脂肪生成抑制劑治療非酒精性脂肪性肝病的研究進(jìn)展

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(dòng)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(gè)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(shí),DNL啟動(dòng),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(gè)結(jié)構(gòu)域組成,是DNL的第一個(gè)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(shí)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,它在肝臟中通過酰基CoA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(dòng)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(shí)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(shí)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(gè)國家和地區(qū)的200多個(gè)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(gè)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(shí),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(shí)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(shí),肝臟脂肪呈劑量依賴性減少達(dá)到50%-65%,同時(shí)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?；视王；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(gè)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(gè)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(shí),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(shí)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(gè)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(shí)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(dòng)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(dòng)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(shí)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.

1 Younossi ZM,Marchesini G,Pinto-Cortez H,Petta S.Epidemiology of Nonalcoholic Fatty Liver Disease and Nonalcoholic Steatohepatitis:Implications for Liver Transplantation.

2019;103:22-27 [PMID:30335697 DOI:10.1097/TP.00000000]

2 Calzadilla Bertot L,Adams LA.The Natural Course of Non-Alcoholic Fatty Liver Disease.

2016;17 [PMID:27213358 DOI:10.3390/ijms17050774]

3 Esler WP,Bence KK.Metabolic Targets in Nonalcoholic Fatty Liver Disease.

2019;8:247-267[PMID:31004828 DOI:10.1016/j.jcmgh.2019.04.007]

4 Cohen JC,Horton JD,Hobbs HH.Human fatty liver disease:old questions and new insights.

2011;332:1519-1523 [PMID:21700865 DOI:10.1126/science.1204265]

5 Postic C,Girard J.Contribution of de novo fatty acid synthesis to hepatic steatosis and insulin resistance:lessons from genetically engineered mice.

2008;118:829-838 [PMID:18317565 DOI:10.1172/JCI34275]

6 Angulo P,Kleiner DE,Dam-Larsen S,Adams LA,Bjornsson ES,Charatcharoenwitthaya P,Mills PR,Keach JC,Lafferty HD,Stahler A,Haflidadottir S,Bendtsen F.Liver Fibrosis,but No Other Histologic Features,Is Associated With Long-term Outcomes of Patients With Nonalcoholic Fatty Liver Disease.

2015;149:389-97.e10 [PMID:25935633 DOI:10.1053/j.gastro.2015.04.043]

7 Lambert JE,Ramos-Roman MA,Browning JD,Parks EJ.Increased de novo lipogenesis is a distinct characteristic of individuals with nonalcoholic fatty liver disease.

2014;146:726-735[PMID:24316260 DOI:10.1053/j.gastro.2013.11.049]

8 Tong J,Han CJ,Zhang JZ,He WZ,Zhao GJ,Cheng X,Zhang L,Deng KQ,Liu Y,Fan HF,Tian S,Cai J,Huang Z,She ZG,Zhang P,Li H.Hepatic Interferon Regulatory Factor 6 Alleviates Liver Steatosis and Metabolic Disorder by Transcriptionally Suppressing Peroxisome Proliferator-Activated Receptor γ in Mice.

2019;69:2471-2488 [PMID:30748020 DOI:10.1002/hep.30559]

9 Fullerton MD,Galic S,Marcinko K,Sikkema S,Pulinilkunnil T,Chen ZP,O’Neill HM,Ford RJ,Palanivel R,O’Brien M,Hardie DG,Macaulay SL,Schertzer JD,Dyck JR,van Denderen BJ,Kemp BE,Steinberg GR.Single phosphorylation sites in Acc1 and Acc2 regulate lipid homeostasis and the insulin-sensitizing effects of metformin.

2013;19:1649-1654 [PMID:24185692 DOI:10.1038/nm.3372]

10 Wei X,Schultz K,Bazilevsky GA,Vogt A,Marmorstein R.Molecular basis for acetyl-CoA production by ATP-citrate lyase.

2020;27:33-41 [PMID:31873304 DOI:10.1038/s41594-019-0351-6]

11 Aluvila S,Sun J,Harrison DH,Walters DE,Kaplan RS.Inhibitors of the mitochondrial citrate transport protein:validation of the role of substrate binding residues and discovery of the first purely competitive inhibitor.

