徐子葉,吳緯澈,汪以真,單體中
(浙江大學動物分子營養(yǎng)學教育部重點實驗室,浙江大學飼料科學研究所,浙江杭州 310058)
豬肉品質與安全是目前我國養(yǎng)豬業(yè)發(fā)展亟待解決的關鍵問題之一。豬肉品質主要受肌內脂肪含量、肌纖維數(shù)量和肌纖維直徑及肌纖維類型等因素影響,其中,肌內脂肪含量與豬肉的感官品質和食用品質密切相關,直接影響著肉的風味、多汁性、嫩度、色澤。低含量的肌內脂肪嚴重影響了肉的風味和口感,且往往與豬的PSE(Pale,Soft,Exudative)肉發(fā)生率相關。一般認為豬肉的理想肌內脂肪含量約為2.5%~3.0%。因此,如何在保證瘦肉率、不提高皮下脂肪的前提下適當提高肌內脂肪含量和生產(chǎn)優(yōu)質豬肉,是改善豬肉品質的關鍵和難點所在。目前,肌內脂肪細胞來源及其分化沉積調控等已成為研究熱點之一。本文主要從肌內脂肪細胞來源及其分化沉積調控的關鍵基因、信號通路等方面綜述了調控肌內脂肪沉積的分子機制的相關研究進展。
在哺乳動物中,主要有棕色、米色和白色3種脂肪細胞。骨骼肌細胞和棕色脂肪細胞主要來源于Myf5+和Pax3+肌源性祖細胞[1-2],皮下脂肪、腹部脂肪等白色脂肪細胞則主要來源于Myf5-和Pax3-非肌源性祖細胞[2-3]。關于肌內脂肪細胞起源和祖細胞譜系的研究報道較少,早期的研究認為肌內脂肪細胞可能由肌衛(wèi)星細胞分化而來[4]。然而,通過遺傳譜系分析研究發(fā)現(xiàn),肌內脂肪細胞起源于MyoD-、Myf5-和Pax3-非肌源性祖細胞[5-6],表明肌內脂肪細胞可能由間充質干細胞或其他類型干細胞分化而來,是一種分布于肌肉組織內的Myf5-和Pax3-白色脂肪細胞[5]。Uezumi等[7]從骨骼肌中成功分離出了在體外可以高效分化成脂肪細胞的PDGFRα+間充質干細胞。另外,骨骼肌中的其他細胞種類如周細胞(Pericytes)、SP細胞(Side Population Cells)、成纖維細胞等也可以分化成脂肪細胞[8]。綜上所述,肌內脂肪細胞是由PDGFRα+間充質干細胞、周細胞、SP細胞等多種來源的干細胞或祖細胞分化而來的,但由于這些干細胞或祖細胞亞群本身存在異質性,因此關于肌內脂肪細胞的確切來源仍需進一步探究。
影響肌內脂肪沉積的因素主要包括品種、營養(yǎng)、環(huán)境等。遺傳、環(huán)境和營養(yǎng)等因素對動物肌內脂肪沉積的影響及調控,離不開動物機體中相關基因及相關信號網(wǎng)絡的參與,動物分子營養(yǎng)調控脂質代謝及肌內脂肪沉積的機制最終也通過影響基因及基因網(wǎng)絡實現(xiàn)。
2.1 肌內脂肪沉積相關候選基因 與肌內脂肪沉積相關的候選基因包括脂肪酸結合蛋白基因(FABPs)、脂蛋白酯酶(LPL)、激素敏感脂酶(HSL)等,對這些基因的功能已有較多的研究。隨著測序方法的不斷進步和研究的不斷深入,越來越多的候選基因已被挖掘和鑒定。最近對金華豬和長白豬品種差異研究結果表明,F(xiàn)LJ36031和pFAM134B等品種差異基因可正調控肌內脂肪細胞的分化聚酯[9-10]。在沙子嶺豬和大約克豬肌肉中,糖脂代謝相關基因(ENO1、ENO3、ATP5B和TPI1)和肌纖維蛋白合成相關基因(MYLPF、ACTA1和ACTC1)的表達存在顯著差異,提示這些基因可能與肌內脂肪沉積相關[11]。其他研究發(fā)現(xiàn),Pias3、Diras3、Hoxa9、Atp2a2等基因表達與牛的肌內脂肪沉積和大理石紋密切相關[12]。鋅指蛋白Zfp423的表達可以影響牛的肌內脂肪沉積[13-14]。
