动物营养学报 >

2023 , Vol. 35 >Issue 1: 63 - 70

DOI: https://doi.org/10.3969/j.issn.1006-267x.2023.01.007

综述

过氧化物酶体增殖物激活受体γ辅激活因子-1α对奶牛脂肪肝的调节作用及机制

  • 安彦昊 , 1 ,
  • 马贵 1 ,
  • 孙奕烁 1 ,
  • 马燕芬 , 1, 2, *
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  • 1 宁夏大学农学院,宁夏回族自治区反刍动物分子细胞育种重点实验室,银川 750021
  • 2 内蒙古自治区农牧业科学院,动物营养与饲料研究所,呼和浩特 010031
* 马燕芬,研究员,博士生导师,E-mail:

安彦昊(1997—),男,宁夏西吉人,硕士研究生,研究方向为动物营养与免疫。E-mail:

收稿日期: 2022-06-21

  网络出版日期: 2023-01-11

基金资助

宁夏自然科学基金项目(2022AAC02006)

宁夏大学科研启动项目(030900002154)

内蒙古自治区科技计划项目(2021GG0025)

内蒙古农牧业创新基金项目(2019CXJJM06)

宁夏回族自治区乡村振兴科技成果引进示范推广项目(2021CGSF0206)

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Regulatory Effect and Mechanism of Peroxisome Proliferator-Activated Receptor γ Coactivator-1α on Fatty Liver of Dairy Cows

  • AN Yanhao , 1 ,
  • MA Gui 1 ,
  • SUN Yishuo 1 ,
  • MA Yanfen , 1, 2, *
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  • 1 Key Laboratory of Ruminant Molecular Cell Breeding in Ningxia, School of Agriculture, Ningxia University, Yinchuan 750021, China
  • 2 Institute of Animal Nutrition and Feed, Inner Mongolia Academy of Agriculture and Animal Husbandry Sciences, Huhehot 010031, China
* professor, E-mail:

Received date: 2022-06-21

  Online published: 2023-01-11

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摘要

随着畜牧业发展对畜禽养殖和畜产品品质要求的提高,营养代谢疾病在动物群体中的发病率也呈逐渐增加趋势。脂肪肝作为营养代谢性疾病的一种,常发生在围产期高产奶牛群体中,长期处于能量负平衡状态的高产奶牛,过量的动员体脂造成肝脏甘油三酯堆积,从而形成脂肪肝。患有脂肪肝的奶牛不仅会导致其产奶量降低,产犊间隔延长,还会诱发其他疾病的发生,对奶牛的生产性能和畜牧业的发展产生巨大的负面作用。核转录辅激活因子过氧化物酶体增殖物激活受体γ辅激活因子-1α(PGC-1α)参与多种核受体及转录因子相互作用,从而调控相关靶基因的表达。PGC-1α与奶牛脂肪肝、酮病和乳腺炎等疾病有着密切的关系,有可能成为新的疾病治疗靶点。本文综述了PGC-1α调控的各种分子途径,将调控脂质代谢、线粒体功能障碍、氧化应激、胰岛素抵抗和炎症反应联系起来,进一步阐明PGC-1α在奶牛脂肪肝中发挥调节作用的最新研究进展。

关键词： 奶牛; 过氧化物酶体增殖物激活受体γ辅激活因子-1α; 脂肪肝; 作用机制

本文引用格式

安彦昊 , 马贵 , 孙奕烁 , 马燕芬 . 过氧化物酶体增殖物激活受体γ辅激活因子-1α对奶牛脂肪肝的调节作用及机制[J]. 动物营养学报, 2023 , 35(1) : 63 -70 . DOI: 10.3969/j.issn.1006-267x.2023.01.007

