血脂紊亂與骨代謝

中南大學(xué)湘雅二醫(yī)院 蘇甜 羅湘杭

引 言

人口老齡化已經(jīng)成為全球關(guān)注的問題，伴隨而來的是動(dòng)脈粥樣硬化(atherosclorosis，AS)和骨質(zhì)疏松(osteoporosis，OP)患病率的增加。在過去10年中，不斷有研究表明，動(dòng)脈粥樣硬化和骨質(zhì)疏松有關(guān)聯(lián)[1-4]。在骨質(zhì)疏松患者中，動(dòng)脈鈣化也很普遍[5]，并且動(dòng)脈鈣化的進(jìn)程和骨量減少的速度是一致的[1,2]。而且，脈搏波傳導(dǎo)速率的增加(反映動(dòng)脈鈣化的一個(gè)指標(biāo)[6])與骨密度和跟骨的骨定量超聲骨質(zhì)測(cè)量參數(shù)呈負(fù)相關(guān)[7]。這些研究都提示我們，心血管疾病和骨質(zhì)疏松通過一些共同作用于血管和骨細(xì)胞的因素而相互關(guān)聯(lián)。脂肪被公認(rèn)為是動(dòng)脈粥樣硬化和心血管疾病的危險(xiǎn)因素[8]。本文就脂代謝與骨代謝的關(guān)系予以綜述，旨在為骨質(zhì)疏松的治療提供一定的依據(jù)。

脂代謝通路與骨代謝通路

脂肪細(xì)胞和成骨細(xì)胞共同起源于骨髓基質(zhì)細(xì)胞[9]。脂肪細(xì)胞和成骨細(xì)胞的生理平衡是通過一系列信號(hào)通路的調(diào)節(jié)而實(shí)現(xiàn)的。參與這些信號(hào)通路的調(diào)節(jié)因子包括過氧化物酶體增生物激活受體γ2(peroxisome proliferator-activated receptor γ2，PPARγ2)、核因子κB受體活化因子配體(receptor activator of nuclear factor κB ligand，RANKL)、核因子κB受體活化因子(receptor activator of nuclear factor κB，RANK)、骨保護(hù)素(osteoprotegerin，OPG)、Wnt/β-catenin 信號(hào)通路[10]。

PPARγ屬于配體依賴性的核受體超家族的成員，它可以調(diào)節(jié)目標(biāo)基因的表達(dá)[11]。PPARγ基因是決定骨髓多能干細(xì)胞向脂肪細(xì)胞、成骨細(xì)胞或破骨細(xì)胞分化的關(guān)鍵轉(zhuǎn)錄因子。PPARγ有兩種表達(dá)形式：PPARγ1，主要表達(dá)于巨噬細(xì)胞、結(jié)腸上皮細(xì)胞、內(nèi)皮細(xì)胞以及血管平滑肌細(xì)胞；PPARγ2主要表達(dá)于脂肪組織，調(diào)節(jié)脂肪生成[12-14]。脂代謝紊亂可以促使氧化性脂質(zhì)增加，而增加的氧化性脂質(zhì)可以激活骨髓PPARγ2，從而抑制成骨細(xì)胞和骨形成，促進(jìn)脂肪細(xì)胞的分化[15]。噻唑烷二酮類(thiazolidinediones，TZDs)藥物通過與PPARγ結(jié)合并激活其通路，從而刺激細(xì)胞向脂肪分化并抑制成骨分化[16]。也有一些研究報(bào)告，PPARγ可以抑制破骨細(xì)胞生成[17-19]。

Wnt蛋白是一類分泌型的富含半胱氨酸的糖基化蛋白，可在多種細(xì)胞中表達(dá)。Wnt/β-catenin信號(hào)通路是調(diào)節(jié)骨代謝的經(jīng)典通路。Laudes[20]研究發(fā)現(xiàn)，Wnt信號(hào)通路中幾個(gè)Wnt家族成員可以在脂肪形成的早期階段起到抑制作用，減少人類間充質(zhì)干細(xì)胞分化成前脂肪細(xì)胞。相反，Wnt通路的內(nèi)源性抑制物卻會(huì)提高脂肪細(xì)胞的形成而減少成骨細(xì)胞的分化。

