王紅芳 楊維仁* 劉建新 楊在賓

（1.山東農(nóng)業(yè)大學(xué)動物科技學(xué)院,泰安271018;2.浙江大學(xué)動物科技學(xué)院奶業(yè)科學(xué)研究所,杭州 310029）

在動物體內(nèi),脂類物質(zhì)有著多重復(fù)雜的功能,例如作為能源物質(zhì)、細(xì)胞膜的組分等。動物產(chǎn)品中的脂類物質(zhì)與人類健康又有著密切的關(guān)系,例如乳脂成分和含量影響著乳制品的品質(zhì),進(jìn)而影響人類健康。近年來研究表明,動物體內(nèi)的脂類物質(zhì)在動物體內(nèi)的合成過程均受到固醇調(diào)控元件結(jié)合蛋白（sterol-regulation element binding proteins, SREBPs）的調(diào)控[1]。SREBPs能激活參與脂類（固醇類、脂肪酸、甘油三酯等）合成一連串酶的轉(zhuǎn)錄[2],是公認(rèn)的脂類物質(zhì)合成的關(guān)鍵調(diào)節(jié)因子。本文針對SREBPs的結(jié)構(gòu)功能、組織分布、合成調(diào)節(jié)以及其對乳脂合成的調(diào)節(jié)進(jìn)行全面綜述。

1 SREBPs的結(jié)構(gòu)、功能與組織分布

1.1 SREBPs的結(jié)構(gòu)

SREBPs是調(diào)控膽固醇和脂肪酸合成及體內(nèi)平衡的膜錨定轉(zhuǎn)錄因子[3-4],屬于螺旋-環(huán)螺旋亮氨酸拉鏈家族（basic helix-loop-helix-leucine zip-per fam ily,bHLH-LZ）[5]。SREBPs的無活性前體蛋白結(jié)合于內(nèi)質(zhì)網(wǎng)膜上,約由1 150個(gè)氨基酸組成。整個(gè)蛋白質(zhì)分為3個(gè)結(jié)構(gòu)域:1）N端480個(gè)氨基酸區(qū)域,內(nèi)包含轉(zhuǎn)錄激活區(qū)、富含絲氨酸和脯氨酸區(qū)、bHLH-LZ區(qū);2）2個(gè)伸入到內(nèi)質(zhì)網(wǎng)內(nèi)腔的疏水跨膜片段,這2個(gè)跨膜片段之間被一個(gè)約30個(gè)氨基酸大小的短環(huán)隔開;3）羧基端約590個(gè)氨基酸的區(qū)域,該區(qū)域是主要的調(diào)節(jié)區(qū)域,并且在羧基端形成了一個(gè)復(fù)雜的、能緊密結(jié)合于SREBPs裂解激活蛋白（SREBPs-cleacage-activating protein,SCAP）的區(qū)域,起到固醇感受器的作用[6-7]。目前發(fā)現(xiàn),SREBPs由2個(gè)基因編碼合成3個(gè)亞型SREBP-1a、SREBP-1c和SREBP-2,其中SREBP-1a和SREBP-1c來源于同一個(gè)基因SREBP-1,由于轉(zhuǎn)錄的起始位點(diǎn)不同使得SREBP-1a比SREBP-1c少了一段氨基酸序列,而SREBP-2亞型來源于單獨(dú)的基因SREBP-2基因[8],與SREBP-1基因擁有45%的同源序列[9]。

