xiàn)。姜黃素(curcumin)具有調(diào)脂、抗氧化、抗炎、增加胰島素敏感性、抑制肝臟脂肪蓄積與纖維化的功能[1]。近年來，越來越多的學(xué)者開始關(guān)注姜黃素對NAFLD的治療作用。目前，部分細(xì)胞與動物的相關(guān)研究證實了姜黃素對NAFLD的療效，但臨床研究證據(jù)不足。本文將圍繞姜黃素對NAFLD作用的研究進(jìn)展作一概述。

1 NAFLD的流行病學(xué)與自然病程

NAFLD指在除外酒精和其他明確的肝損傷因素下，肝細(xì)胞出現(xiàn)甘油三酯蓄積、>5%的肝細(xì)胞出現(xiàn)脂滴。世界范圍內(nèi)，NAFLD的發(fā)病率為9%～36%，在美國，普通人群與肥胖患者NAFLD的發(fā)病率分別為30%和90%[2]。代謝綜合征包括胰島素抵抗(insulin resistance,IR)、糖尿病、肥胖及高脂血癥，NAFLD的發(fā)病與之相關(guān)，尤其是肥胖[3-4]。

雖然NAFLD是一種良性的病變，通常不進(jìn)展，但是一系列“打擊”，如脂肪因子、氧化應(yīng)激、炎性因子與線粒體功能障礙等，可促使NAFLD向非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)、肝纖維化、肝硬化及肝細(xì)胞癌(hepatocellular carcinoma，HCC)逐步轉(zhuǎn)變、惡化。NASH的發(fā)病率為6%～13%，其中26%～37%的NASH患者出現(xiàn)纖維化，9%～20%的NASH患者進(jìn)展為肝硬化，5～7年后，40%～60%的肝硬化患者可進(jìn)展為HCC[2]。

2 NAFLD的發(fā)病機(jī)制

NAFLD的發(fā)病機(jī)制復(fù)雜，目前學(xué)界普遍認(rèn)同Day和James在1998年首次提出“二次打擊”學(xué)說[5]，認(rèn)為IR和氧化應(yīng)激(oxidative stress，ROS)共同參與了NAFLD的發(fā)生、發(fā)展。IR是首次打擊，導(dǎo)致肝臟脂肪蓄積，在此基礎(chǔ)上，大量的脂肪因子，如瘦素、脂聯(lián)素、抵抗素等，調(diào)控游離脂肪酸(free fatty acids，F(xiàn)FAs)誘導(dǎo)ROS損傷造成“二次打擊”[6]。

ROS可能通過激活Fas配體/Fas系統(tǒng)，誘導(dǎo)Fas死亡區(qū)域結(jié)構(gòu)蛋白上調(diào)下游半胱天冬酶家族成員，產(chǎn)生蛋白酶級聯(lián)反應(yīng)，引起細(xì)胞裂解與凋亡。此外，肝細(xì)胞凋亡可能引起炎性細(xì)胞蓄積，誘發(fā)腫瘤壞死因子α(tumor necrosis factor-α，TNF-α)、白介素-1(interleukin-1，IL-1)、白介素-6(interleukin-6，IL-6)等一系列炎性因子的釋放，出現(xiàn)脂肪性肝炎。某些纖維化因子，如轉(zhuǎn)化生長因子-β(transforming growth factor-β，TGF-β)，還可引起肝細(xì)胞外基質(zhì)合成增加，形成肝進(jìn)行性纖維化。盡管NAFLD的發(fā)生、發(fā)展是一系列復(fù)雜的、相輔相成的過程，但細(xì)胞內(nèi)相關(guān)信號通路,尤其是核因子-κB(nuclear factor-κB，NF-κB)的激活，有可能是NAFLD發(fā)病機(jī)制的關(guān)鍵環(huán)節(jié)。

