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A new anti‐atherogenic strategy
Author(s) -
Ma Chuanrui,
Zhang Wenwen,
Duan Yajun,
Chen Yuanli,
Han Jihong
Publication year - 2017
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.31.1_supplement.782.8
Subject(s) - liver x receptor , metformin , lipogenesis , ampk , endocrinology , medicine , steatosis , amp activated protein kinase , chemistry , fatty liver , abcg1 , abca1 , diabetes mellitus , lipid metabolism , transcription factor , protein kinase a , phosphorylation , biochemistry , nuclear receptor , disease , transporter , gene
The progress on the selective liver X receptor β (LXRβ) modulators, which can reduce atherosclerosis without activation of lipogenesis, is limited. Metformin, a medicine for diabetes treatment, activates AMPKα to enhance energy metabolism. In this study, we investigate if metformin can enhance T0901317 (LXR ligand)‐inhibited atherosclerosis while eliminating T0901317‐activated hypertriglyceridemia. We randomly divided the proatherogenic apoE deficient (apoE −/− ) mice into 4 groups (15 mice/group), and fed them a high‐fat diet (HFD), HFD containing T0901317 [1 mg/kg bodayweight/day (mpk)], metformin (100 mpk), or combined T0901317 and metformin, respectively for 16 weeks. After treatment, we collected mouse aorta and liver samples, and determined atherosclerotic lesions and liver steatosis, respectively. We found that T0901317 alone inhibited en face and aortic root sinus lesions, and the inhibition was enhanced by co‐treatment with metformin. The co‐treatment of T0901317 and metformin also enhanced lesion stability by increasing collagen content in lesion caps while reducing necrotic cores and calcification within lesions. Macrophage/foam cell formation and accumulation were inhibited by the co‐treatment which can be attributed by the LXR‐activated ABCA1/ABCG1 expression. T0901317 induced a severe fatty liver and hyperglyceridemia which was substantially blocked by metformin. Mechanistically, metformin had little effect on T0901317‐induced hepatic LXRα/β expression. However, it selectively reduced T0901317‐mediated LXRα (the main transcription factor controlling lipogenesis) but not LXRβ, nuclear translocation. Thereby, metformin blocked expression of T0901317‐induced lipogenic genes, SREBP1c, FASN and ACC, while increased ACC phosphorylation. Moreover, metformin favored energy dissipation process by inducing ATGL, HSL, PPARα and CAT and inhibiting DGAT1 expression. Furthermore, we used AMPKα knockout HepG2 cells to determine the effect of metformin relied on AMPKα expression. Taken together, our study demonstrates that addition of metformin to T0901317 not only enhances T0901317‐inhibited atherosclerosis, but also blocks T0901317‐induced severe hepatic lipid accumulation, fatty liver and hypertriglyceridemia, which suggests that the co‐treatment of metformin and T0901317 may function as a safe and novel therapy for atherosclerosis treatment. Support or Funding Information The National Science Foundation of China Grants 81473204 to J Han and 81573427 to Y Duan