Abstract

The incidence of nutritional metabolic diseases in animal population is gradually increasing, with the development of animal husbandry to improve the quality of livestock breeding and livestock products. Fatty liver is a kind of nutritional metabolic disease with a high incidence in perinatal high-yielding dairy cows. During the perinatal period, dairy cows are usually in a negative energy balance, leading to excessive mobilization of body fat, resulting in accumulation of liver triglycerides and thus fatty liver. Dairy cows with fatty liver can reduce milk yield, prolong calving interval, and induce the occurrence of other diseases, which have a huge impact on the production performance of dairy cows and the development of animal husbandry. Peroxisome proliferator-activated receptor γ coactivator-1α (PCC-1α) is an important nuclear transcription coactivator, which participates in the interaction of various nuclear receptors and transcription factors to regulate the expression of related target genes. PCC-1α is closely related to fatty liver, ketosis and mastitis in dairy cows, and may be a new therapeutic target for these diseases. In this review, we reviewed the various molecular pathways involved in the regulation of PGC-1α, and further elucidated the latest research progress on the regulatory role of PGC-1α in fatty liver of dairy cows by regulating lipid metabolism, mitochondrial dysfunction, oxidative stress, insulin resistance and inflammatory response.

Key words： dairy cows; proliferator-activated receptor-γ coactivator-1α; fatty liver; mechanism of action

随着现代化养殖水平的不断提高,脂肪肝和酮病等营养性代谢疾病在围产期高产奶牛中多发,其中,中轻度脂肪肝的发病率高达30%~40%[1],且呈不断上升趋势。脂肪肝疾病是一种典型的非酒精性脂肪性肝病(nonalcoholic fatty liver disease,NAFLD),围产期奶牛脂肪肝的发生导致奶牛的淘汰率高达25%[2],不仅会对奶牛的生产性能和繁殖性能产生影响,还会降低产奶量,诱发其他疾病的发生,如酮病、乳房炎、皱胃变位、子宫炎[3⇓-5]等,影响奶牛的健康状况和生产寿命,给奶牛养殖业带来巨大的经济损失。基于此,从分子层面深入挖掘奶牛脂肪肝发病机理,寻找主要调控靶点,对预防奶牛脂肪肝发病,提高奶牛养殖的经济效益和畜牧业发展极为重要。
过氧化物酶体增殖物激活受体γ(peroxisome proliferator-activated receptor gamma,PPARγ)通过影响肝脏脂代谢、糖异生、氧化应激、内质网应激和炎症[6⇓-8]等的生物过程参与调节肝脏中脂肪沉积,而脂肪肝的发生常与这些过程的发生发展联系紧密。PPARγ共激活因子过氧化物酶体增殖物激活受体γ辅激活因子-1α(peroxisome proliferator-activated receptor γ coactivator-1α,PGC-1α)在胰岛素抵抗(insulin resistance,IR)、线粒体功能障碍和脂质代谢紊乱[9]中主要以糖异生、脂肪酸氧化、线粒体呼吸关键酶的形式参与,不仅可以促进线粒体生物合成、消除氧自由基、调节不同纤维类型骨骼肌相互转化,对一些炎性因子也有一定的作用[10]。目前,PGC-1α已被公认参与NAFLD的发生和发展[11]。在NAFLD的治疗中,通过单磷酸腺苷激活的蛋白激酶(adenosine monophosphate activated protein kinase,AMPK)增强PGC-1α转录活性,调控线粒体的生物合成功能和能量代谢,从而促进脂肪酸的氧化,减少肝脏脂肪沉积,达到改善NAFLD的作用[12]。因此,深入探究PGC-1α参与脂肪肝发生发展的不同生物调节过程及影响PGC-1α表达水平变化的相关因素,对了解奶牛脂肪肝的发病机制、预防和治疗提供夯实的理论依据和技术支撑,对减少奶牛养殖业不必要的经济损失有重要意义。