2010;77:26-34[PMID:19843634 DOI:10.1124/mol.109.058750]

12 Fernandez HR,Gadre SM,Tan M,Graham GT,Mosaoa R,Ongkeko MS,Kim KA,Riggins RB,Parasido E,Petrini I,Pacini S,Cheema A,Varghese R,Ressom HW,Zhang Y,Albanese C,üren A,Paige M,Giaccone G,Avantaggiati ML.The mitochondrial citrate carrier,SLC25A1,drives stemness and therapy resistance in non-small cell lung cancer.

2018;25:1239-1258[PMID:29651165 DOI:10.1038/s41418-018-0101-z]

13 Tan M,Mosaoa R,Graham GT,Kasprzyk-Pawelec A,Gadre S,Parasido E,Catalina-Rodriguez O,Foley P,Giaccone G,Cheema A,Kallakury B,Albanese C,Yi C,Avantaggiati ML.Inhibition of the mitochondrial citrate carrier,Slc25a1,reverts steatosis,glucose intolerance,and inflammation in preclinical models of NAFLD/NASH.

2020;27:2143-2157 [PMID:31959914 DOI:10.1038/s41418-020-0491-6]

14 Lemus HN,Mendivil CO.Adenosine triphosphate citrate lyase:Emerging target in the treatment of dyslipidemia.

2015;9:384-389 [PMID:26073398 DOI:10.1016/j.jacl.2015.01.002]

15 Ahrens M,Ammerpohl O,von Sch?nfels W,Kolarova J,Bens S,Itzel T,Teufel A,Herrmann A,Brosch M,Hinrichsen H,Erhart W,Egberts J,Sipos B,Schreiber S,H?sler R,Stickel F,Becker T,Krawczak M,R?cken C,Siebert R,Schafmayer C,Hampe J.DNA methylation analysis in nonalcoholic fatty liver disease suggests distinct disease-specific and remodeling signatures after bariatric surgery.

2013;18:296-302 [PMID:23931760 DOI:10.1016/j.cmet.2013.07.004]

16 Siculella L,Giannotti L,Testini M,Gnoni GV,Damiano F.In Steatotic Cells,ATP-Citrate Lyase mRNA Is Efficiently Translated through a Cap-Independent Mechanism,Contributing to the Stimulation of De Novo Lipogenesis.

2020;21 [PMID:32054087 DOI:10.3390/ijms21041206]

17 Pinkosky SL,Groot PHE,Lalwani ND,Steinberg GR.Targeting ATP-Citrate Lyase in Hyperlipidemia and Metabolic Disorders.

2017;23:1047-1063 [PMID:28993031 DOI:10.1016/j.molmed.2017.09.001]

18 Ishihara K,Oyaizu S,Onuki K,Lim K,Fushiki T.Chronic(-)-hydroxycitrate administration spares carbohydrate utilization and promotes lipid oxidation during exercise in mice.

2000;130:2990-2995 [PMID:11110858 DOI:10.1093/jn/130.12.2990]

19 Semwal RB,Semwal DK,Vermaak I,Viljoen A.A comprehensive scientific overview of Garcinia cambogia.

2015;102:134-148 [PMID:25732350 DOI:10.1016/j.fitote.2015.02.012]

20 Han J,Li L,Wang D,Ma H.(-)-Hydroxycitric acid reduced fat deposition via regulating lipid metabolism-related gene expression in broiler chickens.

2016;15:37[PMID:26912252 DOI:10.1186/s12944-016-0208-5]

21 Li L,Peng M,Ge C,Yu L,Ma H.(-)-Hydroxycitric Acid Reduced Lipid Droplets Accumulation Via Decreasing Acetyl-Coa Supply and Accelerating Energy Metabolism in Cultured Primary Chicken Hepatocytes.

2017;43:812-831[PMID:28954258 DOI:10.1159/000481564]

22 Li L,Chu X,Yao Y,Cao J,Li Q,Ma H.(-)-Hydroxycitric Acid Alleviates Oleic Acid-Induced Steatosis,Oxidative Stress,and Inflammation in Primary Chicken Hepatocytes by Regulating AMP-Activated Protein Kinase-Mediated Reactive Oxygen Species Levels.

2020;68:11229-11241 [PMID:32940033 DOI:10.1021/acs.jafc.0c04648]

23 Han JH,Park MH,Myung CS.Garcinia cambogia Ameliorates Non-Alcoholic Fatty Liver Disease by Inhibiting Oxidative Stress-Mediated Steatosis and Apoptosis through NRF2-ARE Activation.

