BACKGROUND Reverse cholesterol transport (RCT) is an important cardioprotective mechanism and the decrease in cholesterol efflux can result in the dyslipidemia. Although liraglutide, a glucagon like peptide-1 analogue, has mainly impacted blood glucose, recent data has also suggested a beneficial effect on blood lipid. However, the exact mechanism by which liraglutide modulates lipid metabolism, especially its effect on RCT, remain undetermined. Hence, the aim of the present study was to investigate the potential impacts and potential underlying mechanisms of liraglutide on the cholesterol efflux in both db/db mice and HepG2 cells. METHODS Six-week old db/db mice with high fat diet (HFD) and wild type mice were administered either liraglutide (200 μg/kg) or equivoluminal saline subcutaneously, twice daily for 8 weeks and body weight was measured every week. After the 8-week treatment, the blood was collected for lipid evaluation and liver was obtained from the mice for hematoxylin-eosin (HE) staining, red O staining and Western blotting. Cholesterol efflux was assessed by measuring the radioactivity in the plasma and feces after intraperitoneal injection of 3H-labeled cholesterol. HepG2 Cells were treated with different concentrations of glucose (0, 5, 25, and 50 mmol/L) with or without liraglutide (1000 nmol/L) for 24 h. The intracellular cholesterol efflux was detected by BODIPY-cholesterol fluorescence labeling. Real-time PCR or Western blotting was used to examine the expression levels of ABCA1, ABCG1 and SR-B1. RESULTS Liraglutide significantly decreased blood glucose, serum total cholesterol (TC), triglyceride (TG) and low-density lipoprotein cholesterol (LDL-C). It also reduced liver lipid deposition in db/db mice fed with HFD. Moreover, the movement of 3H-cholesterol from macrophages to plasma and feces was significantly enhanced in db/db mice fed with HFD after liraglutide adminstration. In vitro study, liraglutide could promote the cholesterol efflux of HepG2 cells under high glucose, and also increase the expression of ABCA1 by activating the ERK1/2 pathway. CONCLUSIONS Liraglutide could improve lipid metabolism and hepatic lipid accumulation in db/db mice fed with HFD by promoting reversal of cholesterol transport, which was associated with the up-regulation of ABCA1 mediated by the ERK1/2 phosphorylation.

中文翻译：

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利拉鲁肽可通过增强与ABCA1和ERK1 / 2途径相关的胆固醇外流来改善脂质代谢。

背景技术胆固醇逆向转运（RCT）是重要的心脏保护机制，胆固醇外排的减少可导致血脂异常。尽管利拉鲁肽（一种类似肽1的胰高血糖素）主要影响血糖，但最近的数据也表明对血脂有有益作用。但是，利拉鲁肽调节脂质代谢的确切机制，尤其是其对RCT的作用，仍未确定。因此，本研究的目的是研究利拉鲁肽对db / db小鼠和HepG2细胞中胆固醇外流的潜在影响和潜在的潜在机制。方法对六周龄高脂饮食（HFD）的db / db小鼠和野生型小鼠皮下注射利拉鲁肽（200μg/ kg）或等体积的生理盐水，每天两次，共8周，每周测量一次体重。在8周的治疗后，收集血液用于脂质评估，并从小鼠获得肝以进行苏木精-伊红（HE）染色，红色O染色和蛋白质印迹。腹膜内注射3H标记的胆固醇后，通过测量血浆和粪便中的放射性来评估胆固醇的流出。HepG2细胞用不同浓度的葡萄糖（0、5、25和50 mmol / L）加或不加利拉鲁肽（1000 nmol / L）处理24小时。通过BODIPY-胆固醇荧光标记检测细胞内胆固醇流出。使用实时PCR或蛋白质印迹法检查ABCA1，ABCG1和SR-B1的表达水平。结果利拉鲁肽显着降低血糖，血清总胆固醇（TC），甘油三酸酯（TG）和低密度脂蛋白胆固醇（LDL-C）。它也减少了喂有HFD的db / db小鼠的肝脂质沉积。此外，利拉鲁肽给药后，喂食了HFD的db / db小鼠中3H胆固醇从巨噬细胞向血浆和粪便的运动显着增强。在体外研究中，利拉鲁肽可促进高糖下HepG2细胞的胆固醇外流，并通过激活ERK1 / 2途径增加ABCA1的表达。结论利拉鲁肽可通过促进胆固醇转运的逆转来改善HFD喂养的db / db小鼠的脂质代谢和肝脂质蓄积，这与ERK1 / 2磷酸化介导的ABCA1上调有关。利拉鲁肽给药后，喂食HFD的db / db小鼠中3H胆固醇从巨噬细胞向血浆和粪便的运动显着增强。在体外研究中，利拉鲁肽可促进高糖下HepG2细胞的胆固醇外流，并通过激活ERK1 / 2途径增加ABCA1的表达。结论利拉鲁肽可通过促进胆固醇转运的逆转而改善HFD喂养的db / db小鼠的脂质代谢和肝脂质蓄积，这与ERK1 / 2磷酸化介导的ABCA1上调有关。利拉鲁肽给药后，喂食HFD的db / db小鼠中3H胆固醇从巨噬细胞向血浆和粪便的运动显着增强。在体外研究中，利拉鲁肽可促进高糖下HepG2细胞的胆固醇外流，并通过激活ERK1 / 2途径增加ABCA1的表达。结论利拉鲁肽可通过促进胆固醇转运的逆转来改善HFD喂养的db / db小鼠的脂质代谢和肝脂质蓄积，这与ERK1 / 2磷酸化介导的ABCA1上调有关。并通过激活ERK1 / 2途径增加ABCA1的表达。结论利拉鲁肽可通过促进胆固醇转运的逆转来改善HFD喂养的db / db小鼠的脂质代谢和肝脂质蓄积，这与ERK1 / 2磷酸化介导的ABCA1上调有关。并通过激活ERK1 / 2途径增加ABCA1的表达。结论利拉鲁肽可通过促进胆固醇转运的逆转来改善HFD喂养的db / db小鼠的脂质代谢和肝脂质蓄积，这与ERK1 / 2磷酸化介导的ABCA1上调有关。