0 引言

非酒精性脂肪性肝病(non-alcoholic fatty liver disease,NAFLD)已成為發(fā)病率最高的慢性肝病,影響全球超過25%的人群

,高達(dá)30%的NAFLD患者會發(fā)生非酒精性脂肪性肝炎(nonalcoholic steatohepatitis,NASH)

,NASH可引起肝損傷并導(dǎo)致進(jìn)行性肝纖維化、肝硬化和肝細(xì)胞癌(hepatocellular carcinoma,HCC).然而,NAFLD進(jìn)展為NASH的發(fā)病機(jī)制相當(dāng)復(fù)雜,仍未明確.美國食品藥品監(jiān)督管理局(Food and Drug Administration,FDA)尚未批準(zhǔn)用于治療NAFLD的藥物

,治療選擇僅限于飲食調(diào)整、運(yùn)動及減重,臨床上對NAFLD可行的治療靶點(diǎn)和治療策略的需求仍未得到滿足.

肝臟脂肪變性是由肝臟脂質(zhì)代謝失衡引起的,使脂質(zhì)在肝臟內(nèi)儲存

,觸發(fā)肝臟炎癥,導(dǎo)致肝臟纖維化,促進(jìn)NAFLD進(jìn)展.長期以來,肝臟從頭脂肪生成(de novo lipogenesis,DNL)不被認(rèn)為是肝臟脂肪變性的相關(guān)原因,因?yàn)樵诮】等梭w中僅約5%的肝臟甘油三酯(triglyceride,TG)來源于DNL,其余大部分脂肪酸來源于膳食和外周脂解

.但近年來的研究證明,DNL是NAFLD發(fā)生的關(guān)鍵介質(zhì)

,在NAFLD患者中,20%-25%的肝臟TG來源于DNL

,另外,由DNL衍生的脂質(zhì)也可能促進(jìn)脂肪酸代謝物的蓄積,引起脂毒性肝細(xì)胞損傷和炎癥通路上調(diào)

.因此,抑制肝臟DNL成為治療NAFLD的一個有吸引力的治療靶點(diǎn).目前,針對DNL過程中核心酶的抑制劑正處于臨床研發(fā)階段,包括檸檬酸鹽/異檸檬酸鹽載體(citrate/isocitrate carrier,CIC)、ATP-檸檬酸裂解酶(ATP-citrate lyase,ACLY)、乙酰CoA羧化酶(acetyl-CoA carboxylase,ACC)和脂肪酸合成酶(fatty acid synthase,FASN)、硬脂酰輔酶A去飽和酶1(stearoyl-CoA desaturase 1,SCD1)抑制劑(圖1),本文就脂肪生成抑制劑治療NAFLD的研究進(jìn)展作如下闡述.

1 檸檬酸鹽/異檸檬酸鹽載體抑制劑

檸檬酸鹽/異檸檬酸鹽載體(citrate/isocitrate carrier,CIC)又稱檸檬酸鹽轉(zhuǎn)運(yùn)蛋白(citrate transport protein,CTP)、溶質(zhì)載體家族25成員1(SLC25A1),在肝臟、脂肪組織中高表達(dá),位于線粒體內(nèi)膜內(nèi).當(dāng)?shù)孜镞^量(相對于細(xì)胞能量需求)導(dǎo)致線粒體檸檬酸鹽增加時,DNL啟動,檸檬酸鹽通過CIC從線粒體輸出到細(xì)胞質(zhì)中,成為脂肪生成的前體,最終轉(zhuǎn)化為脂肪酸.研究發(fā)現(xiàn)通過抑制在NAFLD人群肝臟中表達(dá)增加的CIC,降低細(xì)胞質(zhì)檸檬酸鹽,可降低ACLY和ACC的底物可用性及變構(gòu)激活來抑制DNL

.第一代CIC抑制劑是苯三羧酸鹽(benzenetricarboxylate,BTC),結(jié)構(gòu)上與檸檬酸鹽相似,親和力高于任何底物,以混合競爭和非競爭方式抑制CIC

