动物营养学报    2019, Vol. 31 Issue (1): 243-250    PDF    
短期限饲对家兔肝脏和骨骼肌脂质代谢的影响
张斌1, 李福昌1, 王诚2, 刘汉中3, 余志菊3, 刘磊1     
1. 山东农业大学动物科技学院, 山东省动物生物工程与疾病防治重点实验室, 泰安 271018;
2. 山东健源生物科技有限公司, 泰安 271000;
3. 四川省草原科学研究院, 成都 610091
摘要: 本试验旨在研究短期限饲对家兔肝脏和骨骼肌中脂质代谢相关基因表达的影响,以阐明短期限饲下家兔脂质代谢的调节机制。选取40日龄、体重相近、健康状况良好的商品代伊拉肉兔40只,随机分为对照组(自由采食)和试验组(限饲,饲喂量为对照组的70%左右),每组20个重复(公母各占1/2),每个重复1只。试验期为5 d。结果显示:短期限饲显著降低了家兔肝脏指数(P < 0.05),有降低家兔后腿肌重量的趋势(P=0.074 3),对家兔前腿肌、背腰肌、总肌肉(前腿肌+后腿肌+背腰肌)重量无显著影响(P>0.05)。短期限饲显著降低了血浆中甘油三酯(TG)和极低密度脂蛋白(VLDL)含量(P < 0.05),对肝脏和背腰肌中TG含量的影响不显著(P>0.05)。肝脏中,短期限饲显著降低了脂肪酸合成酶(FAS)mRNA的相对表达量(P < 0.05),显著上调了肉碱脂酰转移酶1(CPT1)、肉碱脂酰转移酶2(CPT2)、G蛋白偶联受体41(GPR41)、G蛋白偶联受体43(GPR43)、过氧化物酶体增殖物激活受体α(PPARα)mRNA的相对表达量(P < 0.05);骨骼肌中,短期限饲显著上调了脂蛋白脂肪酶(LPL)、脂肪酸结合蛋白(FABP)、GPR41、GPR43 mRNA的相对表达量(P < 0.05),显著下调了CPT2 mRNA的相对表达量(P < 0.05),对CPT1、PPARα、脂肪酸转运蛋白(FATP)mRNA的相对表达量无显著影响(P>0.05)。由此得出,短期限饲抑制了家兔肝脏中脂质的合成和外运,促进了脂肪酸在肝脏中的氧化利用,GPR41、GPR43和PPARα参与此过程;短期限饲促进了家兔骨骼肌对脂肪酸的摄取和利用,GPR41和GPR43参与此过程。
关键词: 家兔     短期限饲     脂质代谢     基因表达     肝脏     骨骼肌    
Effects of Short-Term Feed Restriction on Lipid Metabolism in Liver and Skeletal Muscle of Rabbits
ZHANG Bin1, LI Fuchang1, WANG Cheng2, LIU Hanzhong3, YU Zhiju3, LIU Lei1     
1. Shandong Provincial Key Laboratory of Animal Biotechnology and Disease Control and Prevention, Shandong Agricultural University, Tai'an 271018, China;
2. Shandong Jianyuan Science and Technology Co., Ltd., Tai'an 271000, China;
3. Sichuan Academy of Grassland Sciences, Chengdu 610091, China
Abstract: This experiment was conducted to study the effects of short-term feed restriction on expression of lipid metabolism-related genes in liver and skeletal muscle of rabbits, and to expound the regulatory mechanism of lipid metabolism in rabbits under short-term feed restriction. Forty 40-day-old Hyla rabbits with similar weight and good body state were randomly divided into 2 groups (control group and feed restriction group) with 20 replicates (half male and half female) per group and 1 rabbit per replicate. The rabbits in the control group were fed ad libitum, while the rabbits in the feed restriction group were fed with restricted feeding (feeding amount was about 70% of control group). The test period was 5 days. The results showed that short-term feed restriction significantly reduced the liver index of rabbits (P < 0.05), and had a decreased tendency in hindleg muscle weight (P=0.074 3), but did not significantly affect the weights of foreleg muscle, dorsal lumbar muscle and total muscle (foreleg muscle+hindleg muscle+dorsal lumbar muscle) (P>0.05). The contents of triglyceride (TG) and very low density lipoprotein (VLDL) in plasma were significantly reduced by short-term feed restriction (P < 0.05), but the content of TG in liver and dorsal lumbar muscle was not significantly reduced (P>0.05). In the liver, the mRNA relative expression level of fatty acid synthase (FAS) was significantly down-regulated by short-term feed restriction (P < 0.05), and the mRNA relative expression levels of carnitine acyl transferase 1 (CPT1), carnitine acyl transferase 2 (CPT2), G-protein-coupled receptor 41 (GPR41), G-protein-coupled receptor 43 (GPR43) and peroxisome proliferators activate receptor α (PPARα) were significantly up-regulated by short-term feed restriction (P < 0.05). In the skeletal muscle, the mRNA relative expression levels of lipoprotein lipase (LPL), fatty acid binding protein (FABP), GPR41 and GPR43 were significantly up-regulated by short-term feed restriction (P < 0.05), the mRNA relative expression levels of CPT2 was significantly up-regulated (P < 0.05) by short-term feed restriction, and the mRNA relative expression levels of CPT1, PPARα and fatty acid transporters (FATP) were not significantly influenced by short-term feed restriction (P>0.05). In conclusion, short-term feed restriction inhibits lipid synthesis and output, and promotes the oxidation utilization of fatty acids in the liver, and GPR41, GPR43 and PPARα involved in this process; short-term feed restriction promotes the uptake and utilization of fatty acids in skeletal muscles, and GPR41 and GPR43 involved in this process.
Key words: rabbits     short-term feed restriction     lipid metabolism     gene expression     liver     skeletal muscle    