OPG是一種可溶性糖蛋白，屬于腫瘤壞死因子超家族的成員[21]，它可以與RANK結(jié)合，從而抑制破骨細(xì)胞的生成[22]。Ayina等[23]研究發(fā)現(xiàn)，在肥胖女性中，高密度脂蛋白膽固醇(high density lipoproteincholesterol，HDL-C)與OPG呈正相關(guān)，低密度脂蛋白膽固醇(low density lipoprotein-cholesterol，LDL-C)與OPG呈負(fù)相關(guān)。該研究結(jié)果與Bennett等[24]的研究結(jié)果相一致，在動(dòng)物研究中，OPG是心血管的保護(hù)因素。但是在Ayina等[25]之前的研究中發(fā)現(xiàn)，在老年人群中，HDL-C 的濃度與OPG無關(guān)聯(lián)。

脂肪細(xì)胞因子與骨代謝

目前已經(jīng)有許多研究證實(shí)，脂肪細(xì)胞不僅僅是一個(gè)能量?jī)?chǔ)存器官，它同時(shí)也可以分泌很多生物活性細(xì)胞因子，我們稱之為脂肪細(xì)胞因子，包括纖溶酶原激活物抑制劑-1、腫瘤壞死因子-α(Tumor Necrosis Factor，TNF-α)、抵抗素、瘦素以及脂聯(lián)素。本文主要論述瘦素和脂聯(lián)素。

1. 瘦素

瘦素(Leptin)是由脂肪細(xì)胞分泌的蛋白質(zhì)類激素，主要由白色脂肪組織產(chǎn)生。瘦素作為脂肪組織的保護(hù)因素，目前已經(jīng)被認(rèn)成為是骨代謝的重要調(diào)節(jié)因素，但是瘦素對(duì)骨代謝的具體作用，各學(xué)者的研究結(jié)果不一。有文獻(xiàn)[26]報(bào)道，在編碼瘦素基因缺失的小鼠中，其骨形成和骨量是減少的。Thomas等人以及其他學(xué)者[27-29]研究報(bào)道，成骨細(xì)胞系也有瘦素的作用位點(diǎn)。瘦素可以誘導(dǎo)激活絲裂原活化蛋白激酶(mitogen-activated protein kinases，MAPK)通路，該通路的激活可以刺激成骨細(xì)胞的分化[30]及PPARγ，而PPARγ可以抑制脂肪生成[31]。而且，在人類成骨細(xì)胞培養(yǎng)實(shí)驗(yàn)中，瘦素可以通過抑制凋亡的作用而促進(jìn)成骨細(xì)胞的活動(dòng)[32]。有學(xué)者[33]曾報(bào)道，瘦素可以抑制RANKL的表達(dá)，從而抑制破骨細(xì)胞的生成；而且瘦素還可以刺激OPG的表達(dá)從而抑制骨吸收，促進(jìn)骨形成。瘦素也能夠促進(jìn)人類單核細(xì)胞分泌白細(xì)胞介素-1(interleukin-1，IL-1)[34]，而該受體拮抗劑可以減少與IL-1相關(guān)的骨轉(zhuǎn)換以及雌激素缺乏引起的骨量丟失。與這些研究結(jié)果一致的是，Cornish等[35]的研究也表明，與對(duì)應(yīng)的野生型小鼠相比，瘦素缺乏的ob/ob小鼠，其骨礦物質(zhì)含量(bone mineral conten，BMC)和骨密度(bone mineral density，BMD)較低[29]。對(duì)下丘腦予以瘦素基因治療后，ob/ob小鼠骨量和骨長(zhǎng)度增加[35]。

盡管一些研究者報(bào)道，血清瘦素水平與BMD[36-41]或者BMC[42]呈正相關(guān)，但是其他學(xué)者卻未能發(fā)現(xiàn)兩組之間存在正關(guān)聯(lián)，甚至有些學(xué)者發(fā)現(xiàn)兩者呈負(fù)相關(guān)[42-45]。Ducy及其同事[48]研究發(fā)現(xiàn)，瘦素缺乏的ob/ob小鼠擁有更高的骨量。相反，向下丘腦注射瘦素后，其骨量減少，可能原因是瘦素促進(jìn)了骨吸收、抑制骨形成。有研究[38,40-42]發(fā)現(xiàn)，當(dāng)校正脂肪質(zhì)量以后，兩者之間的正相關(guān)關(guān)系就不存在了。