2021;10 [PMID:34439474 DOI:10.3390/antiox10081226]

24 Márquez F,Babio N,Bulló M,Salas-Salvadó J.Evaluation of the safety and efficacy of hydroxycitric acid or Garcinia cambogia extracts in humans.

2012;52:585-594[PMID:22530711 DOI:10.1080/10408398.2010.500551]

25 Rose-Kahn G,Bar-Tana J.Inhibition of lipid synthesis by beta beta’-tetramethyl-substituted,C14-C22,alpha,omegadicarboxylic acids in cultured rat hepatocytes.

1985;260:8411-8415 [PMID:4008497]

26 Atkinson LL,Kelly SE,Russell JC,Bar-Tana J,Lopaschuk GD.MEDICA 16 inhibits hepatic acetyl-CoA carboxylase and reduces plasma triacylglycerol levels in insulin-resistant JCR:LA-cp rats.

2002;51:1548-1555 [PMID:11978655 DOI:10.2337/diabetes.51.5.1548]

27 Zagelbaum NK,Yandrapalli S,Nabors C,Frishman WH.Bempedoic Acid (ETC-1002):ATP Citrate Lyase Inhibitor:Review of a First-in-Class Medication with Potential Benefit in Statin-Refractory Cases.

2019;27:49-56 [PMID:29939848 DOI:10.1097/CRD.0000000000000218]

28 Pinkosky SL,Newton RS,Day EA,Ford RJ,Lhotak S,Austin RC,Birch CM,Smith BK,Filippov S,Groot PHE,Steinberg GR,Lalwani ND.Liver-specific ATP-citrate lyase inhibition by bempedoic acid decreases LDL-C and attenuates atherosclerosis.

2016;7:13457 [PMID:27892461 DOI:10.1038/ncomms13457]

29 Sanjay KV,Vishwakarma S,Zope BR,Mane VS,Mohire S,Dhakshinamoorthy S.ATP citrate lyase inhibitor Bempedoic Acid alleviate long term HFD induced NASH through improvement in glycemic control,reduction of hepatic triglycerides &total cholesterol,modulation of inflammatory&fibrotic genes and improvement in NAS score.

2021;2:100051 [PMID:34909677 DOI:10.1016/j.crphar.2021.100051]

30 Abu-Elheiga L,Brinkley WR,Zhong L,Chirala SS,Woldegiorgis G,Wakil SJ.The subcellular localization of acetyl-CoA carboxylase 2.

2000;97:1444-1449 [PMID:10677481 DOI:10.1073/pnas.97.4.1444]

31 Savage DB,Choi CS,Samuel VT,Liu ZX,Zhang D,Wang A,Zhang XM,Cline GW,Yu XX,Geisler JG,Bhanot S,Monia BP,Shulman GI.Reversal of diet-induced hepatic steatosis and hepatic insulin resistance by antisense oligonucleotide inhibitors of acetyl-CoA carboxylases 1 and 2.

2006;116:817-824 [PMID:16485039 DOI:10.1172/JCI27300]

32 Shen Y,Volrath SL,Weatherly SC,Elich TD,Tong L.A mechanism for the potent inhibition of eukaryotic acetyl-coenzyme A carboxylase by soraphen A,a macrocyclic polyketide natural product.

2004;16:881-891 [PMID:15610732 DOI:10.1016/j.molcel.2004.11.034]

33 Harwood HJ Jr,Petras SF,Shelly LD,Zaccaro LM,Perry DA,Makowski MR,Hargrove DM,Martin KA,Tracey WR,Chapman JG,Magee WP,Dalvie DK,Soliman VF,Martin WH,Mularski CJ,Eisenbeis SA.Isozyme-nonselective N-substituted bipiperidylcarboxamide acetyl-CoA carboxylase inhibitors reduce tissue malonyl-CoA concentrations,inhibit fatty acid synthesis,and increase fatty acid oxidation in cultured cells and in experimental animals.