2.2 Lkb1-AMPK信號通路 AMPK(AMP-activated protein kinase)是細胞重要的能量感受器,調節(jié)代謝和能量平衡。大量研究表明,AMPK通過Wnt/β-catenin、mTORC1、MAPK和SIK等信號通路,調控脂肪前體細胞分化聚酯相關基因(PPARγ、C/EBPα、FAS、SREBP-1c等)的表達,表明AMPK可能是調控肌內脂肪合成的一條最重要的信號通路[15-16]。在骨骼肌中,AMPK激活可以通過磷酸化ACC2增加糖攝取,增強脂肪氧化,減少甘油三酯的合成[17]。最近的研究發(fā)現(xiàn),AMPK可以通過FTO調控mRNA的m6A去甲基化修飾,調節(jié)骨骼肌細胞中的脂滴聚集[18]。另外,飼料中添加亮氨酸等能通過AMPK及其信號轉導途徑,調控肌內脂肪含量,改善豬肉品質[19];而白藜蘆醇、低聚糖等可以通過Sirt1-AMPKα-FOXO1信號通路抑制肌內脂肪細胞的脂肪形成[20-21]。
Lkb1(Liver kinase B1)是一種絲氨酸/蘇氨酸蛋白激酶,可直接磷酸化并激活AMPK活性,還可以磷酸化調控SIK等其他12種AMPK家族的相關激酶[22],
在控制和調節(jié)細胞能量代謝、脂質沉積等過程中發(fā)揮著重要作用。激活Lkb1-AMPK通路會下調PPARγ、C/EBPα、SREBP-1c、FAS和FABP4的表達,抑制前體脂肪細胞的分化和脂肪形成[23]。而敲除Lkb1則會促進CREB調控轉錄輔活化因子2(CRTC2)和組蛋白去乙?;福℉DACs)的去磷酸化,促進前體脂肪細胞和胚胎成纖維細胞的分化聚酯[24]。最近的研究發(fā)現(xiàn),Lkb1可通過調控mTOR和CRTC3信號通路調控脂肪前體細胞分化聚酯及糖脂代謝[25]。另外,Lkb1可以通過AMPK和GSK3β等信號通路影響肌肉干細胞增殖和成肌分化[26],并可以通過AMPK調控肌肉細胞中的脂質代謝和脂肪沉積[27]。
2.3 Sirt1信號通路Sirt1(Sirtuin type 1)是一種重要的去乙酰化酶,與細胞增殖、分化、衰老、凋亡和代謝密切相關。研究發(fā)現(xiàn),豬Sirt1基因可以通過提高ATGL等基因的表達降低豬脂肪細胞中的脂滴沉積[28-30]。在豬肌內脂肪前體細胞和肌內脂肪細胞中,Sirt1正調控PPARγ、ATGL、HSL的表達,促進肌內脂肪前體細胞分化和肌內脂肪細胞脂肪分解[31]。
2.4 cAMP-PKA信號通路 cAMP-PKA信號通路通過下游的cAMP反應元件結合蛋白(CREB)和它的共激活劑轉錄輔活化因子(CRTCs)發(fā)揮作用,與能量平衡調節(jié)密切相關。激活cAMP-PKA信號通路可以上調HSL,促進脂肪細胞的脂肪分解[32]。CRTC3是CRTCs家族的一個成員,調控葡萄糖和能量代謝。Song等[33]發(fā)現(xiàn),CRTC3缺失小鼠的白色脂肪細胞體積變小,脂肪分解增強。棕色脂肪中Lkb1缺失可以引起CRTC3從胞質轉運至胞核,上調C/EBPβ的轉錄活性,進而增加UCP1表達[25]。肌肉組織中過表達CRTC3能通過上調二酰甘油?;D移酶1(Dgat1)增加肌肉內的甘油三酯沉積[34]。另外,肌肉特異性過表達CRTC2也能增加肌纖維橫截面積和肌內脂肪含量[34]。
2.5 MAPK信號通路 絲裂原活化蛋白激酶(Mitogen Activated Protein Kinase,MAPK)通路,包括細胞外信號調節(jié)激酶 1 和 2(Erk1/2或p44/42)、c-Jun 氨基末端激酶 1-3 (JNK1-3)/應激激活蛋白激酶 (SAPK1A、SAPK1B、SAPK1C)、p38 異構體(p38α、p38β、p38γ和 p38δ)以及Erk5,在脂肪細胞的分化過程中發(fā)揮著重要的作用。研究發(fā)現(xiàn),CTRP6通過AdipoR1/MAPK信號通路抑制豬肌內脂肪細胞增殖,促進其分化[35]。