圈养动物采食量过多将会导致肥胖、消化系统疾病及繁殖性能下降等多种问题,在不同种动物和不同生长时期控制动物采食量,对动物更健康生长和得到高品质动物产品具有重要意义。在肉鸡饲养中,限饲能显著降低肉鸡的死亡率并提高饲料利用率[1]。为了得到生长速率快、瘦肉率高且肉品质好的猪肉,在肉猪生产中也常使用限饲模式[2]。第1次怀孕的母兔从怀孕到分娩若自由采食可增加出生幼兔夭折的风险并降低幼兔的平均窝重,同时还会降低母兔一生的生产性能[3]。刚断奶的生长肉兔消化系统发育不完全,体内消化酶分泌不足,极易导致消化功能紊乱[4]。在实际生产中,家兔饲养也会使用限饲模式。通过限饲21 d(限饲组采食量分别为自由采食对照组的85%、70%、55%),然后恢复自由采食21 d,发现限饲显著降低了家兔的体增重, 但显著提高了饲料转化率,而且限饲显著降低了家兔肾周脂肪和肩胛处脂肪比例,增加了胃肠道的相对重量和长度[5]。限饲1周(限饲组采食量为自由采食对照组的85%左右)可显著促进生长兔小肠绒毛和隐窝的发育[6]。在一定范围内进行限饲时,限饲可以降低断奶幼兔的发病率和死亡率,并改善其肠道的生理状态,引导生长幼兔食粪行为,减缓饲粮在家兔消化道通过速率,改善其在盲肠的发酵[7-8]。由此可见,限饲可改善畜禽肠道发育,降低发病率、死亡率,改善肉品质及降低脂肪沉积,但限饲对脂肪沉积的影响机制仍未明确。肝脏是与脂质代谢相关的重要器官,在脂质的消化、分解、合成、转运过程中发挥着重要作用。肌肉是脂肪酸氧化的主要部位,血浆中的游离脂肪酸可被肌肉组织在脂肪酸转运蛋白(FATP)和脂肪酸结合蛋白(FABP)作用下摄入,在肉碱脂酰转移酶1(CPT1)作用下经β-氧化供能[9]。本试验拟通过研究短期限饲对家兔肝脏和骨骼肌中脂质代谢相关基因表达的影响,以阐明短期限饲对家兔脂质代谢的影响机制,为实际生产提供指导。

1 材料与方法 1.1 试验设计

选取40日龄、体重[(1 510±10) g]相近的伊拉肉兔40只,随机分为2组:对照组(自由采食,采食量约为149.14 g/d,于08:00、17:00分2次饲喂)、限饲组(限饲采食量为对照组的70%左右,约为104 g/d,于08:00、17:00分2次饲喂),每组20个重复(公母各占1/2),每个重复1只,试验持续5 d(试验肉兔限饲量与试验持续时间参考文献[6-7])。试验兔舍采光、通风良好,试验兔单笼饲养,自由饮水,自然采光、通风。试验兔采食的饲粮为普通商品饲粮,其组成及营养水平见表 1

表 1 饲粮组成及营养水平(风干基础) Table 1 Composition and nutrient levels of the diet (air-dry basis)
1.2 样品采集

饲养试验结束后,每组选取8只试验兔,心脏采血5 mL,分装于肝素钠抗凝管中,室温下放置30 min后,3 000 r/min离心10 min后取上清放置于-20 ℃保存,用于检测血浆中甘油三酯(TG)和极低密度脂蛋白(VLDL)含量。将采血后的试验兔称重后屠宰,分离肝脏、前腿肌、后腿肌、背腰肌并称重,取肝脏、背腰肌样品各5 g左右装入冻存管中,迅速放入液氮中,随后转移到-80 ℃冰箱保存,用于检测肝脏和骨骼肌中TG含量及脂质代谢相关基因mRNA的相对表达量。