1.2 SREBPs的功能與組織分布

SREBPs的3個(gè)亞型具有不同轉(zhuǎn)錄激活作用。SREBP-1c主要調(diào)節(jié)脂肪酸合成和胰島素介導(dǎo)的葡萄糖代謝,尤其是脂肪形成;而SREBP-2主要與膽固醇代謝密切相關(guān);SREBP-1a兼?zhèn)淞松鲜龆叩淖饔肹4]。SREBP-1a的轉(zhuǎn)錄激活作用比SREBP-1c要強(qiáng),主要是因?yàn)樗腘端轉(zhuǎn)錄激活區(qū)域較長[10]。上述三者除了作用不同外,在組織內(nèi)的分布也有明顯的區(qū)別,在人和小鼠等哺乳動物體內(nèi),SREBP-1c是優(yōu)勢表達(dá)的亞型,尤其是在肝臟、白色脂肪組織、骨骼肌、腎上腺和大腦中含量比較高,而SREBP-1a主要在體外培養(yǎng)的細(xì)胞系或者是細(xì)胞增殖程度高的組織中表達(dá),例如脾臟和腸[11]。

2 SREBPs合成的調(diào)節(jié)

SREBPs合成的調(diào)節(jié)可以在不同的水平進(jìn)行,包括轉(zhuǎn)錄水平和轉(zhuǎn)錄后水平的調(diào)節(jié)。

2.1 SREBPs在轉(zhuǎn)錄水平的調(diào)節(jié)

影響SREBPs轉(zhuǎn)錄調(diào)節(jié)的因素很多,機(jī)制也相當(dāng)復(fù)雜,包括動物的營養(yǎng)水平、個(gè)別營養(yǎng)因子、激素、核激素受體和某些酶類等,這些因子相互制約和影響,形成了一個(gè)龐大、復(fù)雜、靈活、多變的SREBPs轉(zhuǎn)錄調(diào)節(jié)網(wǎng)絡(luò)。

在嚙齒動物的禁食后重新給飼的試驗(yàn)中,人們首次發(fā)現(xiàn)SREBP-1c的轉(zhuǎn)錄是可以調(diào)節(jié)的,給小鼠禁食后,小鼠的肝臟[12]、白色脂肪組織[13]和骨骼肌[14-15]中SREBP-1c的m RNA豐度明顯減少,說明動物營養(yǎng)水平的高低可以調(diào)節(jié)SREBP-1c轉(zhuǎn)錄。但是對SREBPs的其他亞型沒有明顯影響。

有試驗(yàn)證明胰島素能誘導(dǎo)SREBP-1c的轉(zhuǎn)錄。例如,在離體的脂肪細(xì)胞[13]、肝細(xì)胞[16]中加入胰島素,發(fā)現(xiàn)SREBP-1c的轉(zhuǎn)錄上調(diào),在人體的脂肪組織和肌肉中也有類似發(fā)現(xiàn)[17-18]。將糖尿病小鼠與正常小鼠相比較,SREBP-1c的轉(zhuǎn)錄活性降低,注入胰島素后,SREBP-1c的轉(zhuǎn)錄會明顯上調(diào)[19]。由此可見,不論是離體細(xì)胞還是活體動物中,胰島素都有誘導(dǎo)SREBP-1c轉(zhuǎn)錄的作用。其效應(yīng)途徑可能是通過3-磷脂酰肌醇激酶[phosphatidy l inositol 3 kinase,PI（3）-K]來實(shí)現(xiàn)的[20-21],并且有資料顯示其下游作用元件可能是蛋白激酶B（protein kinase B, PKB）和蛋白激酶C（protein kinase C, PKC）[21-24]。

肝臟X受體α（liver X receptorα,LXRα）是一種核激素受體,它可以被氧化固醇激活（膽固醇的衍生物）,激活的LXRα可以誘導(dǎo)SREBP-1c的轉(zhuǎn)錄。有研究證明,缺乏LXRα的動物,SREBP-1c呈現(xiàn)出了較低的基因表達(dá)量,但是肝臟X受體β（liver X receptorβ,LXRβ）基因的敲除,卻對SREBP-1c的轉(zhuǎn)錄無影響[25-26]。飼喂動物高膽固醇飼糧或者是LXRα促效藥都能激活LXRα,從而促進(jìn)SREBP-1c的轉(zhuǎn)錄[26-28],有人曾提出,LXRα誘導(dǎo)SREBP-1c轉(zhuǎn)錄是為了使其進(jìn)一步誘導(dǎo)脂肪酸的合成,能使得更多的脂肪酸和游離的膽固醇結(jié)合生成膽固醇酯,使過高的膽固醇濃度得到緩解[29]。LXRα也可以直接誘導(dǎo)個(gè)別脂肪酸生成基因的轉(zhuǎn)錄,例如脂肪酸合成酶（fat acid synthetase,FAS）[30]、乙酰輔酶A羧化酶（acetyl CoA carboxylase,ACC）[31]。但是飼喂SREBP-1c基因無效的小鼠（SREBP-1c null mice）LXRα促效藥卻不能有效促進(jìn)脂肪酸合成[32],這說明SREBP-1c是LXRα誘導(dǎo)脂肪酸合成的必要中間元件。

