CD36对骨骼肌脂肪酸代谢调控的机制研究
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摘要
骨骼肌是胰岛素刺激下糖脂代谢的主要外周组织,在维持机体能量平衡中起到了重要的作用。骨骼肌胰岛素抵抗是2型糖尿病的重要特征,表现为因过量脂肪酸及其衍生物的堆积导致的骨骼肌对胰岛素敏感性的下降。在正常骨骼肌细胞中,脂肪酸的摄取、转运及氧化三者处于平衡状态,使骨骼肌细胞内脂肪酸及其衍生物的浓度保持在较低的水平,避免因高浓度脂类积聚对细胞功能造成的损伤。CD36是一种能够转运长链脂肪酸进入骨骼肌细胞的整合膜蛋白。目前对CD36的研究多集中在脂肪酸的转运及摄取方面,对CD36在脂肪酸氧化代谢中的作用及作用机制研究还较少。AMPK作为调控骨骼肌脂肪酸氧化代谢的关键因素,CD36是否能够通过激活AMPK对脂肪酸氧化代谢进行调控,尚不清楚。
目的：本研究描述了CD36-AMPK通路在骨骼肌脂肪酸摄取及氧化过程中的调控作用。首先利用细胞模型,探讨了基础状态下CD36缺乏激活AMPK的作用机制,期望可以为研究CD36对骨骼肌脂肪酸氧化代谢的调控,提供一个新的思路；另鉴于棕榈酸代谢对骨骼肌及整个机体能量代谢的重要意义,本研究进一步探讨了棕榈酸作用下CD36激活AMPK的作用机制,期望可以为认识胰岛素抵抗等代谢性疾病的发生、发展提供一些科学参考；最后,通过建立骨骼肌脂肪酸氧化代谢水平不同的高脂膳食、自主运动及能量限制干预的动物模型,观察了不同干预方式对CD36总蛋白含量的影响,期望可以为CD36总蛋白含量在小鼠骨骼肌脂肪酸氧化代谢的适应性调控过程中的研究,提供依据。
方法：
1.基础状态下CD36缺乏对小鼠骨骼肌脂肪酸氧化代谢调控的机制研究
(1)CD36缺乏对AMPK活化水平的影响
1)细胞水平研究CD36对AMPK活化水平的影响：利用siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测CD36缺乏对小鼠骨骼肌细胞AMPK磷酸化水平的影响；
2)动物水平研究CD36对AMPK活化水平的影响：以野生型和CD36基因敲除小鼠腓肠肌和心肌组织为研究对象,用western blot法检测CD36缺乏对小鼠骨骼肌和心肌组织AMPK磷酸化水平的影响。
(2)CD36缺乏激活AMPK的作用机制研究
1)CD36缺乏对LKB1磷酸化水平的影响：以CHO-Vector和CHO-CD36细胞为研究对象,用immunoprecipitation法检测CD36缺乏对LKB1磷酸化水平的影响。
2)CD36缺乏对LKB1向细胞核转运的影响：用immunofluorescent microscopy法观测CD36的缺乏对LKB1向细胞核转运的影响。
(3)CD36缺乏对小鼠骨骼肌细胞棕榈酸氧化水平的影响
1)将siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用Oxygraph-2k线粒体呼吸仪检测CD36缺乏对骨骼肌细胞棕榈酸氧化水平的影响；
2)将siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测CD36缺乏对棕榈酸诱导AMPK/ACC活化水平的影响。
2.棕榈酸作用下CD36对小鼠骨骼肌脂肪酸代谢调控的机制研究
(1)棕榈酸对AMPK活化水平的影响：利用棕榈酸作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测棕榈酸对小鼠骨骼肌细胞AMPK磷酸化水平的影响。
(2)CD36在棕榈酸诱导AMPK激活中的作用机制研究：以CHO-CD36细胞为研究对象,经过3001μM棕榈酸作用15分钟后,用immunofluorescent microscopy法检测棕榈酸对LKB1向细胞核转运的影响；用co-immunoprecipitation法检测CD36与Fyn、LKB1及AMPK的结合能力。
(3)棕榈酸对CD36向细胞膜转运的影响：以完全分化的C2C12小鼠骨骼肌细胞为研究对象,经过300gM棕榈酸作用0、5、15、30分钟后,用In-Cell Western法检测棕榈酸对CD36向细胞膜转运的影响；用western blot法检测棕榈酸对小鼠骨骼肌细胞AMPK磷酸化水平的影响；用immunoprecipitation法检测棕榈酸对被AMPK磷酸化的TBC1D1水平的影响。
3.高脂膳食、运动及能量限制干预下小鼠骨骼肌脂肪酸氧化代谢水平不同对CD36总蛋白含量的影响
清洁级雄性C57小鼠40只,随机分为四组：对照组(N,n=10)、高脂膳食组(HD,n=10)、自主跑轮运动组(E,n=10)及能量限制组(CR,n=10)。经过8周干预后,实验结束。小鼠断颈处死,摘取右侧股四头肌。
(1)不同干预方式对小鼠骨骼肌脂肪酸氧化代谢水平的影响：用western blot法分别检测了高脂膳食、自主运动及能量限制对小鼠骨骼肌脂肪酸氧化信号通路AMPK/ACC活化水平的影响。从而建立了小鼠骨骼肌脂肪酸氧化水平不同的动物模型。
(2)小鼠骨骼肌脂肪酸氧化水平不同对CD36总蛋白含量的影响：用western blot法首先检测了不同干预方式对CD36总蛋白含量的影响,然后进一步检测了CD36总蛋白含量在不同骨骼肌脂肪酸氧化代谢水平中的差异。
结果：
