Acanthoic Acid Can Partially Prevent Alcohol Exposure-Induced Liver Lipid Deposition and Inflammation.
Acanthoic Acid Can Partially Prevent Alcohol Exposure-Induced Liver Lipid Deposition and Inflammation.
复制标题
棘皮酸可以部分预防酒精暴露引起的肝脏脂质沉积和炎症
DOI：
10.3389/fphar.2017.00134
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发表时间：
2017
影响因子：
5.6
通讯作者：
Wu YL
中科院分区：
文献类型：
--
作者：
Yao YL;Han X;Li ZM;Lian LH;Nan JX;Wu YL
目的：本研究旨在观察刺五加酸（AA）对酒精诱导的肝脏脂质沉积和炎症反应的影响，并探讨其作用机制。研究方法：C57 BL/6小鼠经口灌胃给予单剂量AA（20和40 mg/kg）或等体积生理盐水，然后在24 h内灌胃给予3个剂量的乙醇（5 g/kg体重，25%，w/v）。在最后一次乙醇给药后6 h处死小鼠。采用Western blot、RT-PCR和组织病理学方法检测血清和肝脏指标。分别用AA（5、10、20 μM）或AICAR（500 μM）、GW 3965（1 μM）、SRT 1720（6 μM）、烟酰胺（20 mM）预处理AML-12细胞2 h，然后用EtOH（200 mM）和脂多糖（LPS）（10 ng/ml）再处理48 h。收集细胞蛋白和mRNA进行蛋白质印迹和RT-PCR。ELISA法检测细胞因子白细胞介素-1 β（IL-1β）和肿瘤坏死因子-α（TNF-α）的释放。结果如下：结果表明，AA能显著降低急性乙醇引起的小鼠血清ALT/AST、LDH、ALP、肝脏和血清甘油三酯水平的升高，并能减少肝内脂肪滴的堆积。AA显著抑制乙醇诱导的固醇调节元件结合蛋白1（SREBP-1）、细胞色素P4502 E1（CYP 2 E1）、IL-1β和caspase-1的水平。此外，与正常组相比，乙醇组小鼠的sirtuin 1（Sirt 1）和肝脏X受体（LXRs）水平显著下降。与乙醇组相比，AA预处理组Sirt 1和LXR水平升高，肝激酶B-1（LKB-1）、腺苷酸活化蛋白激酶（AMPK）、乙酰辅酶A羧化酶（ACC）蛋白磷酸化水平降低。AA可逆转急性乙醇诱导的过氧化物酶体增殖物激活受体α或γ（PPAR-a或PPAR-γ）的表达。在EtOH/LPS培养的AML-12细胞中，与EtOH/LPS处理相比，AA降低IL-1β和TNF-α水平、脂滴以及SREBP-1和CYP 2 E1表达。与EtOH/LPS处理组相比，AA处理组Sirt 1、p-LKB 1、p-ACC、PPARα蛋白表达显著增加，而PPARγ蛋白表达显著降低。结论：胡萝卜酸可通过调节LKB 1/Sirt 1/AMPK/ACC和LXR通路部分预防酒精诱导的肝脏脂质沉积和炎症。
Aims: The present study aims to detect the effect of acanthoic acid (AA) on alcohol exposure-induced liver lipid deposition and inflammation, and to explore the mechanisms. Methods: C57BL/6 mice were pretreated with single dose of AA (20 and 40 mg/kg) by oral gavage or equal volume of saline, and then exposed to three doses of ethanol (5 g/kg body weight, 25%, w/v) by gavage within 24 h. The mice were sacrificed at 6 h after the last ethanol dosing. Serum and hepatic indexes were detected by western blot, RT-PCR, and histopathological assay. AML-12 cells were pretreated with AA (5, 10, 20 μM), or AICAR (500 μM), GW3965 (1 μM), SRT1720 (6 μM), Nicotinamide (20 mM) for 2 h, respectively, and then following treated with EtOH (200 mM) and lipopolysaccharide (LPS) (10 ng/ml) for additional 48 h. Cell protein and mRNA were collected for western blot and RT-PCR. Cytokines interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α) release were detected by ELISA assay. Results: It was found that AA significantly decreased acute ethanol-induced increasing of the serum ALT/AST, LDH, ALP levels, and hepatic and serum triglyceride levels, and reduced fat droplets accumulation in mice liver. AA significantly suppressed the levels of sterol regulatory element binding protein 1 (SREBP-1), cytochrome P4502E1 (CYP2E1), IL-1β, and caspase-1 induced by ethanol. Furthermore, a significant decline of sirtuin 1 (Sirt1) and liver X receptors (LXRs) levels was observed in EtOH group, compared with normal group mice. And AA pretreatment increased the Sirt1 and LXRs levels, and also ameliorated phosphorylation of liver kinase B-1 (LKB-1), adenosine monophosphate-activated protein kinase (AMPK), acetyl CoA carboxylase (ACC) proteins, compared with EtOH group. However, the levels of peroxisome proliferator activated receptor -α or -γ (PPAR-α or PPAR-γ) induced by acute ethanol were reversed by AA. In EtOH/LPS cultivated AML-12 cells, AA decreased IL-1β and TNF-α levels, lipid droplets, and SREBP-1 and CYP2E1 expressions, compared with EtOH/LPS treatment. AA also significantly increased protein expressions of Sirt1, p-LKB1, p-ACC, PPARα, and decreased protein expression of PPARγ, compared with EtOH/LPS treatment. Conclusion: Acanthoic acid can partially prevent alcohol exposure-induced liver lipid deposition and inflammation via regulation of LKB1/Sirt1/AMPK/ACC and LXRs pathways.