Functional interplay between liver X receptor and AMP‐activated protein kinase α inhibits atherosclerosis in apolipoprotein E‐deficient mice − a new anti‐atherogenic strategy

Background and Purpose 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. Experimental Approach 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. Key Results 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. Conclusions and Implications 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.