(1)与siCont相比,经2种siCD36干扰后的C2C12细胞中pAMPK(T172)/AMPK显著增加(P<0.05,P<0.01)；与WT小鼠相比,CD36-/小鼠骨骼肌(P<0.01)及心肌组织中pAMPK(T172)/AMPK显著增加(P<0.05)。
(2)与CHO-CD36细胞相比,CHO-Vector细胞中LKB1的磷酸化水平有明显的减少,并且LKB1大量存在于细胞质中(P<0.05)。与此同时,CHO-Vector细胞中AMPK磷酸化水平整体较高(P<0.01)。
(3)棕榈酸作用于经siCont转染的C2C12细胞15分钟后,AMPK活化水平明显增加(P<0.001),然而棕榈酸并没有导致经siCD36转染的C2C12细胞AMPK活化水平的进一步增加(P>0.05)。
(4)在CHO-CD36细胞中,棕榈酸能够明显抑制LKB1向细胞核的转运。
(5)在CHO-CD36细胞中,棕榈酸能够减少CD36与Fyn的结合能力,同时增加CD36与LKB1及AMPK的结合能力。
(6)在完全分化的C2C12细胞中,细胞膜CD36的含量随着棕榈酸作用时间的延长而增加,其中在棕榈酸作用30分钟时,细胞膜CD36的含量有显著的增加(P<0.05)；并且AMPK、TBC1D1磷酸化水平的增加也呈棕榈酸作用的时间依赖性。
(7)与对照组小鼠相比,经过8周高脂膳食干预的小鼠骨骼肌CD36总蛋白表达水平显著减少(P<0.01),经过8周自主运动干预的小鼠骨骼肌CD36总蛋白表达水平无明显变化(P>0.05),经过8周能量限制干预的小鼠骨骼肌CD36总蛋白表达水平显著增加(P<0.01)；与高脂膳食组小鼠相比,经过8周自主跑轮运动及能量限制的小鼠骨骼肌CD36总蛋白表达水平有显著增加(P<0.01)。
结论：
(1)离体、在体实验均表明,CD36缺乏能够激活骨骼肌AMPK。其作用机制可能为：CD36缺乏导致了CD36对Fyn的磷酸化水平减少,进一步减少了Fyn对LKB1的磷酸化作用,LKB1磷酸化水平的减少抑制了LKB1向细胞核的转运,从而激活AMPK。
(2)基础状态下CD36的缺乏导致了骨骼肌AMPK/ACC磷酸化水平及脂肪酸氧化水平的增加,然而CD36的缺乏又损伤了棕榈酸对AMPK激活的敏感性。说明CD36的存在对骨骼肌脂肪酸氧化代谢的调控起到了重要作用。
(3)当外源性棕榈酸附着于细胞膜CD36表面时,Fyn与CD36相分离,减少了Fyn对LKB1的磷酸化作用,抑制LKB1向细胞核的转运,从而增加了LKB1对AMPK的激活作用。与此同时,棕榈酸与CD36的结合,还可能通过增加CD36与LKB1及CD36与AMPK的结合能力,在棕榈酸的作用下形成CD36-LKB1-AMPK复合物,LKB1与AMPK空间距离的靠近,进一步增加了LKB1对AMPK的激活作用。
(4)棕榈酸可能通过激活骨骼肌AMPK/TBC1D1信号通路,诱导CD36向细胞膜的转运,但无法诱导CD36向线粒体膜的转运。
(5)骨骼肌脂肪酸氧化水平较高的自主运动及能量限制小鼠CD36的总蛋白含量也显著高于高脂膳食小鼠。该结果说明了CD36总蛋白含量的变化可能是对不同小鼠骨骼肌脂肪酸氧化代谢水平的一种适应性调控。
Skeletal muscle plays a key role in maintaining FA homeostasis. The balance of fatty acid uptake, transportation and oxidation is well maintained in healthy skeletal muscle. However, the accumulation of FA derivatives and metabolites would compromise muscle function, and result in insulin resistant which is a key characteristic of type2diabetes. CD36is an integral membrane protein and plays an important role in transporting long chain fatty acids (LCFAs) into skeletal muscle cells. Most findings of CD36focus on its role in facilitating fatty acid uptake. However, the role that CD36plays in regulating FA oxidation remains unclear. Adenosine monophosphate-activated protein kinase (AMPK) is a known major regulator of FA metabolism in skeletal muscle. The role of CD36in regulating FA oxidation by triggering AMPK signaling activation remains unclear.
