Transcription coactivator mediator subunit MED1 is required for the development of fatty liver in the mouse.
Transcription coactivator mediator subunit MED1 is required for the development of fatty liver in the mouse.
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转录共激活介质亚基 MED1 是小鼠脂肪肝发生所必需的。
DOI：
10.1002/hep.24155
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发表时间：
2011-04
期刊：
影响因子：
13.5
通讯作者：
Reddy, Janardan K.
中科院分区：
文献类型：
--
作者：
Bai, Liang;Jia, Yuzhi;Viswakarma, Navin;Huang, Jiansheng;Vluggens, Aurore;Wolins, Nathan E.;Jafari, Nadereh;Rao, M. Sambasiva;Borensztajn, Jayme;Yang, Gongshe;Reddy, Janardan K.
过氧化物酶体增殖物激活受体-γ（PPARγ）是一种核受体，当其在肝脏中过表达时，可刺激脂肪细胞特异性基因和脂肪生成相关基因的诱导，导致肝脏脂肪变性。我们在此报告，MED 1（也称为PBP或TRAP 220）是高脂饮食诱导的肝脂肪变性以及PPARγ刺激的脂肪形成性肝脂肪变性所需的介体复合物的关键亚基。介体形成转录激活因子和RNA聚合酶II之间的桥梁。MED 1与核受体如PPARγ和其他转录激活因子相互作用。肝脏特异性MED 1基因敲除（MED 1 Δliv）小鼠在喂食高脂肪（60%千卡脂肪）饮食长达4个月时未发生脂肪肝。同样，尾静脉注射腺病毒-PPAR γ（Ad/PPARγ）的MED 1 Δliv小鼠也没有发生脂肪肝，而喂食高脂饮食或注射Ad/PPARγ的MED 1（MED 1fl/fl）小鼠发生了严重的肝脂肪变性。Ad/PPARγ注射小鼠肝脏的基因表达谱和北方印迹分析显示，在MED 1 Δliv小鼠肝脏中，脂肪形成标记物如aP 2、adipsin、脂联素和脂滴相关基因（包括小窝蛋白-1、CideA、S3-12等）的诱导受损。这些脂肪细胞特异性和脂肪生成相关基因在MED 1fl/fl小鼠肝脏中响应于Ad/PPARγ而被强烈诱导。在MED 1 ΔLiv小鼠肝脏中使用Ad/MED 1重新表达MED 1恢复了PPARγ刺激的肝脏脂肪形成反应。这些研究还表明，破坏编码其他共激活因子（如SRC-1、PRIC 285、PRIP和PIMT）的基因对PPARγ过表达诱导的肝脏脂肪生成没有影响。结论：我们的结论是，转录辅激活因子MED 1是高脂饮食诱导和PPARγ刺激的脂肪肝发展所必需的，这表明MED 1可能被认为是肝脂肪变性的潜在治疗靶点。
Peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that MED1 (also known as PBP or TRAP220) a key subunit of the Mediator complex is required for high-fat diet-induced hepatic steatosis as well as PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1Δliv) mice when fed a high fat (60% kcal fat) diet for up to 4 months failed to develop fatty liver. Similarly, MED1Δliv mice injected with adenovirus-PPARγ (Ad/PPARγ) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1fl/fl) fed a high-fat diet or injected with Ad/PPARγ developed severe hepatic steatosis. Gene expression profiling and Northern blot analyses of Ad/PPARγ injected mouse livers showed impaired induction in MED1Δliv mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin and lipid droplet-associated genes, including caveolin-1, CideA, S3-12 and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1fl/fl mouse liver in response to Ad/PPARγ. Re-expression of MED1 using Ad/MED1 in MED1ΔLiv mouse liver restored PPARγ-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPARγ overexpression. Conclusion: We conclude that transcription coactivator MED1 is required for high-fat diet-induced and PPARγ-stimulated fatty liver development, which suggest that MED1 may be considered a potential therapeutic target for hepatic steatosis.
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DOI：
10.1073/pnas.182426699
发表时间：
2002-09-03
影响因子：
11.1
作者：
Surapureddi, S;Yu, ST;Reddy, JK
通讯作者：
Reddy, JK
影响因子：
6.5
作者：
Kimmel AR;Brasaemle DL;McAndrews-Hill M;Sztalryd C;Londos C
通讯作者：
Londos C
影响因子：
4.8
作者：
Qi, C;Surapureddi, S;Reddy, JK
通讯作者：
Reddy, JK
DOI：
10.1621/nrs.08002
发表时间：
2010-04-16
期刊：
Nuclear receptor signaling
影响因子：
--
作者：
Pyper, Sean R;Viswakarma, Navin;Reddy, Janardan K
通讯作者：
Reddy, Janardan K
影响因子：
15.9
作者：
Matsusue, K;Haluzik, M;Gonzalez, FJ
通讯作者：
Gonzalez, FJ