1.3 组织总RNA提取与分析

采用Trizol法提取组织中总RNA,并用TaKaRa试剂盒将总RNA反转录为cDNA,荧光定量PCR过程采用TaKaRa荧光定量试剂盒进行(所需引物参照Fu等[10],见表 2)。PCR具体过程参照Wang等[11]研究所描述,以甘油醛-3-磷酸脱氢酶(GAPDH)为内参基因进行校正,反应体系为20 μL,其中SYBR 10 μL、上游引物(F)0.5 μL、下游引物(R)0.5 μL、cDNA 2 μL、灭菌水7 μL。反应条件为:预变性(50 ℃,2 min;95 ℃,10 min),1个循环数;PCR(95 ℃,15 s;60 ℃,1 min),40个循环数;熔解曲线(95 ℃,15 s;60 ℃,1 min;95 ℃,15 s),1个循环数。采用2-ΔΔCt方法对目标基因mRNA的相对表达量进行定量。

表 2 相关基因的引物序列 Table 2 Primer sequences of related genes
1.4 血浆中TG、VLDL含量及组织中TG含量测定

血浆中TG含量使用7170A全自动生化分析仪(日本日立公司)测定,组织中TG和血浆中VLDL含量采用南京建成生物工程研究所生产的试剂盒通过酶标仪(SpectraMax iD3,美国)测定。

1.5 数据统计与分析

试验数据采用SAS 8.0统计软件的ANOVA程序进行单因素方差分析。差异达到显著水平(P < 0.05)时,采用Duncan氏法进行多重比较,数据用平均值±标准误表示。

2 结果 2.1 短期限饲对家兔组织生长的影响

表 3可知,短期限饲显著降低了家兔的肝脏指数(P < 0.05),有降低家兔后腿肌重量的趋势(P=0.074 3),对家兔前腿肌、背腰肌和总肌肉(前腿肌+后腿肌+背腰肌)重量的影响不显著(P>0.05)。

表 3 短期限饲对家兔组织生长的影响 Table 3 Effects of short-term feed restriction on tissue growth of rabbits(n=8)
2.2 短期限饲对家兔血浆中TG和VLDL含量及组织中TG含量的影响

表 4可知,短期限饲显著降低了家兔血浆中TG和VLDL含量(P < 0.05);短期限饲对家兔肝脏和背腰肌中TG含量的影响不显著(P>0.05)。

表 4 短期限饲对家兔血浆中TG和VLDL含量及组织中TG含量的影响 Table 4 Effects of short-term feed restriction on TG and VLDL contents in plasma and TG content in tissues of rabbits (n=8)
2.3 短期限饲对家兔肝脏中脂质代谢相关基因表达的影响

图 1所示,短期限饲显著降低了家兔肝脏中脂肪酸合成酶(FAS)mRNA的相对表达量(P < 0.05),显著上调了CPT1、肉碱脂酰转移酶2(CPT2)、G蛋白偶联受体41(GPR41)、G蛋白偶联受体43(GPR43)和过氧化物酶体增殖物激活受体α(PPARα)mRNA的相对表达量(P < 0.05),对家兔肝脏中乙酰辅酶A羧化酶1(ACC1)mRNA的相对表达量无显著影响(P>0.05)。

数据柱形标注无字母或相同字母表示差异不显著(P>0.05),不同小写字母表示差异显著(P<0.05)。下图同。 Value columns with no letter or the same letter superscripts mean no significant difference (P>0.05), while with different small letters mean significant difference (P<0.05). The same as below. 图 1 短期限饲对家兔肝脏中脂质代谢相关基因表达的影响 Fig. 1 Effects of short-term feed restriction on expression of lipid metabolism-related genes in liver of rabbits (n=8)
2.4 短期限饲对家兔骨骼肌中脂质代谢相关基因表达的影响

图 2所示,短期限饲显著上调了家兔骨骼肌中脂蛋白脂肪酶(LPL)、FABPGPR41和GPR43 mRNA的相对表达量(P < 0.05),显著下调了家兔骨骼肌中CPT1和CPT2 mRNA的相对表达量(P < 0.05),对家兔骨骼肌中PPARαFATP mRNA的相对表达量无显著影响(P>0.05)。

图 2 短期限饲对家兔肌肉中脂质代谢相关基因表达的影响 Fig. 2 Effects of short-term feed restriction on expression of lipid metabolism-related genes in skeletal muscle of rabbits (n=8)
3 讨论