1 脂肪肝

NAFLD被认为是一种以脂肪酸积累、氧化应激和脂毒性为特征的慢性肝病,常与炎性反应、肥胖、Ⅱ型糖尿病、脂质代谢功能障碍、氧化应激和胰岛素抵抗密切相关[13]。奶牛产犊后由于干物质采食量(dry matter intake,DMI)下降,产奶量升高,通过饲粮摄取的养分不足以满足机体能量需求,导致奶牛发生严重的能量负平衡(negative energy balance,NEB)。为了满足机体能量的需求,机体动员体脂分解产生非酯化脂肪酸(non-esterified fatty acids,NEFA),但大量的体脂动员会使血浆中NEFA浓度升高,肝脏脂质摄入超过NEFA的氧化和分解能力时,过量的脂质就会以甘油三酯(triacylglycerol,TG)的形式蓄积在肝脏中[14],使肝脏的代谢功能发生障碍,从而诱发脂肪肝的发生[5,15]。肝脏中TG含量是诊断奶牛脂肪肝的黄金标准,根据肝脏中TG含量可以将脂肪肝分为重度脂肪肝(肝脏TG含量大于10%)、中度脂肪肝(肝脏TG含量为5%~10%)、轻度脂肪肝(肝脏TG含量为1%~5%)和健康肝脏(肝脏TG含量小于1%)[5]。研究发现,在分娩后的第1个月内患有重度脂肪肝的奶牛占5%~10%,患有轻度脂肪肝和重度脂肪肝的奶牛占30%~40%[5,16]。因此,深入探究奶牛脂肪肝的发病机制及影响因素,可为预防和治疗奶牛脂肪肝提供充分的技术支撑。

2 PGC-1α

核转录辅助激活因子PGC-1α被认为是线粒体生物功能发挥的主要调节因子[17],在调节线粒体功能和能量稳态方面起着关键作用。PGC-1α作为转录共激活因子过氧化物酶体增殖物激活受体(peroxisome proliferators-activated receptors,PPAR)家族的重要成员,一般存在于肝脏、肾脏、骨骼肌、棕色脂肪组织和心肌等[18-19]线粒体丰富的组织和器官中,并与许多炎性疾病和代谢性疾病如Ⅱ型糖尿病、心血管疾病和脂肪变性紧密关联。近年来,PGC-1α的作用备受关注,PGC-1α可以在线粒体功能、氧化应激、炎症和不同组织代谢途径中发挥重要的调节作用[20-21]。

3 PGC-1α调节脂肪肝的作用及机制

目前,PGC-1α在脂肪肝中的研究主要体现在人和小鼠及体外的细胞模型,在奶牛脂肪肝作用机制研究中的内容极少。PGC-1α对脂肪肝的调节作用及机制主要体现在脂质代谢、线粒体功能障碍、氧化应激、胰岛素抵抗及炎症反应等方面。

3.1 PGC-1α与脂质代谢

脂质积累是肝脏脂肪代谢发生紊乱的基础,这与脂肪肝的发生发展密切相关,而脂肪变性的发生发展主要是以上调生脂基因甾醇调节元件结合蛋白-1c信号通路或下调脂质氧化基因沉默信息调节因子1(sirtuin 1,SIRT1)/PGC-1α信号通路进一步影响脂质代谢,最终导致脂质代谢发生紊乱[22]。AMPK作为细胞能量状态的监测器,在调节脂质代谢中发挥重要作用[23]。AMPK可以通过增加烟酰胺腺嘌呤二核苷酸的水平来增强SIRT1活性,进一步导致SIRT1下游靶标PGC-1α的脱乙酰化和活性调节[24]。而SIRT1作为AMPK的下游分子,可以控制参与能量代谢基因的表达,增强AMPK/SIRT1的表达可以抑制乙酰辅酶A羧化酶(acetyl CoA carboxylase,ACC)活性并增加脂肪分解和β-氧化[25-26],且SIRT1可以通过PGC-1α和PPARα等多个传感器调节脂质稳态。Chen等[27]首次通过体内和体外试验证明AMPK/SIRT1通路可以调节肝脏脂肪生成和脂肪酸氧化,并显著改善肝脏脂肪变性,有可能成为NAFLD治疗的潜在途径。此外,在阿司匹林刺激的氧化磷酸化途径中[28],通过激活PPAR/AMPK/PGC-1α信号通路来提高脂质代谢,抑制脂质生物合成和炎症发生,进而降低NAFLD的发病。
成纤维细胞生长因子21(fibroblast growth factor 21,FGF21)具有与内分泌激素相似的功能,可以降低血脂,改善肥胖相关的血脂异常[29]。体内和体外试验证实FGF21可以激活肝脏中AMPK/SIRT1/PGC-1α信号通路,增加SIRT1及其下游PGC-1α的蛋白表达,从而加强脂肪酸氧化,减少脂肪生成,发挥调节脂质代谢的作用[30]。葡萄糖转运蛋白4(glucose transporter 4,GLUT4)作为葡萄糖摄取的主要转运蛋白,在调节血糖中发挥重要作用[31]。PGC-1α和GLUT4是反映脂肪和肌肉组织中葡萄糖摄取和能量消耗水平的主要指标[32],而PGC-1α作为PPAR家族重要的成员,在脂质代谢和脂肪积累方面发挥着重要的调节作用。有研究表明,通过激活AMPK/PGC-1α/GLUT4信号通路可以降低血糖和改善脂质代谢紊乱导致的酒精性脂肪肝损伤[33]。单核细胞趋化蛋白-1诱导蛋白1(monocyte chemoattractant protein-1-induced protein 1,MCPIP1)核酸内切酶是一种重要的炎症负调节因子[34],可以降解炎症相关因子[35],MCPIP1主要是通过硫氧还蛋白相互作用蛋白(thior-edoxin-interacting protein,TXNIP)/PGC-1α激活PPARγ转录因子,从而调节肝细胞的脂质代谢[36]。此外,外源性功能活性物质如黄芩素也可通过显著提高油酸诱导的雄性C57BL/6小鼠的HepG2细胞激活PPARγ、PGC-1α、线粒体核呼吸因子(nuclear respiratory factor,NRF)-1/2、谷胱甘肽S-转移酶(glutathione S-transferase,GST)的mRNA和蛋白表达水平,降低血脂水平,提高抗氧化能力,揭示黄芩素可以通过PPARγ/PGC-1α/NRF-1/2通路改善NAFLD的脂质代谢[37]。