也有資料顯示雄性激素和孕酮能誘導(dǎo)SREBP-1c的轉(zhuǎn)錄[33-35],但機(jī)理尚無報(bào)道,一般認(rèn)為這些激素有誘導(dǎo)脂肪合成的作用,而SREBP-1c被認(rèn)為是這一誘導(dǎo)過程中的中間調(diào)節(jié)物。

此外,一磷酸腺苷活化蛋白激酶（AM P-activated protein kinase,AMPK）對SREBP-1c的轉(zhuǎn)錄有抑制作用[36]。AMPK是一種催化AMP生成ATP的酶,通常在動物體供能不足的情況下,AMPK活性增強(qiáng),此時(shí),往往伴隨著動用體脂分解供能,因此AM PK活性增強(qiáng)會促進(jìn)脂肪酸分解,并通過抑制SREBP-1c的轉(zhuǎn)錄來抑制脂肪酸合成。

至于SREBP-1a和SREBP-2的轉(zhuǎn)錄,常在固醇缺乏的情況下被激活,SREBP-1a的轉(zhuǎn)錄激活通常在體外培養(yǎng)的細(xì)胞中實(shí)現(xiàn)[11]。而SREBP-2的轉(zhuǎn)錄主要是通過一個(gè)前饋機(jī)制,在SREBP-2基因中有固醇調(diào)節(jié)元件（stero l regulation elem ent,SRE）,細(xì)胞核中的SREBP-2（nSREBP-2）結(jié)合于SRE上,能激活SREBP-2自身的轉(zhuǎn)錄[37],有資料顯示SREBP-1c也有類似的前饋調(diào)節(jié)[38-39]。

2.2 SREBPs在轉(zhuǎn)錄后水平的調(diào)節(jié)

SREBPs轉(zhuǎn)錄后水平的調(diào)節(jié),概括起來可以分為3個(gè)途徑:固醇介導(dǎo)的SCAP/SREBPs復(fù)合物從內(nèi)質(zhì)網(wǎng)到高爾基體的轉(zhuǎn)運(yùn)和加工活化過程,活化后的SREBPs的修飾過程以及泛素-26S蛋白酶體對活性nSREBPs的降解作用。

SREBPs翻譯后的加工活化過程主要受細(xì)胞內(nèi)固醇水平的調(diào)節(jié)。SREBPs基因轉(zhuǎn)錄成m RNA后,繼而被翻譯成蛋白質(zhì),該蛋白質(zhì)無生物活性,被稱為SREBPs的前體蛋白。SREBPs前體蛋白與SCAP緊密結(jié)合并錨定在內(nèi)質(zhì)網(wǎng)膜上。當(dāng)細(xì)胞內(nèi)固醇含量較充足時(shí),SCAP與內(nèi)質(zhì)網(wǎng)上的insig蛋白（insulinsensitive protein,一種胰島素敏感蛋白）結(jié)合,使得SREBPs前體蛋白停留在內(nèi)質(zhì)網(wǎng)膜上,不參加后續(xù)的加工過程;當(dāng)細(xì)胞內(nèi)固醇含量低于生理要求時(shí), SCAP與insig蛋白斷裂,此時(shí)SCAP起到一個(gè)運(yùn)輸和伴侶蛋白的作用,以小泡的形式運(yùn)載著SREBPs前體蛋白到達(dá)高爾基體,在高爾基體的加工過程主要是由水解酶S1P（site 1 protease）和S2P（site 2 p rotease）起作用,經(jīng)2步水解反應(yīng),釋放出N端的轉(zhuǎn)錄激活區(qū)[40]。加工后的蛋白質(zhì)是一個(gè)二聚體,稱之為成熟的SREBPs,經(jīng)細(xì)胞內(nèi)核質(zhì)轉(zhuǎn)運(yùn)受體（importinβ,負(fù)責(zé)細(xì)胞內(nèi)大部分蛋白質(zhì)和核酸分子的跨核膜轉(zhuǎn)運(yùn)）運(yùn)輸進(jìn)入細(xì)胞核[41]內(nèi)發(fā)揮作用。