Objective:The current research was designed to study the role of CD36in regulating FA uptake and FA oxidation in muscle, as well as its underlying mechanism. The role of CD36in activating AMPK at basal level was observed firstly, which would provide a new view in CD36-mediated muscle FA oxidation. Secondly, due to the importance of PA in regulating the metabolic homeostasis of skeletal muscle as well as whole body, the mechanism of CD36in regulating AMPK activation with the addition of PA was further investigated, which might be helpful for understanding the occurrence and development of metabolic diseases. Finally, in order to reveal the impact of oxidation level of FAs on CD36contents, an animal model displaying different muscle FA oxidation levels was built to support the possible role of CD36in participating FA oxidation.
Methods:
1. The role and corresponding mechanism of CD36in regulating muscle fatty acid oxidation in basal conditions
(1) The effect of CD36depletion on AMPK activation.
1) Cell culture study with C2C12:Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD). The effect of CD36deficiency on AMPK phosphorylation levels was detected by Western Blot;
2) Animal study:To investigate the contribution of CD36to AMPK activation regulation in vivo, AMPK phosphorylation levels in skeletal muscle (gastrocnemius) and cardiac muscle of CD36-/-and WT mice were detected by Western Blot.
(2) The mechanism of CD36depletion on AMPK activation.1) The effect of CD36depletion on LKB1phosphorylation level was detected by IP in CHO-Vector and CHO-CD36cells;
2) The effect of CD36depletion on LKB1relocation to nuclear was observed by IF in CHO-Vector and CHO-CD36cells.
(3) The effect of CD36depletion on palmitic acid oxidation in myotubes.
1) Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD). The effect of CD36deficiency on PA oxidation was determined by high-resolution respirometry (Oxygraph-2k);
2) Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD) and then incubated with PA. The effect of CD36deficiency on PA-induced AMPK and ACC phosphorylation levels was detected by Western Blot.
2. The role of CD36in regulating muscle fatty acid metabolism with the stimulation of PA.
(1) The effect of PA on AMPK activation:Differentiated C2C12cells were stimulated by PA, and AMPK phosphorylation levels were detected by Western Blot.
