Laboratory of Environment and Health, College of Life Sciences, University of Chinese Academy of Sciences, No. 19A Yuquan Road, Beijing 100049, China.
National Laboratory of Biomacromolecules, Institute of Biophysics, Chinese Academy of Sciences, 15 Datun Road, Beijing 100101, China.
J Inorg Biochem. 2018 Jun;183:66-76. doi: 10.1016/j.jinorgbio.2018.03.006. Epub 2018 Mar 14.
Numerous studies have demonstrated that vanadium compounds are able to improve lipemia and triglyceridemia in both humans and animals. However, the molecular mechanism remains elusive. The present study was conducted to investigate the anti-hyperlipidemic effect of vanadium(IV) complex with 4-chlorodipicolinic acid (VOdipic-Cl)-induced autophagy on hepatic lipid accumulation. To explore the possible underlying mechanisms, primary rat hepatocytes, human hepatoma cell line HepG2, and liver tissue from C57BL/6 mice fed a high-fat diet (HFD) were used. In vitro, cultured primary rat hepatocytes were treated with palmitate (0.25, 0.5 and 0.75 mM) prior to VOdipic-Cl (50, 100, and 200 μM) for 24 h, respectively. In vivo, C57BL/6 mice were fed with high-fat diet for 16 weeks. VOdipic-Cl (10 mg V/kg body weight) was given by daily gavage for 4 weeks. In vitro results showed that VOdipic-Cl significantly inhibited lipid droplet formation by increasing the level of conversion and punctuation of microtubule-associated proteins light chain 3 (LC3) in a dose-dependent manner, and activated liver kinase B-1 (LKB1) and adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Confocal microscopy images also showed that VOdipic-Cl induced sequestration of lipid droplets (LDs) by autophagy. In vivo, VOdipic-Cl attenuated the increase in serum and liver triglyceride levels in the mice fed with high-fat diet, while significantly increased autophagy induction and activated LKB1 and AMPK phosphorylation in the liver. Taken together, these results suggest that VOdipic-Cl reduces hepatic lipid accumulation by inducing autophagy via the activation of LKB1/AMPK-dependent signaling pathway.
大量研究表明，钒化合物能够改善人和动物的脂血症和甘油三酯血症。然而，其分子机制仍不清楚。本研究旨在探讨 4-氯二吡啶酸（VOdipic-Cl）-诱导的自噬对肝脂质蓄积的抗高脂血症作用。为了探索可能的潜在机制，使用原代大鼠肝细胞、人肝癌细胞系 HepG2 和高脂肪饮食（HFD）喂养的 C57BL/6 小鼠的肝组织进行了研究。在体外，用棕榈酸（0.25、0.5 和 0.75 mM）预处理培养的原代大鼠肝细胞，然后分别用 VOdipic-Cl（50、100 和 200 μM）处理 24 小时。在体内，C57BL/6 小鼠用高脂肪饮食喂养 16 周。用每日灌胃给予 VOdipic-Cl（10 mg V/kg 体重）4 周。体外结果表明，VOdipic-Cl 显著抑制脂质滴形成，呈剂量依赖性增加微管相关蛋白轻链 3（LC3）的转化和标点水平，并激活肝激酶 B-1（LKB1）和腺苷单磷酸激活蛋白激酶（AMPK）磷酸化。共聚焦显微镜图像也显示 VOdipic-Cl 诱导自噬吞噬脂质滴（LDs）。在体内，VOdipic-Cl 减轻了高脂肪饮食喂养小鼠血清和肝脏甘油三酯水平的升高，同时显著增加了肝脏自噬诱导和激活 LKB1 和 AMPK 磷酸化。综上所述，这些结果表明 VOdipic-Cl 通过激活 LKB1/AMPK 依赖性信号通路诱导自噬来减少肝脂质蓄积。