3.2 PGC-1α与线粒体功能障碍

线粒体作为真核细胞内能量的生产者,为满足机体能量的需求发挥着重要作用,而线粒体功能障碍则会导致高能量需求组织如大脑、心脏、肝脏和肌肉等功能发生紊乱,加剧氧化应激、炎性反应和细胞凋亡。线粒体功能障碍在脂肪肝发生发展中发挥重要作用,其功能障碍被认为是导致脂肪肝的一个重要发病机制之一[38]。PGC-1α作为线粒体生物发生的标志和AMPK/SIRT1参与线粒体生物发生的主要靶标,其稳定性与线粒体功能紧密相关[39-40],PGC-1α含量的减少会使线粒体损伤,最终导致细胞调亡[41]。研究发现,AMPK/SIRT1/PGC-1α能量传感网络在线粒体生物发生中对能量代谢和线粒体稳态有着极其关键的作用[42],AMPK磷酸化后通过上调PGC-1α和SIRT1的表达[43],调节线粒体的生物发生,维持脂肪酸氧化和细胞增殖稳态[44]。因此,直接或间接靶向调控AMPK/SIRT1/PGC-1α信号通路可能是改善或治疗奶牛脂肪肝的重要途径。而在脂肪肝中产生的过量脂肪则会通过下调AMPK/SIRT1/PGC-1α途径损伤线粒体生物活性,减少质粒形成,导致肝细胞中脂质积累发生脂毒性,最终引起细胞调亡[45]。如脂肪肝奶牛血液中过量的NEFA可显著损伤线粒体功能,增加活性氧(reactive oxygen species,ROS)产生,产生的过量ROS则会激活c-Jun氨基末端激酶(c-jun n-terminal kinase,JNK)和p38丝裂原活化蛋白激酶(p38 mitogen-activated protein kinase,p38MAPK)通路,诱导奶牛肝细胞胰岛素抵抗;而过表达PGC-1α则可显著降低NEFA诱导的ROS生成和炎性因子的表达,缓解NEFA对线粒体功能的抑制作用,减弱ROS/JNK/p38MAPK通路的过度激活,进而减轻NEFA诱导的奶牛肝细胞线粒体功能障碍和胰岛素抵抗[46]。Yes相关蛋白(yes-associated protein,YAP)的副产物转录效应因子(tafazzin,TAZ)可通过WW结构域与PPARγ的基序间的相互作用抑制PPARγ活性[47],过表达YAP可通过YAP/TAZ-PPARγ/PGC-1α通路缓解线粒体功能障碍,从而改善NAFLD[48]。
此外,外源性添加物质也可通过上调PGC-1α通路缓解肝细胞线粒体功能障碍。体内和体外研究发现,虾青素通过上调FGF21/PGC-1α通路显著改善线粒体生物发生和功能,减少ROS过量产生,增加线粒体DNA(mtDNA)拷贝数,进而减轻高脂饲粮(high-fat diet,HFD)和弗氏酵母诱导的肝脏脂质积聚、氧化应激、细胞凋亡、炎症和纤维化,进一步说明虾青素可以通过上调PGC-1α通路缓解肝损伤和线粒体功能障碍[49]。添加丙酸能显著提升NEFA诱导的奶牛肝细胞线粒体功能损伤的相关调节因子PGC-1α、电压依赖性阴离子通道蛋白1(voltage-dependent anion channel protein 1,VDAC1)、线粒体转录因子A(mitochondrial transcription factor A,Tfam)、细胞色素c氧化酶Ⅳ(cytochrome c oxidase Ⅳ,COXⅣ)的表达,降低氧化物含量,提高抗氧化物活力,增强细胞的抗氧化能力,而高表达的PGC-1α是线粒体功能恢复的关键调控因子;但是在高浓度NEFA处理的奶牛肝细胞中沉默PGC-1α,经丙酸处理后则不能提高线粒体中相关调节因子PGC-1α、VDAC1、Tfam和COXⅣ的表达量,无法改善NEFA诱发的线粒体功能损伤[50]。蓝莓叶多酚(polyphenols in blueberry leaves,PBL)通过升高沉默信息调节因子2相关酶3(silent information regulator 2 related enzyme 3,SIRT3)蛋白表达和AMPKα磷酸化而提升PGC-1α的表达量,从而激活雌激素相关受体(estrogen-related receptors,ERR)和NRF转录因子,进一步增强线粒体功能[42]。综上所述,上调PGC-1α的表达量可缓解肝细胞线粒体功能障碍,进而对脂肪肝的发生起到保护性抑制作用。