(2) CHO-CD36cells were stimulated by300μM PA for15mins. The direct association of CD36with Fyn, LKB1and AMPK was determined by co-IP; The effect of PA on LKB1relocation to nuclear was observed by IF.
(3) PA-induced CD36translocation to plasma membrane via AMPK/TBC1D1signaling pathway:The differentiated C2C12cells were stimulated by300μM PA for 0,5,15and30mins, respectively. The PA-facilitated CD36translocation to plasma membrane was examined by In-Cell Western; The effect of PA on AMPK phosphorylation levels were detected by Western Blot; The effect of PA on AMPK-dependent phosphorylation of TBC1D1was examined by TBC1D1immunoprecipitation followed by probing with phospho-(Ser/Thr) antibody specific for AMPK phosphorylation motifs.
3. The effect of fatty acid oxidation level in groups HD, E and CR on muscle CD36contents.
40male C57mice were randomly assigned into four groups:control (N), high fat diet (HD), voluntary exercise (E) and caloric restriction (CR) with10mice in each group. The intervention peroid lasted for8weeks and the body weight of the four groups was recorded weekly.
(1) An animal model with different muscle FA oxidation levels was built: AMPK/ACC phosphorylation levels in skeletal muscle of groups HD, E and CR were measured by Western Blot.
(2) Groups HD, E and CR were used to determine the effect of muscle fatty acid oxidation level on CD36content. CD36expression level in skeletal muscle was measured by Western Blot.
Results:
(1) CD36depletion in C2C12myotubes with2independent siCD36oligonucleotides resulted in a robust increase of AMPK phosphorylation at T172(P<0.05, P<0.01). Moreover, CD36deficiency in CD36-/-mouse resulted in a significant increase in AMPK phosphorylation at T172in both skeletal muscle (P<0.01) and cardiac muscle (P<0.05).
(2) Compared with CHO-CD36cells, CHO-Vector cells showed a significant decrease in LKB1phosphorylation, and LKB1was predominantly found in the cytoplasma (P<0.05). This was also accompanied with a higher basal level of AMPK phosphorylation (P<0.01).
(3) The addition of PA to C2C12cells treated with irrelevant siRNA significantly increased AMPK T172-phosphorylation at15min of stimulation (P<0.001). The basal level of pAMPK in CD36-depleted cells was higher and did not increase further in response to PA stimulation (P>0.05).
(4) PA could obviously inhibit LKB1relocation into nucleus in CHO-CD36cells.
(5) The addition of PA markedly weakened the direct association of CD36with Fyn, however significantly enhanced the direct association of CD36with LKB1and AMPK.
(6) AMPK and TBC1D1phosphorylation levels were increased with PA stimulation in a time-dependent manner, which was associated with the increase in CD36relocation to the plasma membrane (P<0.05).
(7) Compared with group N, the expression level of CD36in the skeletal muscle of HD mice was significantly decreased (P<0.01), the expression of CD36in the skeletal muscle of CR group was significantly increased (P<0.01), and the expression of CD36in the skeletal muscle of E group was not changed (P>0.05); When compared to group HD, the total CD36content in skeletal muscle of E and CR groups was with a higher level (P<0.01).
Conclusions:
(1) CD36depletion induced an increase in muscle AMPK activation in vitro and in vivo. In the absence of CD36, Fyn-dependent LKB1phosphorylation decreased results in LKB1nuclear relocation inhibited, thus advancing its access to cytosolic AMPK and resulting in increased LKB1phosphorylation of AMPK.
(2) In basal condition, the deficiency of CD36induced an increase in AMPK and ACC phosphorylation levels, as well as FA oxidation levels. However, the depletion of CD36could not induce PA-stimulated AMPK phosphorylation levels further increased, suggesting the existence of CD36played a key role in regulating FA oxidation via AMPK/ACC signaling pathway.
(3) PA binding to CD36induced Fyn dissociating from the CD36-LKB1-AMPK complex, allowing LKB1to remain in the cytosol and to phosphorylate AMPK. Besides that, the addition of PA could enhance the direct association of CD36with LKB1and AMPK, which could further increase LKB1phosphorylation of AMPK.