.然而,BTC具有與其它檸檬酸鹽結(jié)合蛋白的潛在結(jié)合性,限制了它在治療方面的研發(fā).第二代抑制劑檸檬酸鹽轉(zhuǎn)運(yùn)蛋白抑制劑-1(citrate transport protein inhibitor-1,CTPI-1),與檸檬酸鹽無結(jié)構(gòu)相似性,可競爭性結(jié)合CIC檸檬酸鹽結(jié)合位點(diǎn),親和力略高于BTC,但它是在酵母中發(fā)現(xiàn),與人的CIC結(jié)合欠佳,需要高劑量才能在人體內(nèi)發(fā)揮活性

.為了優(yōu)化得到針對人類CIC的特異性抑制劑,Tan等

研究出了檸檬酸鹽轉(zhuǎn)運(yùn)蛋白抑制劑-2(citrate transport protein inhibitor-2,CTPI-2),相對于CTPI-1,結(jié)合親和力提高了20倍,可在較低濃度下抑制檸檬酸轉(zhuǎn)運(yùn);并使用CTPI-2治療NAFLD/NASH小鼠模型,發(fā)現(xiàn)能夠逆轉(zhuǎn)肝細(xì)胞脂肪變性,阻止向脂肪性肝炎進(jìn)展,減少肝臟中炎性巨噬細(xì)胞浸潤,對治療NAFLD可能產(chǎn)生有利影響.遺憾的是上述研究未評價(jià)CTPI-2的安全性,CTPI-2尚未進(jìn)入臨床試驗(yàn),仍需要進(jìn)一步研究驗(yàn)證其有效性和安全性.

非公有制企業(yè)設(shè)置多套賬的目的是為偷稅、漏稅以及操縱會計(jì)信息，為不同使用者提供“對口”賬簿，導(dǎo)致非公有制企業(yè)會計(jì)信息嚴(yán)重失真。

2 ATP-檸檬酸裂解酶抑制劑

ATP-檸檬酸裂解酶(ATP-citrate lyase,ACLY)是一種細(xì)胞質(zhì)酶,在脂肪組織、肝臟中高表達(dá),負(fù)責(zé)催化檸檬酸鹽和輔酶A(coenzyme A,CoA)轉(zhuǎn)化為乙酰CoA和草酰乙酸,用于脂肪酸(fatty acid,FA)和膽固醇的從頭合成

.ACLY通過控制葡萄糖碳流向胞質(zhì)的乙酰CoA及控制TG合成,將細(xì)胞葡萄糖分解代謝與脂質(zhì)生物合成聯(lián)系起來.研究發(fā)現(xiàn)NAFLD患者的ACLY mRNA量高于健康者,刺激DNL

.雖然ACLY不是限速酶,但由于其在脂肪酸、膽固醇和葡萄糖代謝方面的戰(zhàn)略地位,使ACLY被認(rèn)為是治療脂質(zhì)代謝相關(guān)疾病的有效靶點(diǎn)

.

脂肪酸合成酶(fatty acid synthase,FASN)位于細(xì)胞質(zhì)中,在肝臟、脂肪組織中高表達(dá),將乙酰輔酶a和丙二酰輔酶a轉(zhuǎn)化為棕櫚酸酯.棕櫚酸酯在肝臟產(chǎn)生過量脂肪及生成某些脂毒性分子中起主要作用,在實(shí)驗(yàn)?zāi)Ｐ椭锌芍苯右鸶螕p傷和NASH

.NAFLD患者的FASN基因表達(dá)水平升高

,臨床前研究表明在FASN基因敲除小鼠模型中,DNL減少和M-CoA增加

.初步臨床試驗(yàn)顯示,在代謝綜合征患者中,抑制FASN可抑制DNL,且不使循環(huán)TG升高

;針對ACC和FASN抑制劑對循環(huán)TG的不同影響,可以用二者對肝臟M-CoA濃度的相反作用解釋,M-CoA是合成多不飽和脂肪酸(polyunsaturated fatty acids,PUFA)所必需的中間體,抑制ACC可降低M-CoA水平,可能影響PUFA的合成,進(jìn)而導(dǎo)致LXR/SREBP1c靶基因表達(dá)增加,隨后刺激VLDL分泌和血漿TG濃度升高

,而抑制FASN則使M-CoA水平升高.因此,抑制FASN成為一種有吸引力的治療NAFLD的方法.

