运动对2,3,7,8-TCDD持续染毒大鼠肝脏LXRa蛋白、ACC1、FAS、SCD1 mRNA表达的影响
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摘要
研究运动对2,3,7,8-四氯二苯并二噁英(2,3,7,8-TCDD)持续染毒大鼠肝脏脂质合成代谢关键酶乙酰辅酶A羧化酶1(ACC1)、脂肪酸合成酶(FAS)、硬脂酰辅酶A去饱和酶1(SCD1)m RNA及转录因子肝X受体a(LXRa)蛋白表达的影响,探讨环境污染物引发代谢性疾病的发病机制,为运动锻炼防控环境健康风险提供理论支持。将24只8周龄雄性大鼠随机分为对照组(C组)、染毒组(T组)、运动染毒组(ET组)。T、ET组腹腔注射首剂量6.4μg·kg-1(以单位体重计)的2,3,7,8-TCDD,之后每隔1周给予上述剂量的21%持续染毒,连续7周。ET组尾部负重(5%体重)进行游泳运动,每周5 d,每次30 min。8周后处死动物,计算肝脏相对重量,检测肝脏甘油三酯(TG)含量,实时荧光定量PCR检测肝脏ACC1、FAS、SCD1 m RNA表达,免疫印迹法(Western Blot)检测肝脏LXRa蛋白表达。结果显示8周2,3,7,8-TCDD持续染毒可显著增加肝脏脂质合成代谢关键酶ACC1、FAS、SCD1 m RNA及转录因子LXRa蛋白表达,8周游泳运动可显著降低染毒大鼠ACC1、FAS、SCD1 m RNA及LXRa蛋白表达。上述结果表明2,3,7,8-TCDD可以引起大鼠肝脏LXRa蛋白表达增高,进而LXRa通过调控靶基因ACC1、FAS、SCD1 m RNA的表达,造成脂质代谢紊乱,肝脏甘油三酯沉积,而有氧运动降低了肝脏中脂质的沉积,提示运动干预可以改善二噁英类污染物造成的肝脏脂质代谢紊乱。
To investigate the mechanisms of metabolic diseases induced by environmental pollutants, this study evaluated the effects of exercise on the expression of ACC1, FAS, SCD1 m RNA, which are crucial enzymes during lipid metabolism in the liver, and the transcriptional factor LXRa in continuously 2,3,7,8-TCDD exposed rats, andconsequently, provided the theoretic support for controlling and decreasing the environmental risks by exercise.Twenty-four 8-week old male SD rats were randomly assigned into control(C) group, toxic(T) group and exercise toxic(ET) group. The rats in the latter two groups were injected intraperitoneally with 2,3,7,8-TCDD(dissolved in the corn oil) at a dose of 6.4 μg·kg-1 of body weight during the first week. Thereafter, a maintenance dose of 21%of first dose were administered every week during the following 2-8 weeks. In addition, the rats in ET group swam5 times per week(at least 30 min every time) for eight weeks with a load of 5% body weight attached to the tails.After finishing the experiment, the livers from the rats of all three groups were weighted and collected for the following measures, including the triglyceride(TG), the expression of ACC1, FAS, and SCD1 m RNA determined by RT-PCR, and the concentration of LXRa determined via Western Blot. Continuous exposure to 2,3,7,8-TCDD increased the m RNA expression of the crucial enzymes during liver lipid metabolism and the concentration of TG and the transcriptional factor LXRa, while these indexes might be decreased by 8 weeks of swimming. The exposure of 2,3,7,8-TCDD could increase the concentration of LXRa in rat liver, and then the expression of LXRa-targeted genes, including ACC1, FAS and SCD1 m RNA, might be upregulated, consequently leading to disorder of lipid metabolism and deposition of triglyceride in the liver. The results of decreasing in lipid deposition in the liver by aerobic exercise indicated that exercise could reverse the lipid metabolic disorder induced by exposure to 2,3,7,8-TCDD.
