核受体PPARα在小鼠代谢综合征发生发展中的作用与机制研究
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摘要
目的探究过氧化物酶体增殖物激活受体(peroxisome proliferator-activated receptorα, PPARα)在高脂饲料诱导小鼠代谢综合征(metabolic syndrome, MS)发生发展过程中的作用与机制。方法选用129/Sv雄性健康的野生型(WT)和Ppara敲除型(KO)小鼠各10只,各自分为对照组和实验组。对照组小鼠食饲普通饲料(WT-Con/KO-Con),实验组小鼠食饲40%脂肪供能饲料(High-fat diet,HFD)(WT-HFD/KO-HFD),连续干预3月。实验结束前3 d对各组小鼠进行口服葡萄糖耐量试验;所有小鼠收集血清后处死,取附睾脂肪组织。检测血清中TC和TG的含量,分析脂肪组织的病理学变化以及炎症基因表达。结果 KO-HFD组小鼠体质量增加明显,且发生糖耐量损害,其血清TC和TG显著高于KO-Con组;且脂肪细胞体积明显大于KO-Con组,炎症基因mRNA的表达明显增加,且STAT3通路被激活;在WT两组小鼠中各指标均无明显差别。结论小鼠PPARα可对抗HFD诱导MS的发生与发展,该作用与STAT3炎症通路密切相关。[营养学报,2019,41(1):89-94]
Objective To explore the role of peroxisome proliferator-activated receptor α(PPARα) in metabolic syndrome(MS) development induced by high-fat diet(HFD, 40% kcal fat) and the mechanism involved. Methods Ten male wild-type(WT) mice and 10 male Ppara-null(KO) mice on the 129/Sv background were divided into 2 groups(n=5),vehicle/control(WT-Con/KO-Con) and HFD(WT-HFD/KO-HFD). All the mice were treated with HFD for 3 months. Oral glucose tolerance test was performed 3 days before the end of treatment. After blood collection, all the mice were killed, and testicular adipose tissues were collected. The serum TC and TG were determined. Pathological changes of adipose tissues and expression of inflammatory genes were assayed. Results The insulin resistance was observed in KO-HFD mice. Both serum TC and TG were significantly higher than those in the KO-Con group. In the KO-HFD group, the fat cells were bigger than those in the KO-Con group. Pro-inflammatory factors(Tnf-a, Srebf1 and Icam1) and STAT3 target genes were activated.However, all of the above indicators were negative in WT mice. Conclusion PPARα protects against MS development induced by HFD, and the action is closely related with activation of STAT3 pathway. [ACTA NUTRIMENTA SINICA, 2019, 41(1):89-94]
Objective To explore the role of peroxisome proliferator-activated receptor α(PPARα) in metabolic syndrome(MS) development induced by high-fat diet(HFD, 40% kcal fat) and the mechanism involved. Methods Ten male wild-type(WT) mice and 10 male Ppara-null(KO) mice on the 129/Sv background were divided into 2 groups(n=5),vehicle/control(WT-Con/KO-Con) and HFD(WT-HFD/KO-HFD). All the mice were treated with HFD for 3 months. Oral glucose tolerance test was performed 3 days before the end of treatment. After blood collection, all the mice were killed, and testicular adipose tissues were collected. The serum TC and TG were determined. Pathological changes of adipose tissues and expression of inflammatory genes were assayed. Results The insulin resistance was observed in KO-HFD mice. Both serum TC and TG were significantly higher than those in the KO-Con group. In the KO-HFD group, the fat cells were bigger than those in the KO-Con group. Pro-inflammatory factors(Tnf-a, Srebf1 and Icam1) and STAT3 target genes were activated.However, all of the above indicators were negative in WT mice. Conclusion PPARα protects against MS development induced by HFD, and the action is closely related with activation of STAT3 pathway. [ACTA NUTRIMENTA SINICA, 2019, 41(1):89-94]
引文
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[8]Inoue H,Ogawa W,Ozaki M,et al.Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo[J].Nat Med,2004,10:168-174.
[9]Cernkovich ER,Deng J,Bond MC,et al.Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity[J].Endocrinology,2008,149:1581-1590.
[10]Makia NL,Goldstein JA.CYP2C8 is a novel target of peroxisome proliferator-activated receptor alpha in human liver[J].Mol Pharmacol,2016,89:154-164.
[11]Hotamisligil GS.Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[J].Cell,2010,140:900-917.
[12]Chan SM,Sun RQ,Zeng XY,et al.Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress[J].Diabetes,2013,62:2095-2105.
[13]Yang Y,Smith DL,Jr,Keating KD,et al.Variations in body weight,food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice[J].Obesity(Silver Spring),2014,22:2147-2155.
[14]Dai M,Hua H,Lin H,et al.Targeted metabolomics reveals a protective role for basal PPAR alpha in cholestasis induced by alpha-naphthylisothiocyanate[J].J Proteome Res,2018,17:1500-1508.
[2]顾东风,Reynolds K,杨文杰,等.中国成年人代谢综合征的患病率[J].中国糖尿病杂志,2005,13:181-186.
[3]Samson SL,Garber AJ.Metabolic syndrome[J].Endocrinol Metab Clin North Am,2014,43:1-23.
[4]Bugge A,Mandrup S.Molecular mechanisms and genome-wide aspects of PPAR subtype specific transactivation[J].PPAR Res,2010,2010,Pii169506.
[5]Nan YM,Wang RQ,Fu N.Peroxisome proliferator-activated receptor alpha,a potential therapeutic target for alcoholic liver disease[J].World J Gastroenterol,2014,20:8055-8060.
[6]Han MS,Jung DY,Morel C,et al.JNK expression by macrophages promotes obesity-induced insulin resistance and inflammation[J].Science,2013,339:218-222.
[7]Abed El-Gaphar OAM,Abo-Youssef AM,Halal GK.Levetiracetam mitigates lipopolysaccharide-induced JAK2/STAT3 and TLR4/MAPK signaling pathways activation in a rat model of adjuvant-induced arthritis[J].Eur J Pharmacol,2018,826:85-95.
[8]Inoue H,Ogawa W,Ozaki M,et al.Role of STAT-3 in regulation of hepatic gluconeogenic genes and carbohydrate metabolism in vivo[J].Nat Med,2004,10:168-174.
[9]Cernkovich ER,Deng J,Bond MC,et al.Adipose-specific disruption of signal transducer and activator of transcription 3 increases body weight and adiposity[J].Endocrinology,2008,149:1581-1590.
[10]Makia NL,Goldstein JA.CYP2C8 is a novel target of peroxisome proliferator-activated receptor alpha in human liver[J].Mol Pharmacol,2016,89:154-164.
[11]Hotamisligil GS.Endoplasmic reticulum stress and the inflammatory basis of metabolic disease[J].Cell,2010,140:900-917.
[12]Chan SM,Sun RQ,Zeng XY,et al.Activation of PPARalpha ameliorates hepatic insulin resistance and steatosis in high fructose-fed mice despite increased endoplasmic reticulum stress[J].Diabetes,2013,62:2095-2105.
[13]Yang Y,Smith DL,Jr,Keating KD,et al.Variations in body weight,food intake and body composition after long-term high-fat diet feeding in C57BL/6J mice[J].Obesity(Silver Spring),2014,22:2147-2155.
[14]Dai M,Hua H,Lin H,et al.Targeted metabolomics reveals a protective role for basal PPAR alpha in cholestasis induced by alpha-naphthylisothiocyanate[J].J Proteome Res,2018,17:1500-1508.