1.4統(tǒng)計(jì)學(xué)方法本次實(shí)驗(yàn)數(shù)據(jù)采用SPSS12.0軟件進(jìn)行統(tǒng)計(jì)學(xué)分析。計(jì)量資料以均數(shù)±標(biāo)準(zhǔn)差(±s)表示,采用t檢驗(yàn);計(jì)數(shù)資料以率(%)表示,采用X2檢驗(yàn)。P<0.05表示差異具有統(tǒng)計(jì)學(xué)意義。

乙酰CoA羧化酶(acetyl-CoA carboxylase,ACC)存在于胞液中,由生物素羧化酶(biotin carboxylase,BC)、生物素羧基載體蛋白(biotin carboxyl carrier protein,BCCP)和羧基轉(zhuǎn)移酶(carboxyl transferase,CT)3個結(jié)構(gòu)域組成,是DNL的第一個限速酶,主要催化依賴ATP的乙酰CoA轉(zhuǎn)化為丙二酰CoA(Malonyl-CoA,M-CoA).ACC有兩種亞型,ACC1主要存在于脂肪生成組織(肝臟和脂肪組織)的細(xì)胞質(zhì)中,催化產(chǎn)生的M-CoA是脂肪酸的合成單位;ACC2主要存在于氧化組織(骨骼肌、心臟)的線粒體中,催化生成的M-CoA是肉堿棕櫚酰轉(zhuǎn)移酶1(carnitine palmityl transferase 1,CPT-1)的抑制劑.因?yàn)镃PT-1是負(fù)責(zé)將長鏈脂肪酸?；鵆oA運(yùn)輸?shù)骄€粒體進(jìn)行β-氧化的關(guān)鍵酶,所以ACC2能夠抑制脂肪酸的β-氧化

.Savage等

使用反義寡核苷酸抑制NAFLD大鼠模型ACC1、ACC2的表達(dá),抑制ACC1可減少脂肪生成,抑制ACC2可增加線粒體脂肪酸氧化,導(dǎo)致肝臟脂肪變性減少;可見ACC1、ACC2在DNL和脂肪酸β-氧化中的核心作用,為治療NAFLD/NASH提供了一種有吸引力的方法.

進(jìn)入結(jié)果期后，應(yīng)加強(qiáng)肥水管理。早春干旱，萌芽前應(yīng)灌1次水，以延遲花期，免遭春寒。落花后幼果生長期，噴0.3%磷酸二氫鉀水溶液2～3次，每株溝施硫酸鉀 1～1.5 kg，促進(jìn)果實(shí)膨大著色。果實(shí)膨大前后，土壤含水量要保持在80%左右。采果后，如遇高溫干旱，要及時灌水，提高花芽質(zhì)量。秋季落葉前株施有機(jī)肥50 kg、高鉀復(fù)合肥2～3 kg，為來年優(yōu)質(zhì)高產(chǎn)打下基礎(chǔ)。

3 乙酰CoA羧化酶抑制劑

隨后研究發(fā)現(xiàn)了一種肝臟特異性ACLY抑制劑-苯甲酸,又稱ETC1002或ESP-55016,它在肝臟中通過?；鵆oA合成酶(僅在肝臟中高度表達(dá))轉(zhuǎn)化為具有活性的ETC-1002CoA,能夠抑制ACLY和增加AMPK的活性,從而避免了抑制肌肉和脂肪組織中ACLY導(dǎo)致的肌無力和脂肪代謝障礙不良反應(yīng)的發(fā)生

.Sanjay等

研究苯甲酸在長期高脂飲食(high fat diet,HFD)誘導(dǎo)的NASH動物模型中的作用,結(jié)果顯示苯甲酸能夠通過降低肝臟TG和總膽固醇、抑制體重增加、降低血糖、調(diào)節(jié)炎癥和纖維化基因以及改善NAS評分來減輕HFD誘導(dǎo)的NASH.可見苯甲酸可能是代謝綜合征和NAFLD的一種潛在的治療選擇,但目前對苯甲酸的研究未進(jìn)入到臨床階段,苯甲酸是否能有效逆轉(zhuǎn)NAFLD和纖維化仍有待確定.