To investigate the mechanisms of metabolic diseases induced by environmental pollutants, this study evaluated the effects of exercise on the expression of ACC1, FAS, SCD1 m RNA, which are crucial enzymes during lipid metabolism in the liver, and the transcriptional factor LXRa in continuously 2,3,7,8-TCDD exposed rats, andconsequently, provided the theoretic support for controlling and decreasing the environmental risks by exercise.Twenty-four 8-week old male SD rats were randomly assigned into control(C) group, toxic(T) group and exercise toxic(ET) group. The rats in the latter two groups were injected intraperitoneally with 2,3,7,8-TCDD(dissolved in the corn oil) at a dose of 6.4 μg·kg-1 of body weight during the first week. Thereafter, a maintenance dose of 21%of first dose were administered every week during the following 2-8 weeks. In addition, the rats in ET group swam5 times per week(at least 30 min every time) for eight weeks with a load of 5% body weight attached to the tails.After finishing the experiment, the livers from the rats of all three groups were weighted and collected for the following measures, including the triglyceride(TG), the expression of ACC1, FAS, and SCD1 m RNA determined by RT-PCR, and the concentration of LXRa determined via Western Blot. Continuous exposure to 2,3,7,8-TCDD increased the m RNA expression of the crucial enzymes during liver lipid metabolism and the concentration of TG and the transcriptional factor LXRa, while these indexes might be decreased by 8 weeks of swimming. The exposure of 2,3,7,8-TCDD could increase the concentration of LXRa in rat liver, and then the expression of LXRa-targeted genes, including ACC1, FAS and SCD1 m RNA, might be upregulated, consequently leading to disorder of lipid metabolism and deposition of triglyceride in the liver. The results of decreasing in lipid deposition in the liver by aerobic exercise indicated that exercise could reverse the lipid metabolic disorder induced by exposure to 2,3,7,8-TCDD.
引文
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[15]Heald A,Sein K,Anderson S,et al.Diet,exercise and the metabolic syndrome in Schizophrenia:A cross-sectional study[J].Schizophrenia Research,2015,169(1-3):494-495
[16]Lee S,Norheim F,Gulseth H L,et al.Interaction between plasma fetuin-A and free fatty acids predicts changes in insulin sensitivity in response to long-term exercise[J].Physiological Reports,2017,5(5):1-14
[17]Zhao J,Su Z,Qu C,et al.Effects of 12 weeks resistance training on serum irisin in older male adults[J].Frontiers in Physiology,2017,8:171-175
[18]Croutch C R,Lebofsky M,Schramm K,et al.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin(Hx CDD)alter body weight by decreasing insulin-like growth factor I(IGF-I)signaling[J].Toxicological Sciences,2005,85(1):560-571
[19]严翊,谢敏豪.大鼠游泳运动的最大乳酸稳态负荷的确定——乳酸最小试验[J].北京体育大学学报,2010,33(9):43-45Yan Y,Xie M H.The selection of rat swimming training load in maximal lactate steady state-lacate minimum test[J].Journal of Beijing Sport University,2010,33(9):43-45(in Chinese)
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[25]Ciftci O,Tanyildizi S,Godekmerdan A.Protective effect of curcumin on immune system and body weight gain on rats intoxicated with 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)[J].Immunopharmacology and Immunotoxicology,2010,32(1):99-104
[26]Medina-Contreras J M,Colado-Velázquez J,GómezViquez N L.Effects of topical capsaicin combined with moderate exercise on insulin resistance,body weight and oxidative stress in hypoestrogenic obese rats[J].International Journal of Obesity,2017,41(5):750-758
[27]Machado M V,Vieira A B,Nascimento A R,et al.Physical exercise restores microvascular function in obese rats with metabolic syndrome[J].Metabolic Syndrome and Related Disorders,2014,12(9):484-492
[28]魏冰,白厚增,靳一哲,等.运动、EGCG和肉碱对肥胖大鼠体重、内脏脂肪及肝脏CPT1表达的影响[J].中国运动医学杂志,2012(4):331-335,352Wei B,Bai H Z,Jin Y Z,et al.Exercise combined with administration of egcg and l-carnitine affects the weight,visceral fat and cpt1 expression in obese rats[J].Chinese Journal Sports Medicine,2012(4):331-335,352(in Chinese)
