Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice.
Fenofibrate improves renal lipotoxicity through activation of AMPK-PGC-1α in db/db mice.
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DOI：
10.1371/journal.pone.0096147
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Park CW
中科院分区：
文献类型：
--
作者：
Hong YA;Lim JH;Kim MY;Kim TW;Kim Y;Yang KS;Park HS;Choi SR;Chung S;Kim HW;Kim HW;Choi BS;Chang YS;Park CW
过氧化物酶体增殖物激活受体（Peroxisome proliferator-activated receptor，PPAR）-α是一种脂敏转录因子，在脂毒性中起重要作用。我们评估了非诺贝特是否通过改善肾脏的脂毒性而具有肾脏保护作用。将8周龄雄性C57 BLKS/J db/m对照和db/db小鼠分为4组，接受非诺贝特12周。在db/db小鼠中，非诺贝特可改善蛋白尿、系膜区扩张和炎性细胞浸润。非诺贝特可抑制肾内游离脂肪酸和甘油三酯的蓄积，这些蓄积与PPARα表达增加、AMP活化蛋白激酶（AMPK）磷酸化和过氧化物酶体增殖物活化受体γ共激活因子1α（PGC-1α）-雌激素相关受体（ERR）-1α-磷酸化乙酰辅酶A羧化酶（pACC）激活有关，以及抑制固醇调节元件结合蛋白（SREBP）-1和碳水化合物调节元件结合蛋白（ChREBP）-1，脂质代谢的关键下游效应物。非诺贝特可降低肾脏中磷脂酰肌醇-3激酶（PI 3 K）-Akt磷酸化和FoxO 3 a磷酸化的活性，增加B细胞白血病/淋巴瘤2（BCL-2）/BCL-2相关X蛋白（BAX）比值和超氧化物歧化酶（SOD）1水平。因此，非诺贝特从肾细胞凋亡和氧化应激中恢复，如24小时尿8-异前列腺素所反映。在培养的系膜细胞中，非诺贝特通过磷酸化AMPK、激活PGC-1α-ERR-1α以及抑制SREBP-1和ChREBP-1来防止高糖诱导的细胞凋亡和氧化应激。我们的研究结果表明，非诺贝特通过激活AMPK-PGC-1α-ERR-1α-FoxO 3a信号通路改善脂毒性，显示其作为糖尿病肾病治疗方式的潜力。
Peroxisome proliferator-activated receptor (PPAR)-α, a lipid-sensing transcriptional factor, serves an important role in lipotoxicity. We evaluated whether fenofibrate has a renoprotective effect by ameliorating lipotoxicity in the kidney. Eight-week-old male C57BLKS/J db/m control and db/db mice, divided into four groups, received fenofibrate for 12 weeks. In db/db mice, fenofibrate ameliorated albuminuria, mesangial area expansion and inflammatory cell infiltration. Fenofibrate inhibited accumulation of intra-renal free fatty acids and triglycerides related to increases in PPARα expression, phosphorylation of AMP-activated protein kinase (AMPK), and activation of Peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α)-estrogen-related receptor (ERR)-1α-phosphorylated acetyl-CoA carboxylase (pACC), and suppression of sterol regulatory element-binding protein (SREBP)-1 and carbohydrate regulatory element-binding protein (ChREBP)-1, key downstream effectors of lipid metabolism. Fenofibrate decreased the activity of phosphatidylinositol-3 kinase (PI3K)-Akt phosphorylation and FoxO3a phosphorylation in kidneys, increasing the B cell leukaemia/lymphoma 2 (BCL-2)/BCL-2-associated X protein (BAX) ratio and superoxide dismutase (SOD) 1 levels. Consequently, fenofibrate recovered from renal apoptosis and oxidative stress, as reflected by 24 hr urinary 8-isoprostane. In cultured mesangial cells, fenofibrate prevented high glucose-induced apoptosis and oxidative stress through phosphorylation of AMPK, activation of PGC-1α-ERR-1α, and suppression of SREBP-1 and ChREBP-1. Our results suggest that fenofibrate improves lipotoxicity via activation of AMPK-PGC-1α-ERR-1α-FoxO3a signaling, showing its potential as a therapeutic modality for diabetic nephropathy.
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DOI：
10.1016/j.bbrc.2007.10.038
发表时间：
2007-12-21
影响因子：
3.1
作者：
Ishigaki, Naomi;Yamamoto, Takashi;Shimano, Hitoshi
通讯作者：
Shimano, Hitoshi
影响因子：
10.8
作者：
Alvarez-Guardia, David;Palomer, Xavier;Vazquez-Carrera, Manuel
通讯作者：
Vazquez-Carrera, Manuel
影响因子：
8.2
作者：
Kim, M. Y.;Lim, J. H.;Park, C. W.
通讯作者：
Park, C. W.
DOI：
10.1073/pnas.0705070104
发表时间：
2007-07-17
影响因子：
11.1
作者：
Jaeger, Sibylle;Handschin, Christoph;Spiegelman, Bruce M.
通讯作者：
Spiegelman, Bruce M.
影响因子：
4.4
作者：
Cantó C;Auwerx J
通讯作者：
Auwerx J