前文已述及瘦素可以增加OPG的生成，減少RANKL的表達(dá)，進(jìn)而抑制破骨細(xì)胞的分化，并可以抑制骨髓間充質(zhì)干細(xì)胞(bone marrow mesenchymal stem cells，BMSCs)向脂肪細(xì)胞的分化、促進(jìn)成骨細(xì)胞的分化。但是高水平的瘦素卻可以導(dǎo)致BMSCs的凋亡[46]，同時(shí)也可以增加骨吸收、減少骨形成。Hamrick等[47]提出這一假設(shè)：脂肪生成增加可以增加骨髓微環(huán)境瘦素的濃度，從而導(dǎo)致骨量減少。這也許可以解釋為何各學(xué)者關(guān)于瘦素與BMD關(guān)系的研究結(jié)果不一，其他的原因還包括種族的差異、研究人群的數(shù)量以及統(tǒng)計(jì)學(xué)方法的差異。

2. 脂聯(lián)素

脂聯(lián)素(Adiponectin，ADPN)是脂肪細(xì)胞分泌的一種內(nèi)源性生物活性多肽或蛋白質(zhì)。脂聯(lián)素又被稱作Acrp30、apM1、AdipoQ、GBP28，在分化的脂肪細(xì)胞中高度特異性表達(dá)，在血漿中含量豐富[48-50]。脂聯(lián)素是分子量為30KD的多肽，由氨基末端的分泌信號(hào)序列、一段特異序列、一組由22個(gè)氨基酸組成的膠原重復(fù)序列和一段球狀序列組成[48-50]。成熟的脂肪細(xì)胞和成骨細(xì)胞表達(dá)和分泌一些共同的因子，提示我們這些細(xì)胞之間存在密切聯(lián)系[51]。有研究[52]報(bào)道，脂聯(lián)素及其受體也可以在骨形成細(xì)胞中表達(dá)。這些研究可以表明，脂聯(lián)素可以將脂肪組織的信號(hào)傳遞到骨組織，但是脂聯(lián)素對(duì)骨代謝的影響，目前意見尚未統(tǒng)一。

在羅湘杭等[53]的研究中發(fā)現(xiàn)，脂聯(lián)素可以促進(jìn)成骨細(xì)胞的增殖和分化。這種增殖應(yīng)答反應(yīng)是由AdipoR/JNK信號(hào)通路調(diào)控，而分化應(yīng)答反應(yīng)是由AdipoR/p38 MAPK信號(hào)通路調(diào)控，這些發(fā)現(xiàn)表明人類破骨細(xì)胞是脂聯(lián)素的直接調(diào)控靶點(diǎn)。Kazuya Oshima等[54]也認(rèn)為脂聯(lián)素可以通過抑制破骨細(xì)胞生成、激活成骨細(xì)胞生成而增加骨量。

Kajimura等[55]研究認(rèn)為，根據(jù)作用部位和作用方式不同，脂聯(lián)素具有雙向作用：脂聯(lián)素直接作用于成骨細(xì)胞，會(huì)抑制成骨細(xì)胞的增殖；而在中樞信號(hào)通路中，脂聯(lián)素卻會(huì)促進(jìn)成骨細(xì)胞的增殖。羅湘杭等[56]在他們的另一研究中指出，脂聯(lián)素通過促進(jìn)成骨細(xì)胞RANKL的表達(dá)，抑制OPG的表達(dá)，間接促進(jìn)破骨細(xì)胞的形成。

在脂聯(lián)素過度表達(dá)的小鼠模型中，小鼠的骨量和骨形成增加，遠(yuǎn)高于野生型小鼠[57]。但是，Ealey等[58]卻發(fā)現(xiàn)了不一樣的結(jié)果，跟對(duì)照小鼠相比，脂聯(lián)素過度表達(dá)的小鼠其股骨的BMC和股骨頸的峰值負(fù)荷能力更低。另外有學(xué)者發(fā)現(xiàn)，在脂聯(lián)素編碼基因敲除的小鼠模型中，其骨量是增加的[59-62]。