2003;278:37099-37111[PMID:12842871 DOI:10.1074/jbc.M304481200]

34 Kelly KL,Reagan WJ,Sonnenberg GE,Clasquin M,Hales K,Asano S,Amor PA,Carvajal-Gonzalez S,Shirai N,Matthews MD,Li KW,Hellerstein MK,Vera NB,Ross TT,Cappon G,Bergman A,Buckeridge C,Sun Z,Qejvanaj EZ,Schmahai T,Beebe D,Pfefferkorn JA,Esler WP.De novo lipogenesis is essential for platelet production in humans.

2020;2:1163-1178 [PMID:32929234 DOI:10.1038/s42255-020-00272-9]

35 Ross T,Kelly K,Rinaldi A,Lech M,Esler W.PS-132-The acetyl-CoA carboxylase inhibitor PF-05221304 exerts direct effects on hepatic inflammation and fibrosis independent of benefits on steatosis.

2019;70:86 [DOI:10.1016/S0618-8278(19)30150-1]

36 Ross TT,Crowley C,Kelly KL,Rinaldi A,Beebe DA,Lech MP,Martinez RV,Carvajal-Gonzalez S,Boucher M,Hirenallur-Shanthappa D,Morin J,Opsahl AC,Vargas SR,Bence KK,Pfefferkorn JA,Esler WP.Acetyl-CoA Carboxylase Inhibition Improves Multiple Dimensions of NASH Pathogenesis in Model Systems.

2020;10:829-851 [PMID:32526482 DOI:10.1016/j.jcmgh.2020.06.001]

37 Goedeke L,Bates J,Vatner DF,Perry RJ,Wang T,Ramirez R,Li L,Ellis MW,Zhang D,Wong KE,Beysen C,Cline GW,Ray AS,Shulman GI.Acetyl-CoA Carboxylase Inhibition Reverses NAFLD and Hepatic Insulin Resistance but Promotes Hypertriglyceridemia in Rodents.

2018;68:2197-2211[PMID:29790582 DOI:10.1002/hep.30097]

38 Bergman A,Carvajal-Gonzalez S,Tarabar S,Saxena AR,Esler WP,Amin NB.Safety,Tolerability,Pharmacokinetics,and Pharmacodynamics of a Liver-Targeting Acetyl-CoA Carboxylase Inhibitor (PF-05221304):A Three-Part Randomized Phase 1 Study.

2020;9:514-526 [PMID:32065514 DOI:10.1002/cpdd.782]

39 Calle RA,Amin NB,Carvajal-Gonzalez S,Ross TT,Bergman A,Aggarwal S,Crowley C,Rinaldi A,Mancuso J,Aggarwal N,Somayaji V,Inglot M,Tuthill TA,Kou K,Boucher M,Tesz G,Dullea R,Bence KK,Kim AM,Pfefferkorn JA,Esler WP.ACC inhibitor alone or co-administered with a DGAT2 inhibitor in patients with non-alcoholic fatty liver disease:two parallel,placebo-controlled,randomized phase 2a trials.

2021;27:1836-1848 [PMID:34635855 DOI:10.1038/s41591-021-01489-1]

40 Stiede K,Miao W,Blanchette HS,Beysen C,Harriman G,Harwood HJ Jr,Kelley H,Kapeller R,Schmalbach T,Westlin WF.Acetyl-coenzyme A carboxylase inhibition reduces de novo lipogenesis in overweight male subjects:A randomized,doubleblind,crossover study.

2017;66:324-334 [PMID:28470676 DOI:10.1002/hep.29246]

41 Loomba R,Kayali Z,Noureddin M,Ruane P,Lawitz EJ,Bennett M,Wang L,Harting E,Tarrant JM,McColgan BJ,Chung C,Ray AS,Subramanian GM,Myers RP,Middleton MS,Lai M,Charlton M,Harrison SA.GS-0976 Reduces Hepatic Steatosis and Fibrosis Markers in Patients With Nonalcoholic Fatty Liver Disease.

2018;155:1463-1473.e6 [PMID:30059671 DOI:10.1053/j.gastro.2018.07.027]

42 Lawitz EJ,Coste A,Poordad F,Alkhouri N,Loo N,McColgan BJ,Tarrant JM,Nguyen T,Han L,Chung C,Ray AS,McHutchison JG,Subramanian GM,Myers RP,Middleton MS,Sirlin C,Loomba R,Nyangau E,Fitch M,Li K,Hellerstein M.Acetyl-CoA Carboxylase Inhibitor GS-0976 for 12 Weeks Reduces Hepatic De Novo Lipogenesis and Steatosis in Patients With Nonalcoholic Steatohepatitis.