成熟的SREBPs進(jìn)入細(xì)胞核后,還要經(jīng)過一系列的修飾才能發(fā)揮作用。在細(xì)胞核內(nèi),成熟的SREBPs轉(zhuǎn)錄激活作用一般通過共價(jià)鍵修飾或者通過與其他蛋白質(zhì)的相互作用來調(diào)節(jié)[13]。進(jìn)一步研究發(fā)現(xiàn),胰島素也能調(diào)節(jié)細(xì)胞核內(nèi)成熟的SREBP-2和SREBP-1a的轉(zhuǎn)錄激活作用,這一調(diào)節(jié)主要通過活化的促細(xì)胞分裂蛋白激酶（m itogen-activated protein kinase,MAPK）途徑來實(shí)現(xiàn)。Ser-117是成熟的SREBP-1a的MAPK途徑的磷酸化位點(diǎn)[42]。體內(nèi)和體外的試驗(yàn)結(jié)果證明:成熟SREBP-2的磷酸化位點(diǎn)是Ser-432和Ser-455[43]。但是,成熟SREBPs通過MAPK途徑的磷酸化來調(diào)節(jié)轉(zhuǎn)錄激活的說法是有爭議的,Ser-117也存在于SREBP-1c中,試驗(yàn)卻證明了,SREBP-1c并沒有通過MAPK的磷酸化途徑來調(diào)節(jié)轉(zhuǎn)錄激活[44-45]。

具有轉(zhuǎn)錄催化活性的SREBPs在細(xì)胞核內(nèi)還要受到泛素-26S蛋白酶體的快速降解。Botolin等[46]用試驗(yàn)證明加入26S的蛋白酶抑制劑后, SREBPs相對于未添加抑制劑組更加穩(wěn)定,目的基因的表達(dá)也相應(yīng)提高。

