肝X受体(LXR)包括α和β两个亚型，配体(T0901317，T317)激活的LXRβ有效防治动脉粥样硬化，但同时被激活的LXRα诱发脂肪肝等副作用。我们发现metformin通过激活AMPKα选择性抑制LXRα但不影响LXRβ功能；NgBR表达缺失抑制AMPKα、激活LXRα而导致脂肪肝，但NgBR表达缺失对LXRβ无作用。由此我们推断metformin与T317联用可防治动脉粥样硬化并通过对LXR两个亚型的差别性调控而阻断T317诱导的脂肪肝。基于此，本申请拟研究：1、metformin与T317联用能有效防治动脉硬化且消除脂肪肝等副作用；2、药物联用抗动脉硬化、保护血管的作用机理；3、metformin选择性抑制LXRα活性与拮抗脂肪肝作用机制；4、NgBR在AMPKα调控LXR中的作用。我们的工作将阐明AMPKα与LXR相互作用的机制，确定药物联用是抗动脉粥样硬化的新策略。

The liver X receptors consist of two isoforms, LXRα and LXRβ. The ligand activated-LXRβ can substantially inhibit the development of atherosclerosis, while the simultaneous ligand activated-LXRα activates lipogenesis which results in fatty liver and hypertriglyceridemia. Our preliminary study indicated that metformin can selectively inhibit ligand-induced LXRα activity while having no effect on LXRβ functions by activating AMPKα. Meanwhile, we determine that deficiency of NgBR expression in hepatocytes inactivates AMPKα and activates LXRα, thereby inducing fatty liver, which implies that the combined metformin and T0901317 (an LXR ligand) can reduce atherosclerosis without lipogenic adverse effects. In this proposal, we anticipate to complete the following studies to determine: 1. If the co-treatment of pro-atherogenic animals with T0901317 and metformin can substantially reduce atherosclerotic lesions while eliminating T0901317-induced lipogenic side effects; 2. The mechanisms by which the co-treatment of metformin and T0901317 reduces atherosclerosis, such as enhancement of macrophage cholesterol efflux and reverse cholesterol transport, inhibition of macrophage/foam cell formation, amelioration of endothelial cell and smooth muscle cell functions; 3. The anti-lipogenic mechanisms in which metformin can selectively inhibit LXRα activity. Therefore, the combined metformin and T0901317 can reduce lipogenesis while enhancing lipid/energy metabolism thereby antagonizing T0901317-induced adverse side effects. 4. The important role of NgBR in AMPKα-mediated LXR expression/functions. By completing the above studies, we will be able to unveil the interaction between AMPKα and LXR signaling pathways, and demonstrate that the combined metformin and T0901317 is a novel strategy in anti-atherosclerosis.