AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response.
AMPK activation prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 signaling and endoplasmic reticulum stress response.
复制标题
DOI：
10.1016/j.bbadis.2014.07.002
复制
发表时间：
2014-09
期刊：
影响因子：
--
通讯作者：
Xie Z
中科院分区：
文献类型：
--
作者：
Li H;Min Q;Ouyang C;Lee J;He C;Zou MH;Xie Z
脂质堆积是包括肥胖和2型糖尿病在内的慢性代谢性疾病发展过程中的中心事件，但导致脂质堆积的机制尚不完全清楚。本研究旨在探讨过量营养诱导脂肪堆积的机制，以及AMP活化蛋白激酶(AMPK)的激活是否能阻止过度营养处理的HepG2细胞和高脂饮食(HFD)喂养的小鼠的肝脏脂肪堆积。高糖或棕榈酸酯可诱导细胞内质网应激反应，激活固醇调节元件结合蛋白-1，促进脂质堆积，这些都对内质网应激抑制剂和真核细胞起始因子2α的基因沉默敏感。内质网应激反应和脂质积累的增加与哺乳动物雷帕霉素复合体靶标1(MTORC1)信号的激活有关。抑制mTORC1信号可减弱高糖或结节硬化2基因缺失引起的内质网应激反应和脂质堆积。此外，AMPK激活可阻止mTORC1激活、内质网应激反应和脂质堆积。这一效应分别被结构性活性AMPK突变体和显性负性AMPK突变体的过度表达所模拟或取消。最后，用5-aminoimidazole-4-carboxamide-1-β−4-ribofuranoside治疗高脂饲料喂养的小鼠可以抑制mTORc1途径，抑制内质网应激反应，并防止胰岛素抵抗和肝脏脂质堆积。我们的结论是，AMPK的激活通过抑制mTORC1和内质网应激反应来防止过度营养诱导的肝脏脂质堆积。
Lipid accumulation is a central event in the development of chronic metabolic diseases, including obesity and type 2 diabetes, but the mechanisms responsible for lipid accumulation are incompletely understood. This study was designed to investigate the mechanisms for excess nutrient-induced lipid accumulation and whether activation of AMP-activated protein kinase (AMPK) prevents the hepatic lipid accumulation in excess nutrient-treated HepG2 cells and high fat diet (HFD)-fed mice. Exposure of HepG2 cells to high levels of glucose or palmi-tate induced the endoplasmic reticulum (ER) stress response, activated sterol regulatory element-binding protein-1 (SREBP-1), and enhanced lipid accumulation, all of which were sensitive to ER stress inhibitor and gene silencing of eukaryotic initiation factor 2α. The increases in ER stress response and lipid accumulation were associated with activation of mammalian target of rapamycin complex 1 (mTORC1) signaling. Inhibition of mTORC1 signaling attenuated the ER stress response and lipid accumulation induced by high glucose or by deletion of tuberous sclerosis 2. In addition, AMPK activation prevented the mTORC1 activation, ER stress response, and lipid accumulation. This effect was mimicked or abrogated, respectively, by overexpression of constitutively active and dominant-negative AMPK mutants. Finally, treatment of HFD-fed mice with 5-aminoimidazole-4-carboxamide-1-β−4-ribofuranoside inhibited the mTORC1 pathway, suppressed the ER stress response, and prevented insulin resistance and hepatic lipid accumulation. We conclude that activation of AMPK prevents excess nutrient-induced hepatic lipid accumulation by inhibiting mTORC1 and ER stress response.
登录
查看更多内容
影响因子：
7.7
作者：
He C;Zhu H;Li H;Zou MH;Xie Z
通讯作者：
Xie Z
DOI：
10.1152/ajpheart.01279.2010
发表时间：
2011-10-01
影响因子：
4.8
作者：
Cacicedo, Jose M.;Gauthier, Marie-Soleil;Ido, Yasuo
通讯作者：
Ido, Yasuo
DOI：
10.1152/ajpendo.00198.2012
发表时间：
2012-11-01
影响因子：
5.1
作者：
Li, Hongliang;Xu, Mingjiang;Xie, Zhonglin
通讯作者：
Xie, Zhonglin
影响因子：
2.1
作者：
Kimura, N;Tokunaga, C;Yonezawa, K
通讯作者：
Yonezawa, K
DOI：
10.1152/ajpendo.00202.2013
发表时间：
2014-01-01
影响因子：
5.1
作者：
Li, Hongliang;Lee, Jiyeon;Xie, Zhonglin
通讯作者：
Xie, Zhonglin