3 NF-κB信號通路與NAFLD

NF-κB是一種細(xì)胞核轉(zhuǎn)錄因子，多種細(xì)胞因子、生長因子、免疫受體、遞質(zhì)、應(yīng)激、細(xì)菌及其產(chǎn)物、病毒與其產(chǎn)物、外源物質(zhì)、環(huán)境等可能激活NF-κB信號通路[6]。NF-κB信號通路的激活，是重要的促炎途徑，能促進(jìn)炎性細(xì)胞因子的表達(dá)，參與肝臟的炎性反應(yīng)、纖維化與凋亡。FFA、ROS激活NF-κB信號通路，可促進(jìn)促炎細(xì)胞因子的表達(dá)，如TNF-α、IL-1、IL-6、IL-8等，而這類炎性細(xì)胞因子反過來又再一次促進(jìn)NF-κB的活化，進(jìn)一步加劇炎癥反應(yīng)[7]。TNF-α、IL-1、IL-6、脂肪細(xì)胞因子等促炎細(xì)胞因子、轉(zhuǎn)錄因子及c-Jun氨基端激酶(c-Jun N-terminal kinase，JNK)加劇了IR。IR與炎性細(xì)胞因子共同參與了NAFLD的發(fā)生、發(fā)展。Leclercq等[8]研究發(fā)現(xiàn)，蛋氨酸與膽堿缺乏飲食構(gòu)建的NAFLD小鼠肝臟組織NF-κB表達(dá)顯著增加，應(yīng)用姜黃素可降低肝臟炎性反應(yīng)，由此推斷NF-κB信號通路可能參與了NAFLD的發(fā)生，而姜黃素則通過抑制NF-κB信號通路的激活及促炎基因的表達(dá)發(fā)揮作用。

4 姜黃素對NAFLD的潛在治療作用

姜黃素是從姜黃中提取的一種植物多酚，是姜黃最重要的活性成分。盡管針對NAFLD患者的臨床研究尚缺，但是動物模型與細(xì)胞研究發(fā)現(xiàn)，姜黃素是一種多效的多酚類化合物，具有抗氧化[9]、抗炎[9]、護(hù)肝[10]、抗癌[11]、調(diào)脂[12]、調(diào)節(jié)免疫[13]等功能。而NAFLD的發(fā)病恰恰涉及高脂血癥、IR、氧化應(yīng)激、炎癥反應(yīng)及肝星狀細(xì)胞的激活等。因此，我們可以推斷姜黃素可能通過多種機(jī)制調(diào)控脂代謝相關(guān)疾病的發(fā)生、發(fā)展，成為NAFLD潛在的治療藥物之一。

5 姜黃素的作用機(jī)制

姜黃素可降低血脂水平，抑制肝臟脂質(zhì)蓄積。Pungcharoenkul等[14]針對健康人的研究表明，姜黃素可顯著降低健康人血清膽固醇與甘油三酯水平。Jang等[15]在高脂飲食倉鼠高脂血癥與IR的動物模型研究中發(fā)現(xiàn)，姜黃素通過增加血漿對氧磷酶活性、增加肝脂肪酸氧化、抑制肝臟脂肪酸與膽固醇的生物合成，顯著降低血清FFA、總膽固醇、甘油三酯、瘦素水平，抑制IR。Yiu等[16]發(fā)現(xiàn)，姜黃素顯著降低高膽固醇飲食大鼠血清總膽固醇和低密度脂蛋白膽固醇水平，上調(diào)高密度脂蛋白膽固醇水平，改善肝臟功能，降低肝臟脂質(zhì)蓄積。同時，姜黃素干預(yù)后，大鼠脂代謝與細(xì)胞穩(wěn)態(tài)相關(guān)酶，如膽固醇α-羥化酶、血紅素氧化酶(heme oxygenase 1，HO-1)表達(dá)增加，低密度脂蛋白受體表達(dá)增加，但3-羥甲基戊二酰輔酶A還原酶(3-hydroxy-3-methyl-glutaryl-CoA reductase)表達(dá)下降，表明姜黃素能抑制高膽固醇血癥，并通過調(diào)控相關(guān)酶的表達(dá)抑制脂肪肝的形成。

姜黃素可增加胰島素敏感性。Zhao等[17]發(fā)現(xiàn)，姜黃素可通過誘導(dǎo)Nrf2核轉(zhuǎn)運(yùn)，拮抗氧化應(yīng)激，降低LO2肝細(xì)胞活性氧介導(dǎo)的IR。Shao等[18]發(fā)現(xiàn)，姜黃素通過抑制肝臟脂肪生成基因的表達(dá)，減少脂肪生成，阻斷脂肪組織巨噬細(xì)胞浸潤與炎性通路，降低脂肪因子的炎性作用，增加胰島素敏感性，降低高脂飲食誘導(dǎo)的C57BL/6J小鼠IR。