3 SREBPs對乳脂合成的調(diào)節(jié)

乳脂的成分很復(fù)雜,包括甘油三酯、甘油二酯、甘油一酯、甘油、游離脂肪酸和膽固醇等。其中甘油二酯、甘油一酯、甘油、長鏈脂肪酸是極低密度脂蛋白（V LDL）在乳腺毛細(xì)血管中在脂蛋白酯酶（LPL）的作用下分解生成,后被乳腺上皮細(xì)胞吸收,在乳腺上皮細(xì)胞內(nèi)重新合成甘油三酯;中短鏈脂肪酸和少量膽固醇是乳腺上皮細(xì)胞內(nèi)源合成的。Peterson等[47]用試驗(yàn)證明了,SREBPs也廣泛分布于牛的乳腺組織中,即在乳腺組織中,SREBPs可以調(diào)節(jié)乳脂的生成。SREBPs的不同亞型作用的靶基因不同,它通過對不同靶基因的轉(zhuǎn)錄調(diào)節(jié)作用來實(shí)現(xiàn)對乳脂的內(nèi)源合成和外源攝取的調(diào)節(jié):SREBP-1c優(yōu)先活化脂肪酸合成的相關(guān)酶,如FAS、ACC等,進(jìn)而影響乳腺組織內(nèi)中短鏈脂肪酸的內(nèi)源合成;而SREBP-2則優(yōu)先活化膽固醇生物合成的相關(guān)基因,如羥甲基戊二酸單酰CoA合酶（hydroxymet hylglutaryl CoA synthase HMG CoA synthase）和羥甲基戊二酸單酰CoA還原酶（hydroxym et hylglutaryl CoA reductase,HMG CoA reductase）等酶的基因[48-49],這些基因參與乳脂中的膽固醇酯的合成;另外,SREBPs的目的基因還包括脂肪酸轉(zhuǎn)運(yùn)蛋白（FATP）基因,甘油酯合成相關(guān)酶基因,例如:甘油-1-磷酸脂酰基轉(zhuǎn)移酶（AGPAT）基因,長鏈脂肪酸?；o酶A合成酶（ACSL）基因[50],這些基因分別與乳腺長鏈脂肪酸的外源吸收和乳中甘油酯的合成有關(guān)。綜上所述,SREBPs對乳脂含量和成分的調(diào)節(jié)有3個(gè)途徑:1）可以通過影響甘油酯合成原料（中短鏈脂肪酸和膽固醇）的合成來間接影響乳脂的合成;2）可以通過調(diào)節(jié)脂肪酸轉(zhuǎn)運(yùn)蛋白來調(diào)節(jié)乳腺對脂類物質(zhì)的吸收,進(jìn)而影響乳脂含量;3）直接調(diào)節(jié)甘油酯合成相關(guān)酶來調(diào)節(jié)乳脂的合成。

4 小 結(jié)

SREBPs與脂肪酸合成有著密切的關(guān)系, SREBPs在奶牛的乳腺組織中廣泛分布,對奶牛乳脂的調(diào)控有著重要意義。從分子水平探索SREBPs調(diào)控乳脂的機(jī)理,可為生產(chǎn)中常見的奶牛乳脂合成降低提供理論依據(jù),進(jìn)而起到指導(dǎo)生產(chǎn)的作用。

[1] SH IMANO H.Stero l regulatory element-binding p roteins（SREBPs）:transcrip tional regulators of lipid regulators of lipid synthetic genes[J].Progress in Lipid Research,2001,40（6）:439-452.

[2] MCPHERSON R,GAUTHIER A.Molecular regulation of SREBP function:the Insig-SCAP connection and iso form-specific modu lation of lipid synthesis[J].Biochem istry and Cell Biology,2004,82 （1）:201-211.

[3] HORTON JD,GOLDSTEIN J L,BROWN M S. SREBPs:activators o f the comp lete p rogram of cho lesterol and fatty acid synthesis in the liver[J]. The Journal of Clinical Investigation,2002,109: 1125-1131.

[4] DELPH INE E,BRONWYN H,PASCALE B,et al.SREBP transcrip tion factors:master regulators o f lipid homeostasis[J].Biochim ie,2004,86: 839-848.

[5] HUA X,SAKA IJ,HO Y K,et al.Hairpin orientation o f sterol regulatory elemen t-binding p rotein-2 in cellmembranes as determ ined by protease protection[J].The Journal of Bio logical Chem istry, 1995,270:29422-29427.

[6] BROWN M S,GOLDSTEIN J L.The SREBP pathw ay:regulation o f cholestero l metabo lism by proteolysis o f amembrane-bound transcription factor[J].Cell,1997,89（3）:331-340.

[7] HORTON JD,SH IMOM URA I.Sterol regulatory elem ent-binding proteins:activators of cholestero l and fatty acid biosynthesis[J].Current Opinion in Lipidology,1999,10（2）:143-150.

[8] TONTONOZ P,K IM J B,GRAVES R A,et al. ADD 1:a novel helix-loop-helix transcrip tion factor associated with adipocy te determ ination and differentiation[J].Molecular and Cellular Biology,1993,13:4753-4759.