在肌肉損傷修復模型實驗中發(fā)現(xiàn),抑制p38會顯著減少肌肉修復過程中的肌內脂肪沉積[36]。在肉雞肌肉中,脂聯(lián)素(Adiponectin)通過p38/ATF2信號通路調控肌內脂肪含量[37]。最新的蛋白組學技術發(fā)現(xiàn),MAPK信號通路參與牛肌內脂肪沉積的調控[38]。
2.6 Wnt/β-catenin信號通路 Wnt/β-catenin信號通路的核心成分β-catenin是一種多功能蛋白,可調控C/EBPα、PPARγ影響脂肪細胞分化[39]。過表達脂肪酸運輸?shù)鞍踪|1(FATP1)通過抑制Wnt/β-catenin信號通路促進豬前體肌內脂肪的增殖和肌內脂肪沉積[40]。飼料中添加的精氨酸通過抑制Wnt/β-catenin信號通路,促進豬前體肌內脂肪的分化[41]。二十碳五烯酸(EPA)可以通過抑制Wnt信號通路,上調PPARγ2表達量,促進成肌細胞向脂肪細胞轉化[42]。另外發(fā)現(xiàn)Wnt/β-catenin信號通路與牛、雞的肌內脂肪沉積相關[43-44]。
2.7 Hedgehog信號通路 Hedgehog信號通路調控發(fā)育和疾病的多個方面,調控前體細胞的不同分化命運。激活Hedgehog信號可以下調脂肪分化關鍵基因(C/EBPα、PPARγ)和成熟脂肪標記蛋白(Leptin、aP2)的表達,抑制前體脂肪細胞、多功能間充質干細胞的成脂分化[45-46]。在肌肉損傷修復過程中,Hedgehog信號可以抑制前體細胞向脂肪細胞轉化,抑制骨骼肌中脂肪形成[47]。
2.8 非編碼RNA 高通量測序發(fā)現(xiàn)了一些豬肌內脂肪細胞和皮下脂肪細胞中表達差異顯著的microRNA。研究發(fā)現(xiàn),miR-27b能夠靶向PPARγ調控豬肌內脂肪細胞的分化[48]。miR-125a-5p可靶向調控豬KLF13和ELOVL6,影響豬肌內脂肪細胞的增殖、分化和肌內脂肪的脂肪酸含量[49]。miR-425-5p靶向KLF13抑制豬前體肌內脂肪細胞的增殖和分化[50]。miR-130a通過抑制PPARγ表達調控豬肌內脂肪的脂質沉積[51]。miR-196a/b在皖南花豬和約克夏豬中表達有顯著差異,可能參與調控豬肌內脂肪的形成[52]。另外,lncRNA等非編碼RNA也可能影響動物肌內脂肪沉積[53-54]。
綜上所述,國內外關于肌內脂肪細胞來源及其分化沉積調控的分子機制等方面的研究已取得了較大的研究進展。但由于肌內脂肪細胞發(fā)生、發(fā)展及其沉積是一個復雜的生理生化過程,肌內脂肪分化沉積調控方面的研究中仍然存在一些關鍵問題和可能的突破點,如:肌內脂肪細胞的確切來源需進一步通過遺傳譜系分析等技術明確;肌內脂肪沉積相關候選基因、主效基因需深入挖掘和鑒別;肌內脂肪沉積關鍵窗口期及其生理生化機制需深入探究;我國優(yōu)良地方品種豬(如金華豬、萊蕪豬等)高肌內脂肪沉積的分子機制、遺傳參數(shù)等需進一步解析;肌肉與肌內脂肪之間互作調控機制如何需探明;關鍵信號通路及調控網(wǎng)絡、非編碼RNA、表觀遺傳等在調控肌內脂肪細胞命運決定及分化聚酯中的功能需深入探究;肌內脂肪沉積關鍵信號網(wǎng)絡的精準營養(yǎng)調控技術體系需研究建立等。相信隨著現(xiàn)代分子生物學技術的飛速發(fā)展,對影響肌內脂肪沉積的關鍵基因及信號通路的研究將會更加深入,肌內脂肪含量的分子調控網(wǎng)絡將會更清晰透徹,這將為通過基因編輯技術和新型分子育種技術培育優(yōu)質畜禽新品種提供思路和科學依據(jù),也為通過精準營養(yǎng)靶向分配技術調控動物肌內脂肪特異性沉積奠定基礎,對生產(chǎn)優(yōu)質、安全高端肉產(chǎn)品以滿足人們對優(yōu)質生態(tài)產(chǎn)品的需求具有重要的意義。
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