2018;16:1983-1991.e3[PMID:29705265 DOI:10.1016/j.cgh.2018.04.042]

43 Harrison S,Noureddin M,Herring R,Ruane P,Lawitz E.Preliminary efficacy and safety of acetyl-CoA carboxylase inhibitor GS-0976 in patients with compensated cirrhosis due to NASH.

2018;154:1166 [DOI:10.1016/S0168-8278(18)31425-9]

44 Kohjima M,Enjoji M,Higuchi N,Kato M,Kotoh K,Yoshimoto T,Fujino T,Yada M,Yada R,Harada N,Takayanagi R,Nakamuta M.Re-evaluation of fatty acid metabolism-related gene expression in nonalcoholic fatty liver disease.

2007;20:351-358 [PMID:17671740]

45 Mizojiri R,Asano M,Tomita D,Banno H,Nii N,Sasaki M,Sumi H,Satoh Y,Yamamoto Y,Moriya T,Satomi Y,Maezaki H.Discovery of Novel Selective Acetyl-CoA Carboxylase (ACC) 1 Inhibitors.

2018;61:1098-1117 [PMID:29232514 DOI:10.1021/acs.jmedchem.7b01547]

46 Tamura YO,Sugama J,Iwasaki S,Sasaki M,Yasuno H,Aoyama K,Watanabe M,Erion DM,Yashiro H.Selective Acetyl-CoA Carboxylase 1 Inhibitor Improves Hepatic Steatosis and Hepatic Fibrosis in a Preclinical Nonalcoholic Steatohepatitis Model.

2021;379:280-289 [PMID:34535562 DOI:10.1124/jpet.121.000786]

47 Ogawa Y,Imajo K,Honda Y,Kessoku T,Tomeno W,Kato S,Fujita K,Yoneda M,Saito S,Saigusa Y,Hyogo H,Sumida Y,Itoh Y,Eguchi K,Yamanaka T,Wada K,Nakajima A.Palmitate-induced lipotoxicity is crucial for the pathogenesis of nonalcoholic fatty liver disease in cooperation with gut-derived endotoxin.

2018;8:11365 [PMID:30054551 DOI:10.1038/s41598-018-29735-6]

48 Dorn C,Riener MO,Kirovski G,Saugspier M,Steib K,Weiss TS,G?bele E,Kristiansen G,Hartmann A,Hellerbrand C.Expression of fatty acid synthase in nonalcoholic fatty liver disease.

2010;3:505-514 [PMID:20606731]

49 Wu M,Singh SB,Wang J,Chung CC,Salituro G,Karanam BV,Lee SH,Powles M,Ellsworth KP,Lassman ME,Miller C,Myers RW,Tota MR,Zhang BB,Li C.Antidiabetic and antisteatotic effects of the selective fatty acid synthase (FAS) inhibitor platensimycin in mouse models of diabetes.

2011;108:5378-5383 [PMID:21389266 DOI:10.1073/pnas.1002588108]

50 Syed-Abdul MM,Parks EJ,Gaballah AH,Bingham K,Hammoud GM,Kemble G,Buckley D,McCulloch W,Manrique-Acevedo C.Fatty Acid Synthase Inhibitor TVB-2640 Reduces Hepatic de Novo Lipogenesis in Males With Metabolic Abnormalities.

2020;72:103-118 [PMID:31630414 DOI:10.1002/hep.31000]

51 Kim CW,Addy C,Kusunoki J,Anderson NN,Deja S,Fu X,Burgess SC,Li C,Ruddy M,Chakravarthy M,Previs S,Milstein S,Fitzgerald K,Kelley DE,Horton JD.Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans:A Bedside to Bench Investigation.

2017;26:394-406.e6 [PMID:28768177 DOI:10.1016/j.cmet.2017.07.009]

52 Loomba R,Mohseni R,Lucas KJ,Gutierrez JA,Perry RG,Trotter JF,Rahimi RS,Harrison SA,Ajmera V,Wayne JD,O’Farrell M,McCulloch W,Grimmer K,Rinella M,Wai-Sun Wong V,Ratziu V,Gores GJ,Neuschwander-Tetri BA,Kemble G.TVB-2640 (FASN Inhibitor) for the Treatment of Nonalcoholic Steatohepatitis:FASCINATE-1,a Randomized,Placebo-Controlled Phase 2a Trial.