[9] HUA X,YOKOYAMA C,WU J,et al.SREBP-2,a second basic-helix-loop-helix-leuc ine zipper protein t hat stim ulates t ranscrip tion by binding to a sterol regulatory element[J].Proceedings of the National A cademy Sciences o f United States o f A-merica,1993,90（24）:11603-11607.

[10] SH IMANO H,HORTON J D,SH IMOMURA I, et al.Iso form 1c o f sterol regu latory element binding protein is less active than isoform 1a in livers of transgenic m ice and in cultured cells[J].The Journal o f Clinical Investigation,1997,99:846-854.

[11] SH IMOMURA I,SH IMANO H,HORTON J D, et al.D ifferential expression o f exons 1a and 1c in mRNAs for sterol regulatory element binding protein-1 in hum an andm ouse organs and cu ltured cells [J].The Journal o f Clinical Investigation,1997, 99:838-845.

[12] HORTON JD,BASHMAKOV Y,SH IMOMURA I,et al.Regulation of sterol regulatory element binding proteins in livers o f fasted and refed m ice [J].Proceedings of the National Academ y Sciences of United States of America,1998,95:5987-5992.

[13] KIM JB,SARRAF P,WRIGHT M,et al.Nutritional and insulin regu lation o f fatty acid synthetase and lep tin gene expression through ADD 1/SREBP-1[J].The Journal of C linical Investigation,1998, 101:1-9.

[14] BIZEAU M E,MACLEAN PS,JOHNSON G C, et al.Skeletal muscle stero l regulatory element binding p rotein-1c decreases with food dep rivation and increasesw ith feeding in rats[J].The Journal of Nutrition,2003,133:1787-1792.

[15] COMMERFORD S R,PENG L,DUBE J J,et al.In vivoregu lation of SREBP-1c in ske letalmuscle: effects of nutritional status,glucose,insulin,and lep tin[J].American Journal of Physiology Regulatory,Integrative and Comparative Physiology, 2004,287:R218-R227.

[16] FORETZ M,PACOT C,DUGA IL I,et al. ADD1/SREBP-1c is required in the ac tivation of hepatic lipogenic gene expression by glucose[J]. Mo lecular and Cellu lar Biology,1999,19:3760-3768.

[17] DUCLUZEAU P H,PERRETTI N,LAVILLE M,et al.Regulation by insulin of gene expression in human ske letalm uscle and adipose tissue.Evidence for specific de fects in type2 diabetes[J].D iabetes,2001,50:1134-1142.

[18] SEWTER C,BERGER D,CONSID INE R V,et al.H uman obesity and type2 diabetes are associated w ith alterations in SREBP1 isoform expression that are rep roducedex vivoby tumor necrosis factor-alpha[J].D iabetes,2002,51:1035-1041.

[19] SH IMOM URA I,BASHMAKOV Y,IKEM OTO S,et al.Insulin selectively increases SREBP-1c m RNA in the livers of rats with strep tozotocin-induced diabetes[J].Proceedings of the National A-cademy Sciences of United States o f Am erica, 1999,96:13656-13661.

[20] AZZO UT-M ARNICHE D,BECARD D,GUICHARD C,et al.Insulin ef fects on sterol regulatory-elem ent-binding p rotein-1c（SREBP-1c）transcrip tional activity in rathepatocy tes[J].The Biochem ical Journal,2000,350（Pt.2）:389-393.

[21] FLEISCHMANN M,IYNEDJIAN P B.Regulation o f stero l regu latorye lement binding p rotein 1 gene expression in liver:ro le of insulin and p rotein kinase B/cAkt[J].The Biochem ical Journal,2000, 349:13-17.

[22] RIBAUX P G,IYNEDIJIAN P B.Analysis of the role o f p rotein kinase B（cAKT）in insulin-dependent induction o f glucokinase and stero l regulatory element-binding protein 1（SREBP1）mRNAs in hepatocy tes[J].The Biochem ical Journal,2003, 376:697-705.

