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Lithium chloride promotes lipid accumulation through increased reactive oxygen species generation.
Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids ( IF 4.8 ) Pub Date : 2019-10-31 , DOI: 10.1016/j.bbalip.2019.158552
Yunkyoung Lee 1 , Sang-Min Kim 1 , Eun-Hye Jung 1 , Jiwon Park 1 , Ju Won Lee 1 , Inn-Oc Han 1
Affiliation  

LiCl is widely prescribed for bipolar disorder but adversely associated with a higher incidence of increased body weight. Here, we investigated effects and underlying mechanisms of LiCl on lipid accumulation. LiCl induced dose-dependent lipid accumulation in HepG2 and RAW264.7 cells under normal as well as high glucose conditions. LiCl exposure additionally promoted lipid accumulation in livers of zebrafish. SB216763, a specific GSK-3β inhibitor, did not affect lipid accumulation in HepG2 cells. Expression of key lipogenic enzymes, such as FAS and aP2, as well as SR-B1 were increased in RAW264.7 cells. LiCl enhanced FAS, ACC and SCD-1 mRNA levels while suppressing CPT-1 in HepG2 cells. LiCl stimulated DNA binding activities of SREBP-1c and ChREBP. LiCl activated AMPK phosphorylation but the AMPK inhibitor, AICAR, did not suppress LiCl-induced lipid accumulation in RAW264.7. LiCl, but not SB216763, induced a significant increase in ROS in RAW264.7 and HepG2 cells. NOX activity was dose-dependently enhanced by LiCl. Furthermore, NOX-1, NOX-2 and DUOX-1 mRNA levels were upregulated at an early stage of LiCl stimulation. LiCl-induced lipid accumulation was suppressed by the antioxidant, NAC, and inhibitors of NOX, DPI and APO. Phosphorylation and transcriptional activity of CREB were enhanced by LiCl. The cell-permeable cAMP analog, di-butyryl cAMP, not only promoted lipid accumulation itself but also LiCl-induced lipid accumulation in RAW264.7 cells. H-89, a PKA inhibitor, suppressed CREB activation, lipid accumulation and NOX activity in RAW264.7 cells. Our results indicate that LiCl stimulates lipid accumulation in hepatocyte and macrophage cells potentially through increased PKA-dependent ROS production.

中文翻译:

氯化锂通过增加活性氧的产生来促进脂质的积累。

LiCl被广泛指定用于双相情感障碍,但与体重增加的更高发生率负相关。在这里,我们研究了LiCl对脂质蓄积的影响及其潜在机制。在正常以及高葡萄糖条件下,LiCl诱导HepG2和RAW264.7细胞中剂量依赖性脂质积累。LiCl暴露还促进了斑马鱼肝脏中脂质的积累。SB216763是一种特异性GSK-3β抑制剂,不影响HepG2细胞中的脂质蓄积。在RAW264.7细胞中,关键的脂肪形成酶(例如FAS和aP2以及SR-B1)的表达增加。LiCl增强了HepG2细胞中的CPT-1,同时增强了FAS,ACC和SCD-1 mRNA的水平。LiCl刺激SREBP-1c和ChREBP的DNA结合活性。LiCl激活AMPK磷酸化,但AMPK抑制剂AICAR 在RAW264.7中未抑制LiCl诱导的脂质蓄积。LiCl而不是SB216763诱导RAW264.7和HepG2细胞中ROS的显着增加。LiCl可以剂量依赖性地增强NOX的活性。此外,在LiCl刺激的早期,NOX-1,NOX-2和DUOX-1mRNA水平被上调。LiCl诱导的脂质蓄积被抗氧化剂,NAC和NOX,DPI和APO抑制剂抑制。LiCl增强了CREB的磷酸化和转录活性。细胞可渗透的cAMP类似物二丁酰基cAMP不仅可以促进脂质自身积累,而且还可以促进Li26诱导的RAW264.7细胞中脂质的积累。PKA抑制剂H-89抑制RAW264.7细胞的CREB活化,脂质蓄积和NOX活性。
更新日期:2019-10-31
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