[29]张颢,卜淑敏,朱一力,等.跑台运动对去卵巢大鼠体重、腹腔内脂肪重量以及血清瘦素和脂联素含量的影响[J].中国运动医学杂志,2009(2):175-178Zhang H,Bu S M,Zhu Y L,et al.Effects of treadmill exercise on body weight,intraabdominal fat,serum leptin and adiponedtin levels in ovariectomized rats[J].Chinese Journal Sports Medicine,2009(2):175-178(in Chinese)
[30]Ohbayashi H,Sasaki T,Matsumoto M,et al.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-pdioxin on rat liver[J].The Journal of Toxicological Sciences,2007,32(1):47-56
[31]Korenaga T,Fukusato T,Ohta M,et al.Long-term effects of subcutaneously injected 2,3,7,8-tetrachlorodibenzo-pdioxin on the liver of Rhesus monkeys[J].Chemosphere,2007,67(9):399-404
[32]Du J L,Cao L P,Liu Y J,et al.A study of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced liver injury in Jian carp(Cyprinuscarpio var.Jian)using precision-cut liver slices[J].Bulletin of Environmental Contamination and Toxicology,2016,96(1):55-61
[33]Chiang J Y,Kimmel R,Stroup D.Regulation of cholesterol 7alpha-hydroxylase gene(CYP7A1)transcription by the liver orphan receptor(LXRalpha)[J].Gene,2001,262(1-2):257-265
[34]Vogelvan D,Bosch H M,Wit N J,et al.A cholesterolfree,high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine[J].American Journal of Physiology Gastrointestal and Liver Physiology,2008,294(5):1171-1180
[35]Castrillo A,Tontonoz P.Nuclear receptors in macrophage biology:At the crossroads of lipid metabolism and inflammation[J].Annual Review of Cell and Developmental Biology,2004,20:455-480
[36]Makishima M.Nuclear receptors as targets for drug development:Regulation of cholesterol and bile acid metabolism by nuclear receptors[J].Journal of Pharmacological Sciences,2005,97(2):177-183
[37]Peet D J,Turley S D,Ma W,et al.Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα[J].Cell,1998,93(5):693-704
[38]Chu K,Miyazaki M,Man W C,et al.Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation[J].Molecular and Cellular Biology,2006,26(18):6786-6798
[39]Talukdar S,Hillgartner F B.The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317[J].Journal of Lipid Research,2006,47(11):2451-2461
[40]Schultz J R,Tu H,Luk A,et al.Role of LXRs in control of lipogenesis[J].Genes and Development,2000,14(22):2831-2838
[41]Inaba T,Matsuda M,Shimamura M,et al.Angiopoietinlike protein 3 mediates hypertriglyceridemia induced by the liver X receptor[J].Biochemistry,2003,46(7):21344-21351
[42]Rocco D D,Okuda L S,Pinto R S,et al.Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice[J].Lipids,2011,46(7):617-625
[43]Kazeminasab M M,Ghaedi K,Esfarjani F,et al.Endurance training enhances LXR expression in the liver of male Wistar rats[J].Research in Pharmaceutical Sciences,2012,7(5):S544-553
[44]Yahagi N,Shimano H,Hasegawa K,et al.Cordinate activation of lipogenic enzymes in hepatocellular carcinoma[J].European Journal of Cancer,2005,41(9):1316-1322
[45]Rector R S,Thyfault J P,Morris R T,et al.Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima fatty rats[J].American Journal of Physiology-Gastrointestinal and Liver Physiology,2008,294(3):G619-G626
[46]Yasari S,Prud Homme D,Wang D,et al.Exercise training decreases hepatic SCD-1 gene expression and protein content in rats[J].Molecular and Cellular Biochemistry,2010,335(1):291-299
[2]Boyd S A,Sallach J B,Zhang Y,et al.Sequestration of TCDD by activated carbon eliminates bioavailability and the suppression of immune function in mice[J].Environmental Toxicology and Chemistry,2017,36(10):2671-2678
[3]Yun C,Weiner J A,Chun D S,et al.Mechanistic insight into the effects of aryl hydrocarbon receptor activation on osteogenic differentiation[J].Bone Reports,2017,16(6):51-59
[4]Iszatt N,Stigum H,Govarts E,et al.Perinatal exposure to dioxins and dioxin-like compounds and infant growth and body mass index at seven years:A pooled analysis of three European birth cohorts[J].Environment International,2016,94:399-407
[5]Sofo V,G9tte M,LaganàA S,et al.Correlation between dioxin and endometriosis:Anepigenetic route to unravel the pathogenesis of the disease[J].Archives of Gynecolo-gy and Obstetrics,2015,292(5):973-986