另一公司研究出了與BC結(jié)構(gòu)域結(jié)合,阻斷ACC二聚化,從而抑制ACC酶活性的強(qiáng)效ACC1、ACC2非選擇性抑制劑GS-0976(又稱ND-630、NDI 010976、Firsocostat).由于它被設(shè)計(jì)為對肝臟具有組織特異性的有機(jī)陰離子轉(zhuǎn)運(yùn)肽的底物,從而具有肝臟特異性.臨床前研究表明,GS-0976可減少肝臟DNL并增加氧化,從而減少肝臟脂肪變性和胰島素抵抗

.一項(xiàng)NASH患者的II期隨機(jī)安慰劑對照試驗(yàn)中評價(jià)了GS-0976的安全性和療效,將126例肝臟脂肪變性高于8%且肝臟硬度至少為2.5 kPa的患者隨機(jī)分配至GS-0976 20 mg(

=49)、GS-0976 5mg(

=51)及安慰劑組(

=26)治療12 wk,結(jié)果顯示GS-0976 20mg組患者的DNL相對于基線中位水平下降了22%,纖維化標(biāo)志物組織金屬蛋白酶抑制劑1(tissue metalloproteinase inhibitors 1,TIMP-1)顯著降低;三組中達(dá)到磁共振成像估計(jì)的質(zhì)子密度脂肪分?jǐn)?shù)(magnetic resonance imaging estimates of proton density fat fraction,MRI-PDFF)緩解(相對基線下降至30%)的患者比例分別48%、23%和15%;三組間磁共振彈性成像測量的硬度變化無差異;安全性良好,未觀察到對血小板計(jì)數(shù)或出血風(fēng)險(xiǎn)的影響,但在接受GS-0976 20 mg及5 mg治療的患者觀察到血清TG水平升高,中位相對增幅分別為11%和13%.對于血清TG異常升高的原因,可能是ACC抑制劑過度抑制DNL導(dǎo)致的,因此監(jiān)測血清TG水平可能對ACC抑制劑的研究至關(guān)重要

.另兩項(xiàng)臨床研究同樣表明GS-0976可抑制肝臟DNL,以及能夠改善MRI-PDFF、磁共振彈性成像和肝纖維化標(biāo)志物

.上述研究雖然存在治療時間短、未包括肝硬化患者等局限性,但研究結(jié)果在一程度上支持了未來研究GS-0976靶向抑制ACC治療NASH患者的安全性和有效性.

3.2 選擇性ACC1抑制劑 早期研究提出在NAFLD患者肝臟中是ACC1表達(dá)上調(diào)而非ACC2

,單獨(dú)抑制ACC1可能有改善肝臟脂肪變性和纖維化的潛力,并避免ACC1、ACC2雙重抑制劑過度抑制ACC活性誘導(dǎo)的不良反應(yīng),如血漿TG升高.2018年Mizojiri等

研究出一種新型人選擇性ACC1抑制劑,對ACC1的選擇性是ACC2的17000倍以上,體外抑制ACC1和ACC2的IC50值分別為0.58 nM和＞10000 nM.隨后Tamura等

進(jìn)一步在臨床前NASH模型研究該種選擇性ACC1抑制劑(化合物-1)的療效,結(jié)果顯示化合物-1抑制實(shí)驗(yàn)小鼠ACC1和ACC2的IC50值分別為1.9 nM和＞10000 nM,呈劑量依賴性降低實(shí)驗(yàn)小鼠肝臟M-CoA含量,30 mg/kg時療效最大,比對照組低62%;分別以3 mg/kg、10 mg/kg和30 mg/kg的化合物-1給藥實(shí)驗(yàn)組小鼠,每日1次,連續(xù)8 wk,與對照組相比,肝臟總重量分別降低了9.1%、23.8%和57.1%,此外,化合物-1能顯著降低炎癥標(biāo)志物(MCP-1、F4/80)及肝臟纖維化活性標(biāo)志物(Col1a1、Col1a2、αSMA、TGF-β1)的基因表達(dá)水平;研究結(jié)果表明化合物-1能夠改善肝脂肪變性和肝纖維化,且安全性良好,未顯著升高血漿TG濃度.該研究首次表明選擇性ACC1抑制劑在臨床前模型中具有足夠的療效,從而為治療NAFLD/NASH提供了一種可行的方法.