(4) PA induced CD36translocation to plasma membrane via AMPK/TBC1D1signaling pathway, but not to mitochondrial membrane.
(5) Compared with HD group, CD36content was significantly higher in E and CR groups in which muscle FA oxidation was also higher, indicating that total CD36content was probably related to the adaption of fatty acid oxidation in skeletal muscle.
目的：本研究描述了CD36-AMPK通路在骨骼肌脂肪酸摄取及氧化过程中的调控作用。首先利用细胞模型,探讨了基础状态下CD36缺乏激活AMPK的作用机制,期望可以为研究CD36对骨骼肌脂肪酸氧化代谢的调控,提供一个新的思路；另鉴于棕榈酸代谢对骨骼肌及整个机体能量代谢的重要意义,本研究进一步探讨了棕榈酸作用下CD36激活AMPK的作用机制,期望可以为认识胰岛素抵抗等代谢性疾病的发生、发展提供一些科学参考；最后,通过建立骨骼肌脂肪酸氧化代谢水平不同的高脂膳食、自主运动及能量限制干预的动物模型,观察了不同干预方式对CD36总蛋白含量的影响,期望可以为CD36总蛋白含量在小鼠骨骼肌脂肪酸氧化代谢的适应性调控过程中的研究,提供依据。
方法：
1.基础状态下CD36缺乏对小鼠骨骼肌脂肪酸氧化代谢调控的机制研究
(1)CD36缺乏对AMPK活化水平的影响
1)细胞水平研究CD36对AMPK活化水平的影响：利用siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测CD36缺乏对小鼠骨骼肌细胞AMPK磷酸化水平的影响；
2)动物水平研究CD36对AMPK活化水平的影响：以野生型和CD36基因敲除小鼠腓肠肌和心肌组织为研究对象,用western blot法检测CD36缺乏对小鼠骨骼肌和心肌组织AMPK磷酸化水平的影响。
(2)CD36缺乏激活AMPK的作用机制研究
1)CD36缺乏对LKB1磷酸化水平的影响：以CHO-Vector和CHO-CD36细胞为研究对象,用immunoprecipitation法检测CD36缺乏对LKB1磷酸化水平的影响。
2)CD36缺乏对LKB1向细胞核转运的影响：用immunofluorescent microscopy法观测CD36的缺乏对LKB1向细胞核转运的影响。
(3)CD36缺乏对小鼠骨骼肌细胞棕榈酸氧化水平的影响
1)将siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用Oxygraph-2k线粒体呼吸仪检测CD36缺乏对骨骼肌细胞棕榈酸氧化水平的影响；
2)将siCont或siCD36作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测CD36缺乏对棕榈酸诱导AMPK/ACC活化水平的影响。
2.棕榈酸作用下CD36对小鼠骨骼肌脂肪酸代谢调控的机制研究
(1)棕榈酸对AMPK活化水平的影响：利用棕榈酸作用于分化成熟的C2C12小鼠骨骼肌细胞,用western blot法检测棕榈酸对小鼠骨骼肌细胞AMPK磷酸化水平的影响。
(2)CD36在棕榈酸诱导AMPK激活中的作用机制研究：以CHO-CD36细胞为研究对象,经过3001μM棕榈酸作用15分钟后,用immunofluorescent microscopy法检测棕榈酸对LKB1向细胞核转运的影响；用co-immunoprecipitation法检测CD36与Fyn、LKB1及AMPK的结合能力。
(3)棕榈酸对CD36向细胞膜转运的影响：以完全分化的C2C12小鼠骨骼肌细胞为研究对象,经过300gM棕榈酸作用0、5、15、30分钟后,用In-Cell Western法检测棕榈酸对CD36向细胞膜转运的影响；用western blot法检测棕榈酸对小鼠骨骼肌细胞AMPK磷酸化水平的影响；用immunoprecipitation法检测棕榈酸对被AMPK磷酸化的TBC1D1水平的影响。
3.高脂膳食、运动及能量限制干预下小鼠骨骼肌脂肪酸氧化代谢水平不同对CD36总蛋白含量的影响
清洁级雄性C57小鼠40只,随机分为四组：对照组(N,n=10)、高脂膳食组(HD,n=10)、自主跑轮运动组(E,n=10)及能量限制组(CR,n=10)。经过8周干预后,实验结束。小鼠断颈处死,摘取右侧股四头肌。
(1)不同干预方式对小鼠骨骼肌脂肪酸氧化代谢水平的影响：用western blot法分别检测了高脂膳食、自主运动及能量限制对小鼠骨骼肌脂肪酸氧化信号通路AMPK/ACC活化水平的影响。从而建立了小鼠骨骼肌脂肪酸氧化水平不同的动物模型。
(2)小鼠骨骼肌脂肪酸氧化水平不同对CD36总蛋白含量的影响：用western blot法首先检测了不同干预方式对CD36总蛋白含量的影响,然后进一步检测了CD36总蛋白含量在不同骨骼肌脂肪酸氧化代谢水平中的差异。
结果：
(1)与siCont相比,经2种siCD36干扰后的C2C12细胞中pAMPK(T172)/AMPK显著增加(P<0.05,P<0.01)；与WT小鼠相比,CD36-/小鼠骨骼肌(P<0.01)及心肌组织中pAMPK(T172)/AMPK显著增加(P<0.05)。
