Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Republic of Korea.
Department of Physiology and Biophysics, College of Medicine, Inha University, Incheon, Republic of Korea.
Biochim Biophys Acta Mol Cell Biol Lipids. 2020 Feb;1865(2):158552. doi: 10.1016/j.bbalip.2019.158552. Epub 2019 Oct 31.
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.
氯化锂被广泛用于治疗双相情感障碍，但与体重增加的发生率升高有关。在这里，我们研究了氯化锂对脂质积累的影响及其潜在机制。氯化锂在正常和高葡萄糖条件下诱导 HepG2 和 RAW264.7 细胞中剂量依赖性的脂质积累。氯化锂暴露还促进了斑马鱼肝脏中的脂质积累。SB216763，一种特定的 GSK-3β抑制剂，不影响 HepG2 细胞中的脂质积累。关键的脂肪生成酶，如 FAS 和 aP2，以及 SR-B1 的表达在 RAW264.7 细胞中增加。氯化锂增强了 RAW264.7 细胞中 FAS、ACC 和 SCD-1 的 mRNA 水平，同时抑制了 HepG2 细胞中的 CPT-1。氯化锂刺激 SREBP-1c 和 ChREBP 的 DNA 结合活性。氯化锂激活 AMPK 磷酸化，但 AMPK 抑制剂 AICAR 并未抑制 RAW264.7 中氯化锂诱导的脂质积累。氯化锂而非 SB216763 导致 RAW264.7 和 HepG2 细胞中 ROS 水平显著增加。NOX 活性被氯化锂呈剂量依赖性增强。此外，NOX-1、NOX-2 和 DUOX-1 的 mRNA 水平在氯化锂刺激的早期阶段上调。抗氧化剂 NAC 和 NOX 抑制剂 DPI 和 APO 抑制了氯化锂诱导的脂质积累。氯化锂增强了 CREB 的磷酸化和转录活性。细胞通透性 cAMP 类似物二丁酰环磷腺苷不仅自身促进脂质积累，还促进 RAW264.7 细胞中氯化锂诱导的脂质积累。PKA 抑制剂 H-89 抑制了 RAW264.7 细胞中 CREB 激活、脂质积累和 NOX 活性。我们的结果表明，氯化锂通过增加 PKA 依赖性 ROS 产生来刺激肝实质细胞和巨噬细胞中的脂质积累。