“糧食銀行+”農(nóng)業(yè)綜合服務(wù)平臺是中糧的探索之一，通過這樣的惠農(nóng)大平臺，不僅切實(shí)提高了農(nóng)民的收益，實(shí)現(xiàn)了政府多年倡導(dǎo)的“糧食不落地”精神，還推進(jìn)了農(nóng)村土地集約化、規(guī)?；l(fā)展。

斯普瑞噴霧系統(tǒng)（上海）有限公司是全球噴霧噴嘴、噴霧系統(tǒng)領(lǐng)導(dǎo)者——美國噴霧系統(tǒng)公司在中國的全資子公司，總部位于美國的伊利諾伊州，并在全球擁有12家制造工廠，以及遍布57個國家和地區(qū)的200多個銷售辦事處。公司于1994年進(jìn)入中國市場，專業(yè)從事噴霧噴嘴、噴霧系統(tǒng)的研發(fā)、設(shè)計(jì)、制造和銷售，通過提供高效噴霧技術(shù)解決方案，滿足各行業(yè)客戶個性化的潛在需求。

3.1 ACC1、ACC2雙重抑制劑 2003年,國外某公司研究出了ACC抑制劑關(guān)鍵先導(dǎo)化合物CP-640186,是一種非選擇性、可逆性和ATP非競爭性的ACC1、ACC2雙重抑制劑.在乙?；D(zhuǎn)化為丙二?；^程中,CP-640186能夠占據(jù)生物素-羧基復(fù)合物作用于CT域的位置,阻斷羧化反應(yīng)的發(fā)生從而起到抑制ACC活性的作用

.CP-640186能降低大鼠肝臟、比目魚肌、股四頭肌和心肌M-CoA水平[半最大效應(yīng)濃度EC50分別為(55、6、15、8) mg/kg],對ACC1、ACC2的半抑制濃度相似

,但該公司對CP-640186的研究停留在臨床前階段.隨后,該公司進(jìn)一步研發(fā)出了PF-05221304,是一種強(qiáng)效、選擇性、口服生物可利用的可逆性ACC1、ACC2雙重抑制劑.由ACC1催化生成的脂肪酸對調(diào)節(jié)血小板功能和活化具有重要作用,過度抑制DNL時,可能導(dǎo)致巨核細(xì)胞分界膜形成受損,從而導(dǎo)致血小板減少

,而PF-05221304能夠優(yōu)先分布于肝臟,使肝臟DNL抑制最大化,同時對外周組織(包括骨髓)的DNL抑制最小化

,從而降低抑制血小板生成的不良反應(yīng).臨床前研究表明,PF-05221304能夠直接改善多種NAFLD/NASH致病因素,包括脂肪變性、炎癥和纖維化

,但可導(dǎo)致高甘油三酯血癥發(fā)生

.Ⅰ期臨床試驗(yàn)顯示,在健康受試者中耐受良好的PF-05221304劑量可使NASH患者的DNL正?；?以劑量依賴性方式抑制肝臟DNL,并且安全性良好,在抑制肝臟DNL達(dá)到80%的劑量下,未觀察到血小板計(jì)數(shù)降低及血清TG異常升高

.Ⅱ期臨床試驗(yàn)顯示,PF-05221304單藥治療NAFLD患者,當(dāng)劑量≥10 mg/每天時,肝臟脂肪呈劑量依賴性減少達(dá)到50%-65%,同時還可降低糖化血紅蛋白;305例患者中有23例血清TG呈劑量依賴性升高,但不良事件的總體發(fā)生率不隨PF-05221304劑量增加而增加;當(dāng)PF-05221304和二酰基甘油?；D(zhuǎn)移酶2(diacylgycerol acyltransferase 2,DGAT2)抑制劑聯(lián)合給藥后,ACC抑制劑介導(dǎo)的血清TG類化合物升高效應(yīng)減輕,兩者聯(lián)合給藥有可能解決ACC單獨(dú)抑制的一些局限性

.