(2)与CHO-CD36细胞相比,CHO-Vector细胞中LKB1的磷酸化水平有明显的减少,并且LKB1大量存在于细胞质中(P<0.05)。与此同时,CHO-Vector细胞中AMPK磷酸化水平整体较高(P<0.01)。
(3)棕榈酸作用于经siCont转染的C2C12细胞15分钟后,AMPK活化水平明显增加(P<0.001),然而棕榈酸并没有导致经siCD36转染的C2C12细胞AMPK活化水平的进一步增加(P>0.05)。
(4)在CHO-CD36细胞中,棕榈酸能够明显抑制LKB1向细胞核的转运。
(5)在CHO-CD36细胞中,棕榈酸能够减少CD36与Fyn的结合能力,同时增加CD36与LKB1及AMPK的结合能力。
(6)在完全分化的C2C12细胞中,细胞膜CD36的含量随着棕榈酸作用时间的延长而增加,其中在棕榈酸作用30分钟时,细胞膜CD36的含量有显著的增加(P<0.05)；并且AMPK、TBC1D1磷酸化水平的增加也呈棕榈酸作用的时间依赖性。
(7)与对照组小鼠相比,经过8周高脂膳食干预的小鼠骨骼肌CD36总蛋白表达水平显著减少(P<0.01),经过8周自主运动干预的小鼠骨骼肌CD36总蛋白表达水平无明显变化(P>0.05),经过8周能量限制干预的小鼠骨骼肌CD36总蛋白表达水平显著增加(P<0.01)；与高脂膳食组小鼠相比,经过8周自主跑轮运动及能量限制的小鼠骨骼肌CD36总蛋白表达水平有显著增加(P<0.01)。
结论：
(1)离体、在体实验均表明,CD36缺乏能够激活骨骼肌AMPK。其作用机制可能为：CD36缺乏导致了CD36对Fyn的磷酸化水平减少,进一步减少了Fyn对LKB1的磷酸化作用,LKB1磷酸化水平的减少抑制了LKB1向细胞核的转运,从而激活AMPK。
(2)基础状态下CD36的缺乏导致了骨骼肌AMPK/ACC磷酸化水平及脂肪酸氧化水平的增加,然而CD36的缺乏又损伤了棕榈酸对AMPK激活的敏感性。说明CD36的存在对骨骼肌脂肪酸氧化代谢的调控起到了重要作用。
(3)当外源性棕榈酸附着于细胞膜CD36表面时,Fyn与CD36相分离,减少了Fyn对LKB1的磷酸化作用,抑制LKB1向细胞核的转运,从而增加了LKB1对AMPK的激活作用。与此同时,棕榈酸与CD36的结合,还可能通过增加CD36与LKB1及CD36与AMPK的结合能力,在棕榈酸的作用下形成CD36-LKB1-AMPK复合物,LKB1与AMPK空间距离的靠近,进一步增加了LKB1对AMPK的激活作用。
(4)棕榈酸可能通过激活骨骼肌AMPK/TBC1D1信号通路,诱导CD36向细胞膜的转运,但无法诱导CD36向线粒体膜的转运。
(5)骨骼肌脂肪酸氧化水平较高的自主运动及能量限制小鼠CD36的总蛋白含量也显著高于高脂膳食小鼠。该结果说明了CD36总蛋白含量的变化可能是对不同小鼠骨骼肌脂肪酸氧化代谢水平的一种适应性调控。
Skeletal muscle plays a key role in maintaining FA homeostasis. The balance of fatty acid uptake, transportation and oxidation is well maintained in healthy skeletal muscle. However, the accumulation of FA derivatives and metabolites would compromise muscle function, and result in insulin resistant which is a key characteristic of type2diabetes. CD36is an integral membrane protein and plays an important role in transporting long chain fatty acids (LCFAs) into skeletal muscle cells. Most findings of CD36focus on its role in facilitating fatty acid uptake. However, the role that CD36plays in regulating FA oxidation remains unclear. Adenosine monophosphate-activated protein kinase (AMPK) is a known major regulator of FA metabolism in skeletal muscle. The role of CD36in regulating FA oxidation by triggering AMPK signaling activation remains unclear.