由于脂聯(lián)素對(duì)骨代謝的影響意見尚未統(tǒng)一，還有待進(jìn)一步研究。

血脂異常與骨質(zhì)疏松

血脂異常指血漿中脂質(zhì)量和質(zhì)的異常。OP是一種以骨量降低和骨組織微結(jié)構(gòu)破壞為特征，導(dǎo)致骨脆性增加和易于骨折的的代謝性骨病。骨質(zhì)疏松癥的診斷主要是根據(jù)BMD和臨床表現(xiàn)。骨質(zhì)疏松在女性中的發(fā)病率要高于男性[63]，但是男性骨質(zhì)疏松性骨折卻比女性更為常見[64]，而且絕經(jīng)后女性骨質(zhì)疏松的發(fā)病率要高于絕經(jīng)前女性[65]。

血脂與BMD之間可能存在聯(lián)系，最初是因?yàn)樗☆愃幬飳?duì)BMD有正向作用而被逐漸發(fā)現(xiàn)的[66,67]。各類研究都表明，他汀類藥物(HMG-CoA還原酶抑制劑)可以增加骨密度，降低骨折發(fā)生率[68,69]。在Orozco等[70]的研究中發(fā)現(xiàn)，和血脂正常的女性相比，血脂異常的絕經(jīng)后女性腰椎和股骨骨密度較低，骨量減少的風(fēng)險(xiǎn)增加，提示高脂血癥與骨質(zhì)疏松相關(guān)。

之前有關(guān)骨密度和血清膽固醇(total cholesterol，TC)之間關(guān)系的研究缺乏一致性。有相關(guān)報(bào)道[71-74]指出骨密度和血清膽固醇之間無密切聯(lián)系，即血清膽固醇對(duì)骨細(xì)胞的代謝無顯著作用。但是動(dòng)物實(shí)驗(yàn)和臨床實(shí)驗(yàn)均已證實(shí)血清膽固醇和骨密度相關(guān)聯(lián)，采用膽固醇喂養(yǎng)的兔子髖部的骨小梁減少[75]。該作者認(rèn)為，循環(huán)中血脂增加，導(dǎo)致脂質(zhì)高度聚集在血管組織及動(dòng)脈壁[75]，脂蛋白微粒進(jìn)入血管壁以后會(huì)導(dǎo)致氧化應(yīng)激，從而誘導(dǎo)炎癥反應(yīng)發(fā)生，最終引起斑塊形成[76]。由于成骨細(xì)胞前體與內(nèi)皮下骨血管基質(zhì)相臨，因此上述病理過程會(huì)影響骨形成細(xì)胞的功能[77]。膽固醇及其代謝產(chǎn)物在體內(nèi)和體外試驗(yàn)中都影響著成骨細(xì)胞的功能活動(dòng)[76,77]。Sivas等[78]在土耳其絕經(jīng)后女性中進(jìn)行的研究顯示，血脂譜的改變和骨密度沒有顯著的相關(guān)性，但是與脊椎骨折的發(fā)生存在顯著相關(guān)性。對(duì)所調(diào)查人群的年齡、絕經(jīng)年數(shù)、體質(zhì)指數(shù)及血脂成分進(jìn)行l(wèi)ogistic回歸分析發(fā)現(xiàn)，TC是骨質(zhì)疏松發(fā)生的最強(qiáng)影響因素，平均每升高1mg/dl可以使脊椎骨折發(fā)生風(fēng)險(xiǎn)降低2.2%。日本學(xué)者Yamaguchi[79]也認(rèn)為，適度的內(nèi)臟脂肪的聚集是骨代謝的一個(gè)保護(hù)因素。Cui等[8]研究發(fā)現(xiàn)，血清膽固醇水平與絕經(jīng)前女性腰椎骨密度、絕經(jīng)后女性髖部骨密度呈負(fù)相關(guān)，血清甘油三酯(trigly ceride，TG)水平與絕經(jīng)后女性髖部骨密度呈正相關(guān)。該研究結(jié)果與Adami等的結(jié)果相一致[80]。