3.3 PGC-1α与氧化应激

围产期奶牛机体对氧的需求量显著增加,导致大量ROS的产生,促使氧化物与抗氧化物之间的动态平衡失调,机体抗氧化防御能力不足以清除聚集在机体内的ROS,导致机体发生氧化应激状态。大量产生的ROS则会通过影响脂质代谢介导肝脏脂肪沉积,最终诱发奶牛脂肪肝发生。有研究表明,激活PPARα/PGC-1α信号通路可以减少氧化应激,显著降低ROS和丙二醛(malondialdehyde,MDA)的产生,增强超氧化物歧化酶(superoxide dismutase,SOD)和谷胱甘肽过氧化物酶(glutathione peroxidase,GSH-Px)的活性[51]。因此,生产中可通过激活PPARα/PGC-1α信号通路调节线粒体功能来预防NALFD的发生。但沉默PGC-1α表达后则损害了肝细胞线粒体功能,加剧了肝脏的氧化应激和凋亡[50],而过表达SIRT1基因则可通过上调SIRT1/固醇调节元件结合蛋白-1c(sterol regulatory element binding protein-1c,SREBP-1c)/PGC-1α通路的表达降低氧化应激,进而缓解肝脏脂肪的沉积[52],进一步证明PGC-1α具有调控氧化应激缓解脂肪肝的作用。