肝脏是糖类、脂质和蛋白质三大营养元素的重要代谢平台,可调控机体糖脂代谢,影响脂质的消化、分解、转运、吸收和合成[12]。FAS是脂肪酸从头合成的关键限速酶,是由许多酶结合而成的大分子蛋白质复合体系,动物脂肪沉积需要的脂肪酸多来自FAS的催化产物[13]。ACC1也是脂肪酸合成的限速酶,主要在肝脏中表达,参与脂肪酸合成的第1步反应[14]。CPT能催化脂肪酸β-氧化,该酶有CPT1和CPT2 2种同工酶形式,分别位于线粒体外膜和线粒体内膜的内侧面。CPT1使胞浆内脂酰辅酶A转化为辅酶A和脂酰肉碱,随后脂酰肉碱在CPT2作用下转化为肉碱和脂酰辅酶A,脂酰辅酶A进入线粒体基质进行β-氧化[15]。在本试验中,短期限饲显著下调了肝脏中FAS mRNA的相对表达量,同时显著上调了肝脏中CPT1、CPT2 mRNA的相对表达量,暗示限饲过程中肝脏内脂肪酸合成过程受到抑制,而脂肪酸氧化分解过程增加,这与在家禽上所得研究结果[15]相一致。脂类在肝内质网内合成后,与载脂蛋白、磷脂及胆固醇结合组装成VLDL,然后经由肝细胞分泌进入血液后转运至各组织器官利用[15]。本试验还发现,短期限饲后家兔血浆中TG和VLDL的含量下降,说明从肝脏中运出的脂类降低。虽然肝脏中TG含量并未变化,但肝脏的重量降低,因此,短期限饲后家兔肝脏内总脂类合成减少。

骨骼肌在发育过程需要大量脂肪酸氧化供能,LPL主要催化血浆中乳糜微粒和VLDL中的TG水解,产生甘油和游离脂肪酸,供肌肉组织氧化供能[16]。本试验发现,短期限饲显著增加了骨骼肌中LPL mRNA的相对表达量,这一结果与在鲈鱼[17]和大鼠[18]上研究结果相一致,暗示限饲过程中骨骼肌加速了TG的水解过程。在骨骼肌中,FATP和FABP能促进对长链脂肪酸的绑定、摄取、转运和利用[19]。本试验中,短期限饲显著增加了骨骼肌中FABP mRNA的相对表达量,暗示骨骼肌对脂肪酸的摄取增加;同时,短期限饲抑制了骨骼肌中CPT2的表达,这可能是由于肝脏中输出的脂类降低,造成了骨骼肌中氧化底物的不足,从而引起CPT2的表达下调, 使得骨骼肌中能量供应不足,发育受到限制。

过氧化物酶体增殖物激活受体(PPARs)是可由配体激活的一类核转录因子,PPARα主要在肝脏、心脏和肌肉中表达,PPARα可增强与脂质代谢有关的酶和基因转录,参与脂肪酸氧化[20],PPARγ可以调控与脂质代谢相关基因的表达,从而调控脂肪细胞成脂分化和脂肪沉积[21]。Hsu等[22]研究发现PPARα能调节CPT1的表达,本试验中发现肝脏中PPARαCPT1有相同的表达趋势,暗示限饲过程中PPARα可能参与了CPT1表达的调控。此外,本试验还发现短期限饲对骨骼肌中PPARα的表达无显著影响,暗示限饲过程中PPARα的表达具有组织特异性。

GPR41和GPR43是由2条多肽链经7次跨膜而成的受体,可被短链脂肪酸(SCFAs)激活,参与调控机体代谢和免疫活动。在棕色脂肪细胞中,经GPR43拮抗剂处理后,显著降低了乙酸盐介导的成脂作用和线粒体内的生物合成[23],在牛脂肪细胞中经乙酸盐处理后,细胞瘦素mRNA转录水平显著上调,在经GPR41抑制剂(百日咳毒素)处理后,乙酸刺激瘦素表达的效应消失[24],因此,GPR41和GPR43在脂质代谢过程中具有重要作用。本试验发现短期限饲显著上调了家兔肝脏和骨骼肌中GPR41和GPR43 mRNA的相对表达量,这与Veprik等[25]的研究结果相一致,暗示限饲过程中GPR41和GPR43在家兔能量稳态的调节过程中发挥重要作用。

4 结论

短期限饲显著下调了家兔肝脏中FAS的表达,抑制脂肪酸的合成路径,上调肝脏中CPT1和CPT2的表达,从而促进脂肪酸的氧化分解,PPARα、GPR41和GPR43参与此过程。短期限饲显著上调了家兔骨骼肌中LPLFABP的表达,暗示骨骼肌对脂类的摄取增加,同时骨骼肌中CPT2的表达降低,暗示骨骼肌中脂肪酸的氧化过程降低,GPR41和GPR43参与此过程。

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