Objective:The current research was designed to study the role of CD36in regulating FA uptake and FA oxidation in muscle, as well as its underlying mechanism. The role of CD36in activating AMPK at basal level was observed firstly, which would provide a new view in CD36-mediated muscle FA oxidation. Secondly, due to the importance of PA in regulating the metabolic homeostasis of skeletal muscle as well as whole body, the mechanism of CD36in regulating AMPK activation with the addition of PA was further investigated, which might be helpful for understanding the occurrence and development of metabolic diseases. Finally, in order to reveal the impact of oxidation level of FAs on CD36contents, an animal model displaying different muscle FA oxidation levels was built to support the possible role of CD36in participating FA oxidation.
Methods:
1. The role and corresponding mechanism of CD36in regulating muscle fatty acid oxidation in basal conditions
(1) The effect of CD36depletion on AMPK activation.
1) Cell culture study with C2C12:Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD). The effect of CD36deficiency on AMPK phosphorylation levels was detected by Western Blot;
2) Animal study:To investigate the contribution of CD36to AMPK activation regulation in vivo, AMPK phosphorylation levels in skeletal muscle (gastrocnemius) and cardiac muscle of CD36-/-and WT mice were detected by Western Blot.
(2) The mechanism of CD36depletion on AMPK activation.1) The effect of CD36depletion on LKB1phosphorylation level was detected by IP in CHO-Vector and CHO-CD36cells;
2) The effect of CD36depletion on LKB1relocation to nuclear was observed by IF in CHO-Vector and CHO-CD36cells.
(3) The effect of CD36depletion on palmitic acid oxidation in myotubes.
1) Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD). The effect of CD36deficiency on PA oxidation was determined by high-resolution respirometry (Oxygraph-2k);
2) Differentiated C2C12cells were depleted of CD36by RNAi-mediated knockdown (KD) and then incubated with PA. The effect of CD36deficiency on PA-induced AMPK and ACC phosphorylation levels was detected by Western Blot.
2. The role of CD36in regulating muscle fatty acid metabolism with the stimulation of PA.
(1) The effect of PA on AMPK activation:Differentiated C2C12cells were stimulated by PA, and AMPK phosphorylation levels were detected by Western Blot.
(2) CHO-CD36cells were stimulated by300μM PA for15mins. The direct association of CD36with Fyn, LKB1and AMPK was determined by co-IP; The effect of PA on LKB1relocation to nuclear was observed by IF.