3.4 PGC-1α与胰岛素抵抗

高水平的NEFA不仅是NAFLD的病理因素,还可以损害肝细胞线粒体功能和胰岛素信号传导[53],且线粒体功能障碍被认为是诱发胰岛素抵抗的致病因素。研究发现,脂肪肝奶牛线粒体功能障碍表现出胰岛素抵抗和高浓度的NEFA,但维持线粒体功能和胰岛素敏感性需要调节剂PGC-1α等的参与[54]。Li等[55]在研究脱氢表雄酮(dehydroepiandrosterone,DHEA)的抗糖脂代谢紊乱和胰岛素抵抗的作用中发现,DHEA通过激活AMPK/PGC-1α/NRF1信号通路增加HFD和棕榈酸(palmitic acid,PA)诱导的大鼠BRL-3A细胞中mtDNA拷贝数、ATP水平和线粒体膜电位,抑制ROS的产生,从而改善线粒体功能障碍;此外,DHEA还可激活胰岛素受体底物1(insulin receptor substrate 1,IRS1)/蛋白激酶B(protein kinase B,AKT)/GLUT2信号通路,通过增加大鼠BRL-3A细胞中磷酸化胰岛素受体底物1(phosphorylated insulin receptor substrate 1,p-IRS1)(Tyr612)水平,降低p-IRS1(Ser307)水平来缓解胰岛素抵抗。外源性添加物小檗碱(berberine,BBR)也可以通过上调PGC-1α表达显著改善NEFA诱导的奶牛肝细胞线粒体呼吸链功能损伤和胰岛素信号传导损伤[56],该研究思路为预防和治疗奶牛轻度和中度脂肪肝提供了新的治疗策略。

3.5 PGC-1α与炎症反应

炎症是代谢综合征的重要组成部分,其中特异性免疫细胞和促炎因子如肿瘤坏死因子α(tumors kill factor-α,TNF-α)、白细胞介素-1β(interleukin 1β,IL-1β)、白细胞介素-6(interleukin 6,IL-6)等会促进代谢性疾病的发生和发展,最终诱发炎症反应。机体正常炎症反应对外来物侵害的抵御和机体自身组织的修复发挥重要的作用,然而当机体发生病变或外界因素干扰时炎症反应会进一步加剧机体的恶性循环过程。因此,炎症反应是加速或造成围产期奶牛脂肪肝发生发展的重要因素。
PGC-1α除了参与脂质代谢过程外,还可以调节炎症反应,其活性与炎症的发生过程密切相关。在炎症条件下,PGC-1α表达水平下降,可以促进炎症反应的发生[57]。环氧二十碳三烯酸激动剂(epoxyeicosatrienoic acid-agonist,EET-A)是位于PGC-1α的上游的基因,可通过增加血红素氧合酶-1(heme oxygenase-1,HO-1)/PGC-1α线粒体信号通路改善瘦素受体缺陷小鼠的NAFLD[58]。Raffaele等[58]在小鼠体内使用慢病毒载体递送PGC-1α沉默载体(Ln PGC-1α sh)和EET-A来检验EET-A干预NAFLD进展的效果,结果发现EET-A通过上调PGC-1α和HO-1的表达缓解了脂肪肝综合征,从而抑制炎症标记物TNF-α的表达。Wang等[59]在阐明异甘草素(isoliquiritigenin,ISL)对NAFLD的作用中发现,ISL可显著增加参与脂质代谢的PPARα、肉毒碱棕榈酰基转移酶1α(carnitine palmitoyltransterase 1α,CPT1α)和乙酰辅酶A脱氢酶(acetyl coenzyme A dehydrogenase,ACADS)表达水平,并通过激活PGC-1α抑制ROS、TNF-α、IL-1β和IL-6的表达,通过荧光素酶分析进一步证实miR-138-5p和miR-23a-3p可能与NAFLD中的PGC-1α mRNA结合;此外还发现miR-138-5p和miR-23a-3p的表达在NAFLD中增加,而在ISL处理后的肝细胞中则显著降低,且miR-138-5p和miR-23a-3p的抑制剂还可通过激活PGC-1α促进脂质代谢并抑制NAFLD中的炎症反应[60]。进一步说明ISL可以通过调节miR-138-5p/PGC-1α和miR-23a-3p/PGC-1α介导的脂质代谢和炎症反应减轻NAFLD的发生。

4 小结与展望

围产期奶牛脂质代谢紊乱、线粒体功能障碍、胰岛素抵抗和炎症是奶牛脂肪肝发生的主要原因。而PGC家族中的PGC-1α在脂质代谢、线粒体功能障碍、氧化应激胰岛素抵抗和炎症反应中均发挥重要的作用,PGC-1α不仅在正常的组织代谢途径中不可或缺,并且在疾病的发生发展过程中发挥重要的功能作用。基于此,深层次探究PGC-1α在奶牛脂肪肝发病中的功能作用,将有助于了解奶牛脂肪肝的发病机制,有望成为奶牛脂肪肝诊断和治疗的新靶点。

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