4 脂肪酸合成酶抑制劑

第一個被廣泛研究的ACLY抑制劑是羥基檸檬酸(hydroxycitric acid,HCA),結(jié)構(gòu)與檸檬酸鹽相似,對ACLY的親和力遠(yuǎn)大于檸檬酸鹽,能夠有效競爭性抑制ACLY,減少乙酰CoA的供應(yīng)從而抑制DNL

,并具有抗肥胖、抗氧化和抗炎的潛在作用

.除了抑制ACLY,臨床前研究發(fā)現(xiàn)HCA可通過調(diào)節(jié)腺苷酸活化蛋白激酶(AMP-activated protein kinase,AMPK)介導(dǎo)的信號通路減輕雞肝細(xì)胞脂肪變性、氧化應(yīng)激和炎癥

;還能通過激活核因子紅細(xì)胞2相關(guān)因子2-抗氧化反應(yīng)元件(NRF2-ARE)的抗氧化作用,來調(diào)節(jié)脂肪生成和凋亡,進(jìn)一步改善NAFLD

.HCA用于治療肥胖患者顯示安全性良好,副作用和安慰劑組相比無差異

.目前HCA用于治療NAFLD的臨床研究較少,其療效及安全性仍需進(jìn)一步研究.首次合成的脂肪酸樣ACLY抑制劑之一是化合物MEDICA16,它與檸檬酸鹽競爭性抑制ACLY,早期研究顯示MEDICA16能夠抑制大鼠肝細(xì)胞中的脂肪酸和膽固醇合成

.遺憾的是,MEDICA16特異性差,也能與乙酰CoA和ATP競爭性抑制ACC

,近年來對它的研究較少,且未超出臨床前研究.

TVB-2640是第一個進(jìn)入臨床試驗(yàn)的FASN抑制劑,具有高效(IC50:0.05 μM)、選擇性和可逆性特點(diǎn),通過靶向β-酮?；€原酶結(jié)構(gòu)域抑制FASN.Syed-Abdul等

研究中首次檢測該藥物對DNL通路作用,12例代謝綜合征受試者接受TVB-2640(劑量范圍50 mg/d-150 mg/d)治療10 d,DNL呈劑量依賴性降低,降低程度高達(dá)90%,但需要進(jìn)一步的研究來確定長期使用的適當(dāng)劑量和效果.隨后,一項(xiàng)隨機(jī)、安慰劑對照2期臨床研究評估TVB-2640的安全性并檢測對NASH患者肝臟脂肪及肝臟代謝標(biāo)志物的影響,結(jié)果顯示經(jīng)TVB-2640口服治療12 wk后肝臟脂肪含量顯著呈劑量依賴性降低,50 mg/d治療時,肝臟脂肪平均減少了28.1%;61%的受試者達(dá)到了MRI-PDFF緩解,纖維化血清生物標(biāo)志物蛋白C3和TIMP-1顯著降低;且安全性良好,不會導(dǎo)致TG升高.但該研究的局限性在于樣本量相對較小和給藥持續(xù)時間較短,可能混淆對患者血漿中纖維化生物標(biāo)志物的評估,因此需要進(jìn)一步的研究來直接評估TVB-2640對肝組織學(xué)的影響

.

另一個靶向β-酮?；€原酶結(jié)構(gòu)域的FASN抑制劑是FT-4101,它是一種強(qiáng)效(IC50:23 nM)、選擇性、口服生物可利用的小分子化合物.Beysen等

在健康受試者中研究FT-4101單次口服給藥對肝臟DNL抑制的劑量反應(yīng),結(jié)果示FT-4101呈劑量依賴性抑制DNL,最高劑9 mg下的抑制率為68%.隨后進(jìn)一步納入了NAFLD受試者隨機(jī)(2:1)接受3 mg FT-4101(

=9)或安慰劑(

=5)間歇性治療12 wk(3 wk、6 wk、9 wk和12 wk暫停給藥),評價(jià)FT-4101對肝臟脂肪變性的安全性、耐受性和療效,結(jié)果顯示能夠改善肝臟脂肪變性并抑制了肝臟DNL,22%的受試者達(dá)到相對MRI-PDFF降低≥30%,安全性良好,未發(fā)現(xiàn)皮膚干燥、脫發(fā)及TG升高.但該研究的局限性在于未納入確診NASH或肝纖維化受試者,不能得出FT-4101對NASH緩解和纖維化改善有效性的結(jié)論,需要進(jìn)一步的研究來評價(jià)更高劑量和延長治療時間的療效和安全性.