(3) PA-induced CD36translocation to plasma membrane via AMPK/TBC1D1signaling pathway:The differentiated C2C12cells were stimulated by300μM PA for 0,5,15and30mins, respectively. The PA-facilitated CD36translocation to plasma membrane was examined by In-Cell Western; The effect of PA on AMPK phosphorylation levels were detected by Western Blot; The effect of PA on AMPK-dependent phosphorylation of TBC1D1was examined by TBC1D1immunoprecipitation followed by probing with phospho-(Ser/Thr) antibody specific for AMPK phosphorylation motifs.
3. The effect of fatty acid oxidation level in groups HD, E and CR on muscle CD36contents.
40male C57mice were randomly assigned into four groups:control (N), high fat diet (HD), voluntary exercise (E) and caloric restriction (CR) with10mice in each group. The intervention peroid lasted for8weeks and the body weight of the four groups was recorded weekly.
(1) An animal model with different muscle FA oxidation levels was built: AMPK/ACC phosphorylation levels in skeletal muscle of groups HD, E and CR were measured by Western Blot.
(2) Groups HD, E and CR were used to determine the effect of muscle fatty acid oxidation level on CD36content. CD36expression level in skeletal muscle was measured by Western Blot.
Results:
(1) CD36depletion in C2C12myotubes with2independent siCD36oligonucleotides resulted in a robust increase of AMPK phosphorylation at T172(P<0.05, P<0.01). Moreover, CD36deficiency in CD36-/-mouse resulted in a significant increase in AMPK phosphorylation at T172in both skeletal muscle (P<0.01) and cardiac muscle (P<0.05).
(2) Compared with CHO-CD36cells, CHO-Vector cells showed a significant decrease in LKB1phosphorylation, and LKB1was predominantly found in the cytoplasma (P<0.05). This was also accompanied with a higher basal level of AMPK phosphorylation (P<0.01).
(3) The addition of PA to C2C12cells treated with irrelevant siRNA significantly increased AMPK T172-phosphorylation at15min of stimulation (P<0.001). The basal level of pAMPK in CD36-depleted cells was higher and did not increase further in response to PA stimulation (P>0.05).
(4) PA could obviously inhibit LKB1relocation into nucleus in CHO-CD36cells.
(5) The addition of PA markedly weakened the direct association of CD36with Fyn, however significantly enhanced the direct association of CD36with LKB1and AMPK.
(6) AMPK and TBC1D1phosphorylation levels were increased with PA stimulation in a time-dependent manner, which was associated with the increase in CD36relocation to the plasma membrane (P<0.05).
(7) Compared with group N, the expression level of CD36in the skeletal muscle of HD mice was significantly decreased (P<0.01), the expression of CD36in the skeletal muscle of CR group was significantly increased (P<0.01), and the expression of CD36in the skeletal muscle of E group was not changed (P>0.05); When compared to group HD, the total CD36content in skeletal muscle of E and CR groups was with a higher level (P<0.01).
Conclusions:
(1) CD36depletion induced an increase in muscle AMPK activation in vitro and in vivo. In the absence of CD36, Fyn-dependent LKB1phosphorylation decreased results in LKB1nuclear relocation inhibited, thus advancing its access to cytosolic AMPK and resulting in increased LKB1phosphorylation of AMPK.
(2) In basal condition, the deficiency of CD36induced an increase in AMPK and ACC phosphorylation levels, as well as FA oxidation levels. However, the depletion of CD36could not induce PA-stimulated AMPK phosphorylation levels further increased, suggesting the existence of CD36played a key role in regulating FA oxidation via AMPK/ACC signaling pathway.
(3) PA binding to CD36induced Fyn dissociating from the CD36-LKB1-AMPK complex, allowing LKB1to remain in the cytosol and to phosphorylate AMPK. Besides that, the addition of PA could enhance the direct association of CD36with LKB1and AMPK, which could further increase LKB1phosphorylation of AMPK.
(4) PA induced CD36translocation to plasma membrane via AMPK/TBC1D1signaling pathway, but not to mitochondrial membrane.
(5) Compared with HD group, CD36content was significantly higher in E and CR groups in which muscle FA oxidation was also higher, indicating that total CD36content was probably related to the adaption of fatty acid oxidation in skeletal muscle.
引文
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