目前已經(jīng)有很多關(guān)于HDL-C與骨密度之間關(guān)系的報(bào)道，盡管這些研究結(jié)果不一致。Yamaguchi等[81]認(rèn)為兩者之間呈正相關(guān)，但是Adami、D'Amelio、Buizert、Dennison、Zabaglia等[80,82-85]卻認(rèn)為兩者是負(fù)相關(guān)。而Poli等[86]認(rèn)為在絕經(jīng)后女性中，兩者之間無關(guān)聯(lián)，這與Cui等[8]的研究結(jié)果相一致：在絕經(jīng)前和絕經(jīng)后女性中，腰椎和髖部骨密度與HDL-C無顯著關(guān)系。中國(guó)學(xué)者Li[87]在790例中國(guó)絕經(jīng)后女性的橫斷面研究中指出，跟較低的HDL-C患者相比，較高的HDL-C患者更容易患骨質(zhì)疏松。HDL-C是心血管疾病的保護(hù)因素，卻是骨質(zhì)疏松的危險(xiǎn)因素，這可能與如下因素有關(guān)[88,89]：首先，HDL-C和脂肪量直接相關(guān)。有研究表明非脂肪組織的比例越高，特別是肌肉組織越多，機(jī)械刺激作用越強(qiáng)。肌肉收縮會(huì)使骨骼處于緊張狀態(tài)，這樣就會(huì)通過骨細(xì)胞上的機(jī)械受體在骨皮質(zhì)內(nèi)外促進(jìn)骨重建，使骨量和骨骼幾何結(jié)構(gòu)參數(shù)均增加，從而提高骨強(qiáng)度。而脂肪組織較多，則可能引起骨重建紊亂、骨量和骨結(jié)構(gòu)參數(shù)下降，進(jìn)而易于發(fā)生骨質(zhì)疏松。其次，HDL-C對(duì)骨質(zhì)疏松的影響還可能存在性別差異。研究表明TC和LDL-C是男性重要的心血管疾病風(fēng)險(xiǎn)因素，而在女性中HDL-C和TG卻起著更為重要的作用。

影響骨代謝和脂代謝的臨床藥物

1. 他汀類藥物

他汀類藥物除了具有降低血脂的作用，還對(duì)骨密度具有正向作用。他汀類藥物、骨質(zhì)疏松、脂肪生成擁有共同的信號(hào)通路——RANKL/OPG[90,91]。辛伐他汀和洛伐他汀都可以促進(jìn)骨形態(tài)發(fā)生蛋白-2(bone morphogenetic protein-2，BMP-2)mRNA的表達(dá)[67]。

盡管Lima[92]等認(rèn)為他汀類藥物對(duì)骨修復(fù)具有負(fù)向作用，但是大部分研究[93-96]表明，他汀類藥物可以促進(jìn)成骨細(xì)胞的活動(dòng)并抑制破骨細(xì)胞，從而可以增加骨密度，預(yù)防骨質(zhì)疏松，減少骨折發(fā)生率。故有學(xué)者提出[97]，他汀類藥物可以用來治療骨質(zhì)疏松，但是最小的有效劑量仍在探索中。

2. 雌激素

雌激素主要是用來治療絕經(jīng)后女性骨質(zhì)疏松。雌激素的主要作用是降低骨轉(zhuǎn)換、維持骨形成和骨吸收的動(dòng)態(tài)平衡。骨細(xì)胞內(nèi)有兩種雌激素受體——ERα和ERβ，當(dāng)雌激素與受體結(jié)合后，就會(huì)激活相關(guān)基因。脂肪組織是絕經(jīng)后女性雌激素的主要來源，主要由雄激素在脂肪細(xì)胞通過芳香化作用轉(zhuǎn)變而來。

綜上所述，可見血脂譜對(duì)骨密度的影響仍存在爭(zhēng)議，這可能與研究對(duì)象的種族、年齡、性別、基礎(chǔ)疾病狀態(tài)以及研究方法等不同有關(guān)。此外，一項(xiàng)針對(duì)骨質(zhì)疏松和心血管疾病相互關(guān)系的研究[98]發(fā)現(xiàn)，動(dòng)脈粥樣硬化過程而非血脂本身更加速骨量的丟失。血管壁動(dòng)脈粥樣硬化斑塊形成過程中釋放較多的炎癥因子和脂肪因子，這些因子可能對(duì)骨質(zhì)疏松的發(fā)生發(fā)展起著更為重要的作用。脂代謝對(duì)骨質(zhì)疏松的影響涉及血脂本身、脂肪分布、脂肪因子、炎癥因子等多方面，其對(duì)骨質(zhì)疏松的最終影響也取決于各因素間的平衡。

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