The hydrogel‐encapsulated T0901317 reduces atherosclerosis without effect on lipogenesis in apoE deficient mice

Objective Activation of liver X receptor (LXR) by ligand induces macrophage ATP‐binding cassette transporter A1 and G1 (ABCA1/ABCG1) expression to enhance cholesterol efflux, thereby inhibiting formation of foam cells and development of atherosclerosis. However, LXR activation in hepatocytes induces fatty acid synthesis, which leads to development of fatty liver by an LXR ligand, such as T0901317. Targeting macrophage LXR selectively can avoid the adverse effects of LXR ligand on the liver. A hydrogel can be taken up by monocytes or macrophages, but not by hepatocytes. In this study, we treated apoE deficient mice with a hydrogel‐encapsulated T0901317, and determined whether the hydrogel‐encapsulated T0901317 can inhibit atherosclerosis while eliminating LXR‐induced fatty liver. We also attempted to disclose the involved molecular mechanisms. Approach and Results ApoE −/− mice randomly in three groups received the following treatment for 16 weeks. Group 1 (control group): mice were fed high‐fat diet (HFD); Group 2 (TF group): mice were fed HFD containing T0901317; Group 3 (THI group): mice were fed HFD while subcutaneously injected the hydrogel‐encapsulated T0901317 once every 3 days. At the end of experiment, we found that compared with control group, en face lesions were decreased by ~37.4 and ~33.17% by TF and THI, respectively. In the fibrous cap of aortic wall, the smooth muscle cell/collagen content was increased while necrotic cores, macrophages accumulation and inflammation were decreased by TF and THI. The inhibition of foam cell formation by TF and THI was attributed by LXR‐induced ABCA1/ABCG1 expression. Interestingly, compared with severe liver steatosis induced by TF, THI totally blocked T0901317‐induced fatty liver. Meanwhile, levels of serum total cholesterol, triglyceride and ALT/ALP, and liver triglyceride accumulation induced by LXR were also decreased by THI. Mechanistically, we determined that the hydrogel‐encapsulated T0901317 was taken up by monocyte/macrophages via a receptor‐mediated endocytosis, and the drug‐loaded macrophages were recruited to the lesion areas. Therefore, hepatic LXR and LXR‐targeted genes expression, such as SREBP1, ACC1 and FASN, were not activated by T0901317. As a result, hydrogel‐encapsulated T0901317 eliminated LXR ligand‐induced fatty liver. Conclusions Our study demonstrates that the hydrogel‐encapsulated T0901317 can reduce atherosclerosis while eliminate T0901317‐induced fatty liver, indicating the hydrogel‐encapsulated LXR ligand might be a novel therapy for atherosclerosis treatment. This abstract is from the Experimental Biology 2018 Meeting. There is no full text article associated with this abstract published in The FASEB Journal .