2021;161:1475-1486[PMID:34310978 DOI:10.1053/j.gastro.2021.07.025]

53 Beysen C,Schroeder P,Wu E,Brevard J,Ribadeneira M,Lu W,Dole K,O’Reilly T,Morrow L,Hompesch M,Hellerstein MK,Li K,Johansson L,Kelly PF.Inhibition of fatty acid synthase with FT-4101 safely reduces hepatic de novo lipogenesis and steatosis in obese subjects with non-alcoholic fatty liver disease:Results from two early-phase randomized trials.

2021;23:700-710 [PMID:33289350 DOI:10.1111/dom.14272]

54 García-Serrano S,Moreno-Santos I,Garrido-Sánchez L,Gutierrez-Repiso C,García-Almeida JM,García-Arnés J,Rivas-Marín J,Gallego-Perales JL,García-Escobar E,Rojo-Martinez G,Tinahones F,Soriguer F,Macias-Gonzalez M,García-Fuentes E.Stearoyl-CoA desaturase-1 is associated with insulin resistance in morbidly obese subjects.

2011;17:273-280 [PMID:21060977 DOI:10.2119/molmed.2010.00078]

55 Flowers MT,Ntambi JM.Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism.

2008;19:248-256 [PMID:18460915 DOI:10.1097/MOL.0b013e3282f9b54d]

56 Cao B,Liu C,Zhang Q,Dong Y.Maternal High-Fat Diet Leads to Non-alcoholic Fatty Liver Disease Through Upregulating Hepatic SCD1 Expression in Neonate Rats.

2020;7:581723 [PMID:33282902 DOI:10.3389/fnut.2020.581723]

57 Miyazaki M,Flowers MT,Sampath H,Chu K,Otzelberger C,Liu X,Ntambi JM.Hepatic stearoyl-CoA desaturase-1 deficiency protects mice from carbohydrate-induced adiposity and hepatic steatosis.

2007;6:484-496 [PMID:18054317 DOI:10.1016/j.cmet.2007.10.014]

58 Zhang Z,Dales NA,Winther MD.Opportunities and challenges in developing stearoyl-coenzyme A desaturase-1 inhibitors as novel therapeutics for human disease.

2014;57:5039-5056 [PMID:24295027 DOI:10.1021/jm401516c]

59 Iida T,Ubukata M,Mitani I,Nakagawa Y,Maeda K,Imai H,Ogoshi Y,Hotta T,Sakata S,Sano R,Morinaga H,Negoro T,Oshida S,Tanaka M,Inaba T.Discovery of potent liver-selective stearoyl-CoA desaturase-1 (SCD1) inhibitors,thiazole-4-acetic acid derivatives,for the treatment of diabetes,hepatic steatosis,and obesity.

2018;158:832-852 [PMID:30248655 DOI:10.1016/j.ejmech.2018.09.003]

60 Iruarrizaga-Lejarreta M,Varela-Rey M,Fernández-Ramos D,Martínez-Arranz I,Delgado TC,Simon J,Juan VG,delaCruz-Villar L,Azkargorta M,Lavin JL,Mayo R,Van Liempd SM,Aurrekoetxea I,Buqué X,Cave DD,Pe?a A,Rodríguez-Cuesta J,Aransay AM,Elortza F,Falcón-Pérez JM,Aspichueta P,Hayardeny L,Noureddin M,Sanyal AJ,Alonso C,Anguita J,Martínez-Chantar ML,Lu SC,Mato JM.Role of Aramchol in steatohepatitis and fibrosis in mice.

2017;1:911-927 [PMID:29159325 DOI:10.1002/hep4.1107]

61 Ratziu V,de Guevara L,Safadi R,Poordad F,Fuster F,Flores-Figueroa J,Arrese M,Fracanzani AL,Ben Bashat D,Lackner K,Gorfine T,Kadosh S,Oren R,Halperin M,Hayardeny L,Loomba R,Friedman S;ARREST investigator study group,Sanyal AJ.Aramchol in patients with nonalcoholic steatohepatitis:a randomized,double-blind,placebo-controlled phase 2b trial.

2021;27:1825-1835 [PMID:34621052 DOI:10.1038/s41591-021-01495-3]