[23] MATSUMOTO M,OGAWA W,AK IMOTO K,et al.PKC lam bda in liver mediates insulin-induced SREBP-1c expression and determ ines both hepatic lipid content and overall insu lin sensitivity[J].The Journal of Clinical Investigation,2003,112:935-944.

[24] PORSTM ANN T,GRIFFITHS B,CHUNG Y L, et al.PKB/Ak t induces transcription of enzymes involved in cholesterol and fatty acid biosynthesis via activation o f SREBP[J].Oncegene,2005,24 （43）:6465-6481.

[25] PEET D J,TURLEY SD,MA W,et al.Cholesterol and bile acidmetabolism are impaired inm ice lacking the nuclear oxystero l recep tor LXR alpha [J].Cell,1998,93:693-704.

[26] REPA J J,LIANG G,OU J,et al.Regulation of mouse sterol regulatory element-binding protein-1c gene（SREBP-1c）by oxysterol recep tors,LXR alpha and LXR beta[J].Genes and Developm ent, 2000,14:2819-2830.

[27] SCHULTZ J R,TU H,LUK A,et al.Role of LXRs in control of lipogenesis[J].Genes and Development,2000,14:2831-2838.

[28] LAFFITTE B A,CHAO L C,LI J,et al.Activation o f liver X recep tor imp roves glucose tolerance through coordinate regulation o f g lucose metabolism in liver and adipose tissue[J].Proceedings of the National A cadem y Sciences o f United States of America,2003,100:5419-5424.

[29] REPA J J,LIANG G,OU J,et al.Regulation of mouse stero l regulatory elementbinding p rotein-1c gene（SREBP-1c）by oxysterol receptors,LXR alpha and LXR beta[J].Genes Developmen t,2000, 14:2819-2830.

[30] JOSEPH SB,LAFFITTE B A,PATEL PH,et al. Direct and indirect mechanisms for regulation of fatty acid synthase gene expression by liver X recep tors[J].The Journal o f Biological Chem istry, 2002,277:11019-11025.

[31] ZHANG Y,YIN L,HILLGARTNERF B.SREBP-1 integrates the ac tions of thyroid hormone,insu lin, cAMP,and medium-chain fatty acids on ACC alpha transcrip tion in hepatocy tes[J].Journal of Lipid Research,2003,44:356-368.

[32] LIANG G,YANG J,HORTON JD,et al.D im inished hepatic response to fasting/refeeding and liver X receptor agonists in m ice with selective deficiency o f sterol regu latory element-binding p rotein-1c[J].The Journal o f Bio logical Chem istry,2002, 277:9520-9528.

[33] HEEMERS H,MAES B,FOUFELLE F,et al. Androgens stimulate lipogenic gene expression in prostate cancer cells by ac tivation of the sterol regu latory element-binding p rotein cleavage activating p rotein/sterol regulatory element-binding p rotein pathw ay[J].Molecular Endocrinology,2001,15: 1817-1828.

[34] HEEM ERS H,VANDERHOYDONC F,ROSKAMS T,etal.Androgens stimulate coordinated lipogenic gene exp ression in norm al target tissuesin vivo[J].M olecular and Cellular Endocrinology, 2003,205:21-31.

[35] LACASA D,LE LIEPVRE X,FERRE P,et al. Progesterone stim ulates adipocyte determ ination and dif ferentiation 1/sterol regulatory e lem entbinding protein 1c gene exp ression.Potential mechanism for the lipogenic effect o f progesterone in adipose tissue[J].The Journal o f Bio logical Chem istry,2001,276:11512-11516.

[36] MCFADDEN JW,CORL B A.Activation of AMP-activated p rotein kinase（AMPK）inhibits fatty acid synthesis in bovine mamm ary epithelial cells[J]. Biochem istry and Biophysical Research Communication,2009,390（3）:388-393.

