College of Biomedical Engineering, Hefei University of Technology, Hefei, China.
College of Life Sciences, Key Laboratory of Bioactive Materials of Ministry of Education, Nankai University, Tianjin, China.
Br J Pharmacol. 2018 May;175(9):1486-1503. doi: 10.1111/bph.14156. Epub 2018 Mar 23.
The liver X receptor (LXR) agonist T317 reduces atherosclerosis but induces fatty liver. Metformin activates energy metabolism by activating AMPKα. In this study, we determined if interactions between metformin and T317 could inhibit atherosclerosis without activation of hepatic lipogenesis.
Apolipoprotein E-deficient mice were treated with T317, metformin or both agents, in a high-fat diet for 16 weeks. Then, samples of aorta, liver, macrophage and serum were collected to determine atherosclerotic lesions, fatty liver, lipid profiles and expression of related proteins. Techniques used included immunohistochemistry, histology, qRT-PCR and Western blot.
T317 inhibited en face and aortic root sinus lesions, and the inhibition was further enhanced by addition of metformin. Co-treatment with metformin and T317 increased lesion stability, by increasing collagen content, and reducing necrotic cores and calcification. Formation of macrophages/foam cells and their accumulation in arterial wall were inhibited by the co-treatment, which was accompanied by increased ABCA1/ABCG1 expression, reduced monocyte adhesion and apparent local proliferation of macrophages. Metformin blocked T317-induced fatty liver by inhibiting T317-induced hepatic LXRα nuclear translocation and expression of lipogenic genes and by activating AMPKα. Moreover, co-treatment with T317 and metformin improved triglyceride metabolism by inducing expression of adipose triglyceride lipase, hormone-sensitive lipase, PPARα and carnitine acetyltransferase and by inhibiting acyl-CoA:diacylglycerol acyltransferase 1 expression.
Co-treatment with T317 and metformin inhibited the development of atherosclerosis without activation of lipogenesis, suggesting that combined treatment with T317 and metformin may be a novel approach to inhibition of atherosclerosis.
肝 X 受体（LXR）激动剂 T317 可减少动脉粥样硬化，但会诱导脂肪肝。二甲双胍通过激活 AMPKα 来激活能量代谢。在这项研究中，我们确定了二甲双胍和 T317 之间的相互作用是否可以在不激活肝脂肪生成的情况下抑制动脉粥样硬化。
载脂蛋白 E 缺陷小鼠用 T317、二甲双胍或两者在高脂肪饮食中治疗 16 周。然后收集主动脉、肝脏、巨噬细胞和血清样本，以确定动脉粥样硬化病变、脂肪肝、血脂谱和相关蛋白的表达。使用的技术包括免疫组织化学、组织学、qRT-PCR 和 Western blot。
T317 抑制了主动脉的正面和主动脉根部窦病变，并且与二甲双胍联合使用时抑制作用进一步增强。二甲双胍和 T317 的联合治疗增加了胶原含量，减少了坏死核心和钙化，从而增加了病变的稳定性。联合治疗抑制了巨噬细胞/泡沫细胞的形成及其在动脉壁中的积聚，这伴随着 ABCA1/ABCG1 表达的增加、单核细胞黏附的减少和巨噬细胞的明显局部增殖。二甲双胍通过抑制 T317 诱导的肝 LXRα核易位和脂质生成基因的表达以及激活 AMPKα 来阻止 T317 诱导的脂肪肝。此外，二甲双胍和 T317 的联合治疗通过诱导脂肪甘油三酯脂肪酶、激素敏感脂肪酶、PPARα 和肉毒碱乙酰转移酶的表达以及抑制酰基辅酶 A：二酰基甘油酰基转移酶 1 的表达，改善了甘油三酯代谢。
T317 和二甲双胍的联合治疗抑制了动脉粥样硬化的发展，而没有激活脂肪生成，这表明 T317 和二甲双胍的联合治疗可能是抑制动脉粥样硬化的一种新方法。