[6]Fukushi J,Tokunaga S,Nakashima Y,et al.Effects of dioxin-related compounds on bonemineral density in patients affected by the Yusho incident[J].Chemosphere,2016,145:25-33
[7]Chevrier J,Warner M,Gunier R B,et al.Serum dioxin concentrations and thyroid hormone levels in the seveso women's health study[J].American Journal of Epidemiology,2014,180(5):490-498
[8]Birnbaum L S.Developmental effects of dioxins and related endocrine disrupting chemicals[J].Toxicology letters,1995,82:743-750
[9]Ngwa E N,Kengne A P,Tiedeu-Atogho B,et al.Persistent organic pollutants as risk factors for type 2 diabetes[J].Diabetology and Metabolic Syndrome,2015,7:41-56
[10]Charles J,Olivia M.Associationsof exposure to dioxins and polychlorinated biphenyls with diabetes:Based on epidemiological findings[J].Environmental Research,2012,118(10):107-111
[11]Kim M J,Pelloux V,Guyot E,et al.Inflammatory pathway genes belong to major targets of persistent organic pollutants in adipose cells[J].Environmental Health Perspectives,2012,120(4):508-514
[12]Lee D,Lee I,Song K,et al.Astrong dose-response relation between serum concentrations of persistent organic pollutants and diabetes results from the national health and examination survey 1999-2002[J].Diabetes Care,2006,29(7):1638-1644
[13]PelclováD,Fenclova Z,Preiss J,et al.Lipid metabolism and neuropsychological follow-up study of workers exposed to 2,3,7,8-tetrachlordibenzo-p-dioxin[J].International Archives of Occupational and Environmental Health,2002,75:60-66
[14]Lockard B,Earnest C P,Oliver J,et al.Retrospective analysis of protein-and carbohydrate-focused diets combinedwith exerciseon metabolic syndrome prevalence in overweight and obese women[J].Metabolic Syndrome and Related Disorders,2016,14(4):228-237
[15]Heald A,Sein K,Anderson S,et al.Diet,exercise and the metabolic syndrome in Schizophrenia:A cross-sectional study[J].Schizophrenia Research,2015,169(1-3):494-495
[16]Lee S,Norheim F,Gulseth H L,et al.Interaction between plasma fetuin-A and free fatty acids predicts changes in insulin sensitivity in response to long-term exercise[J].Physiological Reports,2017,5(5):1-14
[17]Zhao J,Su Z,Qu C,et al.Effects of 12 weeks resistance training on serum irisin in older male adults[J].Frontiers in Physiology,2017,8:171-175
[18]Croutch C R,Lebofsky M,Schramm K,et al.2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)and 1,2,3,4,7,8-hexachlorodibenzo-p-dioxin(Hx CDD)alter body weight by decreasing insulin-like growth factor I(IGF-I)signaling[J].Toxicological Sciences,2005,85(1):560-571
[19]严翊,谢敏豪.大鼠游泳运动的最大乳酸稳态负荷的确定——乳酸最小试验[J].北京体育大学学报,2010,33(9):43-45Yan Y,Xie M H.The selection of rat swimming training load in maximal lactate steady state-lacate minimum test[J].Journal of Beijing Sport University,2010,33(9):43-45(in Chinese)
[20]Ngwa E N,Kengne A P,Tiedeu-Atogho B,et al.Persistent organic pollutants as risk factors for type 2 diabetes[J].Diabetology and Metabolic Syndrome,2015,7(1):1-15
[21]Singh K,Chan H M.Persistent organic pollutants and diabetes among Inuit in the Canadian Arctic[J].Environmental International,2017,101:183-189
[22]Thibault V,Bélanger M,Leblanc E,et al.Factors that could explain the increasing prevalence of type 2 diabetes among adults in a Canadian Province:A critical review and analysis[J].Diabetology and Metabolic Syndrome,2016,8(1):71-81
[23]Lee D H,Porta M,Jacobs D R Jr,et al.Chlorinated persistent organic pollutants,obesity,and type 2 diabetes[J].Endocrine Reviews,2014,5(4):557-601
[24]Taylor K W,Novak R F,Anderson H A,et al.Evaluation of the association between persistent organic pollutants(POPs)and diabetes in epidemiological studies:A national toxicology program workshop review[J].Environmental Health Perspectives,2013,121(7):774-783
[25]Ciftci O,Tanyildizi S,Godekmerdan A.Protective effect of curcumin on immune system and body weight gain on rats intoxicated with 2,3,7,8-tetrachlorodibenzo-p-dioxin(TCDD)[J].Immunopharmacology and Immunotoxicology,2010,32(1):99-104
[26]Medina-Contreras J M,Colado-Velázquez J,GómezViquez N L.Effects of topical capsaicin combined with moderate exercise on insulin resistance,body weight and oxidative stress in hypoestrogenic obese rats[J].International Journal of Obesity,2017,41(5):750-758