姜黃素可抑制氧化應(yīng)激反應(yīng)。姜黃素通過抗氧化酶的表達(dá)，如谷胱甘肽過氧化酶、HO-1、谷胱甘肽s-轉(zhuǎn)移酶、過氧化氫酶及超氧化物歧化酶(superoxide dismutase，SOD)等[1]，增強(qiáng)肝臟抗氧化能力。Gaedeke等[19]在對腎小球腎炎的研究中發(fā)現(xiàn)，姜黃素可上調(diào)HO-1水平或活性，抑制氧化應(yīng)激反應(yīng)，阻斷纖維化的進(jìn)程。Panahi等[20]的一項臨床隨機(jī)對照試驗表明，短期、聯(lián)合應(yīng)用姜黃素與胡椒堿，可上調(diào)代謝綜合征患者血清SOD活性，下調(diào)血清丙二醛(malondialdehyde，MDA)水平，抑制氧化應(yīng)激與炎性反應(yīng)。

姜黃素可降低肝臟炎癥反應(yīng)。FFA與ROS可激活NF-κB信號通路，引起肝臟炎性因子的釋放增加與IR，參與了NAFLD的發(fā)生、發(fā)展。姜黃素能與多個炎癥反應(yīng)的分子靶點相互作用，通過抑制NF-κB通路抗炎。Weisberg等[21]發(fā)現(xiàn)，姜黃素能顯著改善糖尿肥胖癥大鼠動物模型肥胖相關(guān)炎癥，抑制白色脂肪組織巨噬細(xì)胞浸潤，抑制肝臟NF-κB信號通路的活性，抑制炎性因子TNF-α、IL-6的生成，降低肝臟炎性反應(yīng)，增加脂聯(lián)素的產(chǎn)生。此外，姜黃素還能降低注射TNF-α誘導(dǎo)的脂肪肝小鼠氧化應(yīng)激、抑制嗜中性粒細(xì)胞浸潤[22]。

姜黃素能抑制肝星狀細(xì)胞活性。Tang等[23]研究發(fā)現(xiàn)，瘦素可通過上調(diào)胞內(nèi)葡萄糖水平，激活肝星狀細(xì)胞。而姜黃素可通過阻斷胰島素受體底物/磷脂酰肌醇3-激酶/AKT信號通路，抑制細(xì)胞膜葡萄糖轉(zhuǎn)運(yùn)蛋白4(glucose transporter 4，GLUT4)膜轉(zhuǎn)位，激動葡萄糖激酶活性，誘導(dǎo)葡萄糖向6-磷酸葡萄糖轉(zhuǎn)化，從而抑制瘦素上調(diào)胞內(nèi)葡萄糖水平的作用，抑制肝星狀細(xì)胞活性，減少細(xì)胞外基質(zhì)的沉積。

目前,由于姜黃素尚不能應(yīng)用于臨床，其對NAFLD患者療效的臨床研究尚缺，盡管如此，大量與脂質(zhì)蓄積、脂代謝異常相關(guān)的動物、細(xì)胞模型的研究證據(jù)已經(jīng)表明，姜黃素具有調(diào)脂、抗炎、抗氧化、降低IR、抑制肝星狀細(xì)胞的激活等功能，因此，姜黃素極有望成為NAFLD及其相關(guān)疾病的潛在治療藥物之一。

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(責(zé)任編輯：王全楚)

Therelationshipbetweencurcuminandnon-alcoholicfattyliverdisease

YU Yuanjie, TAN Shiyun

Department of Gastroenterology, Renmin Hospital of Wuhan University, Wuhan 430060, China

Non-alcoholic fatty liver disease (NAFLD) is one of the most common chronic liver diseases, its disease spectrum contains simple steatosis, non-alcoholic steatohepatitis (NASH), fibrosis, cirrhosis and hepatocellular carcinoma (HCC). The pathogenesis of NAFLD is rather complicated, both insulin resistance (IR) and oxidative stress involved in its occurrence and progress. NF-κB singnal pathway activation could be a crucial mechanism. Recently, curcumin has been an increasingly hot spot in medical field, due to its multiple pharmacological effects, such as regulate hyperlipidemia, antioxidant, anti-inflammation, hepatic protection. Based on numerous evidences of studies, curcumin has enormous potential to be one of the therapeutic drugs for NAFLD. This review focused on research status about the potential relationship between curcumin and NAFLD.

Non-alcoholic fatty liver disease; NF-κB; Curcumin

R575.5

A

1006-5709(2017)10-1107-03

2016-12-01

俞媛潔，博士研究生，研究方向：非酒精性脂肪性肝病的基礎(chǔ)與臨床。E-mail： yuyuanjie0303@yeah.net

譚詩云，博士，教授，博士生導(dǎo)師，研究方向：非酒精性脂肪性肝病的基礎(chǔ)與臨床。E-mail： tanshiyun@medmail.com.cn

10.3969/j.issn.1006-5709.2017.10.009