Department of Pharmacology (State-Province Key Laboratories of Biomedicine - Pharmaceutics of China, Key Laboratory of Cardiovascular Medicine Research, Ministry of Education), College of Pharmacy, Harbin Medical University, Harbin, China.
Northern Translational Medicine Research and Cooperation Center, Heilongjiang Academy of Medical Sciences, Harbin Medical University, Harbin, Heilongjiang 150081, China.
Biomed Pharmacother. 2021 Jan;133:110802. doi: 10.1016/j.biopha.2020.110802. Epub 2020 Nov 14.
Hyperlipidaemia is one of the major risk factors for atherosclerosis, coronary heart disease, stroke and diabetes. In the present study, we synthesized a new anthraquinone compound, 1,8-dihydroxy-3-succinic acid monoethyl ester-6-methylanthraquinone, and named it Kanglexin (KLX). The aim of this study was to evaluate whether KLX has a lipid-lowering effect and to explore the potential molecular mechanism. In this study, Sprague-Dawley rats were fed a high fat diet (HFD) for 5 weeks to establish a hyperlipidaemia model; then, the rats were orally administered KLX (20, 40, and 80 mg kg·d) or atorvastatin calcium (AT, 10 mg kg·d) once a day for 2 weeks. KLX had prominent effects on reducing blood lipids, hepatic lipid accumulation, body weight and the ratio of liver weight/body weight. Furthermore, KLXdramatically reduced the total cholesterol (TC) and triglyceride (TG) levels and lipid accumulation in a HepG2 cell model of dyslipidaemia induced by 1 mmol/L oleic acid (OA). KLX may decrease lipid levels by phosphorylating adenosine monophosphate-activated protein kinase (AMPK) and the downstream sterol regulatory element binding protein 2 (SREBP-2)/proprotein convertase subtilisin/kexin type 9 (PCSK9)/low-density lipoprotein receptor (LDLR) signalling pathway in the HFD rats and OA-treated HepG2 cells. The effects of KLX on the AMPK/SREBP-2/PCSK9/LDLR signalling pathway were abolished when AMPK was inhibited by compound C (a specific AMPK inhibitor) in HepG2 cells. In summary, KLX has an efficient lipid-lowering effect mediated by activation of the AMPK/SREBP-2/PCSK9/LDLR signalling pathway. Our findings may provide new insight into and evidence for the discovery of a new lipid-lowering drug for the prevention and treatment of hyperlipidaemia, fatty liver, and cardiovascular disease in the clinic.
高脂血症是动脉粥样硬化、冠心病、中风和糖尿病的主要危险因素之一。在本研究中，我们合成了一种新的蒽醌化合物，1,8-二羟基-3-琥珀酸单乙酯-6-甲基蒽醌，并将其命名为康莱欣（KLX）。本研究旨在评价 KLX 是否具有降脂作用，并探讨其潜在的分子机制。本研究采用高脂饮食（HFD）喂养 Sprague-Dawley 大鼠 5 周建立高脂血症模型；然后，大鼠每天口服 KLX（20、40 和 80mg·kg·d）或阿托伐他汀钙（AT，10mg·kg·d），连续 2 周。KLX 可显著降低血脂、肝脂质蓄积、体重和肝重/体重比。此外，KLX 可显著降低由 1mmol/L 油酸（OA）诱导的 HepG2 细胞脂代谢紊乱模型中的总胆固醇（TC）和三酰甘油（TG）水平及脂质蓄积。KLX 可能通过磷酸化 AMP 激活蛋白激酶（AMPK）及其下游固醇调节元件结合蛋白 2（SREBP-2）/前蛋白转化酶枯草溶菌素/柯萨奇蛋白酶 9（PCSK9）/低密度脂蛋白受体（LDLR）信号通路降低 HFD 大鼠和 OA 处理的 HepG2 细胞中的脂质水平。在 HepG2 细胞中，用 AMPK 特异性抑制剂 compound C 抑制 AMPK 后，KLX 对 AMPK/SREBP-2/PCSK9/LDLR 信号通路的作用被阻断。综上所述，KLX 通过激活 AMPK/SREBP-2/PCSK9/LDLR 信号通路发挥有效的降脂作用。本研究结果为发现新的降脂药物预防和治疗高脂血症、脂肪肝和心血管疾病提供了新的见解和依据。