5 SCD1抑制劑

硬脂酰輔酶A去飽和酶1(stearoyl-CoA desaturase 1,SCD1)是一種內(nèi)質(zhì)網(wǎng)結(jié)合的微粒體酶,主要在脂肪組織和肝臟中表達(dá),是催化飽和脂肪酸向單不飽和脂肪酸轉(zhuǎn)化的關(guān)鍵限速酶,在DNL的最后階段發(fā)揮關(guān)鍵作用

.研究已證明

SCD1是脂質(zhì)代謝和體重控制的關(guān)鍵因素,SCD1過表達(dá)可使脂肪酸合成增加,脂肪酸β氧化降低,導(dǎo)致肝臟脂質(zhì)蓄積,可能與NAFLD的發(fā)生和進(jìn)展有關(guān)

.因此,抑制SCD1可能成為治療NAFLD的新方法 .由于在SCD1缺陷的小鼠研究中報(bào)告了皮膚異常和眼裂狹窄不良反應(yīng),因此,強(qiáng)效全身分布的SCD1抑制劑可能導(dǎo)致基于機(jī)制的不良反應(yīng)發(fā)生

,為了提高SCD1抑制劑安全性,Iida等

開發(fā)了一種強(qiáng)效肝臟選擇性SCD1抑制劑,即噻唑-4-乙酸類似物48,它在肝脂肪變性動物模型中呈劑量依賴性降低肝臟TG,并有足夠的安全劑量范圍(10-81-fold,AUC水平),安全性良好,治療期間無顯著的不良事件發(fā)生,具有治療NAFLD潛在價(jià)值.

3β-花生四烯酸酰胺膽酸(Aramchol)是另一種肝臟靶向的SCD1部分抑制劑,在體外模型中,Aramchol對SCD1活性的抑制率達(dá)到70%-83%.在動物模型中可部分抑制肝臟SCD1蛋白表達(dá)并降低肝臟TG和纖維化

.一項(xiàng)NASH患者的Ⅱb期隨機(jī)安慰劑對照試驗(yàn)研究了Aramchol的療效和安全性

,納入的247例患者隨機(jī)分為Aramchol 400 mg(

=101)、600 mg(

=98)、安慰劑組(

=48),結(jié)果顯示Aramchol 600 mg和安慰劑組分別有16.7%和5%的受試者達(dá)到 NASH 緩解不伴纖維化惡化(OR=4.74,95%CI:0.1-22.7),分別有29.5%和17.5%達(dá)到纖維化改善≥1期不伴NASH惡化(OR=1.88,95%CI:0.7-5.0);Aramchol 600 mg組的肝臟甘油三酯(通過MRS測量)與安慰劑組相比降低,但無明顯差異;Aramchol安全且耐受性良好,因AE提前終止的發(fā)生率＜5%.雖然該研究種aramchol 600 mg組的肝臟脂肪減少未達(dá)到顯著性水平,但其安全性以及肝臟組織學(xué)變化為SCD1抑制劑作為治療NAFLD/NASH提供了依據(jù),還需要進(jìn)一步在Ⅲ期臨床實(shí)驗(yàn)中進(jìn)行相關(guān)評價(jià).

6 總結(jié)與展望

目前通過治療性生活方式改變來減重仍是NAFLD/NASH的一線治療方法,尚無FDA批準(zhǔn)的藥物用于治療該患者人群.近年來,通過探索DNL在NAFLD/NASH疾病發(fā)生、發(fā)展過程中的作用機(jī)制,開發(fā)出了數(shù)種用于治療NAFLD/NASH的DNL抑制劑,并取得了一定的進(jìn)展.雖然CIC和ACLY抑制劑大部分停留在臨床前研究階段,但ACC抑制劑GS-0976、FASN抑制劑TVB-2640和SCD1抑制劑Aramchol的II期臨床試驗(yàn)結(jié)果顯示的療效令人鼓舞.然而,抑制DNL可能導(dǎo)致循環(huán)TG的增加、血小板減少以及皮膚和眼睛等不良反應(yīng)發(fā)生,因此,提高療效的同時保證安全性對DNL抑制劑的研究亦至關(guān)重要.DNL抑制劑的療效和安全性是否足以用作單藥治療或與其他療法聯(lián)合使用以增強(qiáng)療效或減輕不良反應(yīng),以阻止NAFLD/NASH進(jìn)展為肝硬化,仍需進(jìn)一步臨床研究.

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