[37] SATO R,INOUE J,KAWABE Y,et al.Steroldependen t transcrip tional regulation of stero l regulatory element-binding p rotein-2[J].The Journal o f Bio logical Chem istry,1996,271:26461-26464. [38] AMEM IYA-KUDO M,SHIMANO H,YOSHIKAWA T,et al.Promoter analysis of themouse sterol regu latory elementbinding p rotein-1c gene[J].The Journal o f Biological Chem istry,2000,275: 31078-31085.

[39] HORTON JD,GOLDSTEIN J L,BROWN M S. SREBPs:activators o f the comp lete p rogram of cho lesterol and fatty acid synthesis in the liver[J]. The Journal of Clinical Investigation,2002,109: 1125-1131.

[40] RAWSON R B.The SREBP pathw ay-insights from Insigs and insec ts[J].Nature Reviews M olecular Cell Biolog,2003,4（8）:631-640.

[41] LEE S J,SEK IMOTO T,YAMASH ITA E,et al. The struc ture of im portin-beta bound to SREBP-2: nuclear import of a transcription factor[J].Science,2003,302:1571-1575.

[42] ROTH G,KOTZKA J,KREMER L,et al.MAP kinases Erk1/2 phosphory late sterol regulatory element-binding p rotein（SREBP）-1a at serine 117in vitro[J].The Journal of Biological Chem istry, 2000,275:33302-33307.

[43] KOTZKA J,LEHRS,ROTH G,etal.Insulin-ac-tivated Erk-m itogen-activated protein kinases phosphory late sterol regulatory element-binding protein-2 at serine residues 432 and 455in vivo[J]. The Journal of Biological Chem istry,2004,279: 22404-22411.

[44] WANG D,SUL H S.Insulin stimulation o f the fatty acid synthase p rom oter is mediated by the phosphatidylinositol 3-kinase pathw ay.Involvement of protein kinase B/Ak t[J].The Journal of Biological Chem istry,1998,273:25420-25426.

[45] IYNEDJIAN P B,ROTH R A,FLEISCHMANN M,et al.Ac tivation o f p rotein kinase B/cAk t in hepatocytes is suf ficient for the induction of exp ression of the gene encoding glucokinase[J].The Biochem ical Journal,2000,351（Pt.3）:621-627. [46] BOTOLIN D,WANG Y,CHRISTIAN B,et al. Docosahexaneoic acid（22∶6,n-3）regu lates rat hepatocyte SREBP-1 nuclear abundance by Erkand 26S proteasome-dependent pathw ays[J].Journal o f Lipid Research,2006,47:181-190.

[47] PETERSON D G,MATITASHV ILI E A,BAUMAN D E.The inhibitory effect o ftrans-10,cis-12 CLA on lipid synthesis in bovinem ammary epithelial cells invo lves reduced proteolytic activation o f the transcrip tion factor SREBP-1[J].The Journal o f Nutrition,2004,134:2523-2527.

[48] PAI J,GURYEV O,BROWN M S,et al.Differential stimu lation o f cholestero l and unsaturated fatty acid biosynt hesis in cells exp ressing individual nuclear sterol regulatory element-binding proteins [J].The Journal o f Biological Chem istry,1998, 273（40）:26138-26148.

[49] HORTON JD,SH IMOMURAL I,BROWN M S, et al.Activation o f cholesterol synthesis in p reference to fatty acid synt hesis in liver and adipose tissue of t ransgenic m ice overproducing sterol regulatory element-binding p rotein-2[J].The Journal of Clinical Investigation,1998,101（11）:2331-2339. [50] BIONAZ M,LOOR JJ.ACSL1,AGPAT 6,FABP3, LPIN1,and SLC27A 6 are the most abundant isoforms in bovine mammary tissue and their expression is af fected by stage of lactation[J].The Journalof Nutrition,2008,138:1019-1024.

*Correspond ing au thor,p rofessor,E-m ail:w ryang@sdau.edu.cn

（編輯 武海龍）