[27]Machado M V,Vieira A B,Nascimento A R,et al.Physical exercise restores microvascular function in obese rats with metabolic syndrome[J].Metabolic Syndrome and Related Disorders,2014,12(9):484-492
[28]魏冰,白厚增,靳一哲,等.运动、EGCG和肉碱对肥胖大鼠体重、内脏脂肪及肝脏CPT1表达的影响[J].中国运动医学杂志,2012(4):331-335,352Wei B,Bai H Z,Jin Y Z,et al.Exercise combined with administration of egcg and l-carnitine affects the weight,visceral fat and cpt1 expression in obese rats[J].Chinese Journal Sports Medicine,2012(4):331-335,352(in Chinese)
[29]张颢,卜淑敏,朱一力,等.跑台运动对去卵巢大鼠体重、腹腔内脂肪重量以及血清瘦素和脂联素含量的影响[J].中国运动医学杂志,2009(2):175-178Zhang H,Bu S M,Zhu Y L,et al.Effects of treadmill exercise on body weight,intraabdominal fat,serum leptin and adiponedtin levels in ovariectomized rats[J].Chinese Journal Sports Medicine,2009(2):175-178(in Chinese)
[30]Ohbayashi H,Sasaki T,Matsumoto M,et al.Dose-and time-dependent effects of 2,3,7,8-tetrabromodibenzo-pdioxin on rat liver[J].The Journal of Toxicological Sciences,2007,32(1):47-56
[31]Korenaga T,Fukusato T,Ohta M,et al.Long-term effects of subcutaneously injected 2,3,7,8-tetrachlorodibenzo-pdioxin on the liver of Rhesus monkeys[J].Chemosphere,2007,67(9):399-404
[32]Du J L,Cao L P,Liu Y J,et al.A study of 2,3,7,8-tetrachlorodibenzo-p-dioxin induced liver injury in Jian carp(Cyprinuscarpio var.Jian)using precision-cut liver slices[J].Bulletin of Environmental Contamination and Toxicology,2016,96(1):55-61
[33]Chiang J Y,Kimmel R,Stroup D.Regulation of cholesterol 7alpha-hydroxylase gene(CYP7A1)transcription by the liver orphan receptor(LXRalpha)[J].Gene,2001,262(1-2):257-265
[34]Vogelvan D,Bosch H M,Wit N J,et al.A cholesterolfree,high-fat diet suppresses gene expression of cholesterol transporters in murine small intestine[J].American Journal of Physiology Gastrointestal and Liver Physiology,2008,294(5):1171-1180
[35]Castrillo A,Tontonoz P.Nuclear receptors in macrophage biology:At the crossroads of lipid metabolism and inflammation[J].Annual Review of Cell and Developmental Biology,2004,20:455-480
[36]Makishima M.Nuclear receptors as targets for drug development:Regulation of cholesterol and bile acid metabolism by nuclear receptors[J].Journal of Pharmacological Sciences,2005,97(2):177-183
[37]Peet D J,Turley S D,Ma W,et al.Cholesterol and bile acid metabolism are impaired in mice lacking the nuclear oxysterol receptor LXRα[J].Cell,1998,93(5):693-704
[38]Chu K,Miyazaki M,Man W C,et al.Stearoyl-coenzyme A desaturase 1 deficiency protects against hypertriglyceridemia and increases plasma high-density lipoprotein cholesterol induced by liver X receptor activation[J].Molecular and Cellular Biology,2006,26(18):6786-6798
[39]Talukdar S,Hillgartner F B.The mechanism mediating the activation of acetyl-coenzyme A carboxylase-alpha gene transcription by the liver X receptor agonist T0-901317[J].Journal of Lipid Research,2006,47(11):2451-2461
[40]Schultz J R,Tu H,Luk A,et al.Role of LXRs in control of lipogenesis[J].Genes and Development,2000,14(22):2831-2838
[41]Inaba T,Matsuda M,Shimamura M,et al.Angiopoietinlike protein 3 mediates hypertriglyceridemia induced by the liver X receptor[J].Biochemistry,2003,46(7):21344-21351
[42]Rocco D D,Okuda L S,Pinto R S,et al.Aerobic exercise improves reverse cholesterol transport in cholesteryl ester transfer protein transgenic mice[J].Lipids,2011,46(7):617-625
[43]Kazeminasab M M,Ghaedi K,Esfarjani F,et al.Endurance training enhances LXR expression in the liver of male Wistar rats[J].Research in Pharmaceutical Sciences,2012,7(5):S544-553
[44]Yahagi N,Shimano H,Hasegawa K,et al.Cordinate activation of lipogenic enzymes in hepatocellular carcinoma[J].European Journal of Cancer,2005,41(9):1316-1322
[45]Rector R S,Thyfault J P,Morris R T,et al.Daily exercise increases hepatic fatty acid oxidation and prevents steatosis in Otsuka Long-Evans Tokushima fatty rats[J].American Journal of Physiology-Gastrointestinal and Liver Physiology,2008,294(3):G619-G626
[46]Yasari S,Prud Homme D,Wang D,et al.Exercise training decreases hepatic SCD-1 gene expression and protein content in rats[J].Molecular and Cellular Biochemistry,2010,335(1):291-299