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Functional interplay between liver X receptor and AMP-activated protein kinase ? inhibits atherosclerosis in apolipoprotein E-deficient mice - a new anti-atherogenic strategy.

ABSTRACT: BACKGROUND AND PURPOSE:The liver X receptor (LXR) agonist T317 reduces atherosclerosis but induces fatty liver. Metformin activates energy metabolism by activating AMPK?. 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 LXR? nuclear translocation and expression of lipogenic genes and by activating AMPK?. Moreover, co-treatment with T317 and metformin improved triglyceride metabolism by inducing expression of adipose triglyceride lipase, hormone-sensitive lipase, PPAR? 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.

SUBMITTER: Ma C

PROVIDER: S-EPMC5901167 | biostudies-literature | 2018 May

REPOSITORIES: biostudies-literature

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

Ma Chuanrui C Zhang Wenwen W Yang Xiaoxiao X Liu Ying Y Liu Lipei L Feng Ke K Zhang Xiaomeng X Yang Shu S Sun Lei L Yu Miao M Yang Jie J Li Xiaoju X Hu Wenquan W Miao Robert Q RQ Zhu Yan Y Li Luyuan L Han Jihong J Chen Yuanli Y Duan Yajun Y

British journal of pharmacology 20180323 9

<h4>Background and purpose</h4>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.<h4>Experimental approach</h4>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, m ...[more]

PMID: 29394501

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Project description:BackgroundVinexin ? is a novel adaptor protein that regulates cellular adhesion, cytoskeletal reorganization, signal transduction, and transcription; however, the exact role that vinexin ? plays in atherosclerosis remains unknown.Methods and resultsImmunoblot analysis showed that vinexin ? expression is upregulated in the atherosclerotic lesions of both patients with coronary heart disease and hyperlipemic apolipoprotein E-deficient mice and is primarily localized in macrophages indicated by immunofluorescence staining. The high-fat diet-induced double-knockout mice exhibited lower aortic plaque burdens than apolipoprotein E-/- littermates and decreased macrophage content. Vinexin ? deficiency improved plaque stability by attenuating lipid accumulation and increasing smooth muscle cell content and collagen. Moreover, the bone marrow transplant experiment demonstrated that vinexin ? deficiency exerts atheroprotective effects in hematopoietic cells. Consistent with these changes, the mRNA expression of proinflammatory cytokines were downregulated in vinexin ?-/- apolipoprotein E-/- mice, whereas the anti-inflammatory M2 macrophage markers were upregulated. The immunohistochemical staining and in vitro experiments showed that deficiency of vinexin ? inhibited the accumulation of monocytes and the migration of macrophages induced by tumor necrosis factor ?-stimulated human umbilical vein endothelial cells as well as macrophage proliferation. Finally, the inhibitory effects exerted by vinexin ? deficiency on foam cell formation, nuclear factor ?B activation, and inflammatory cytokine expression were largely reversed by constitutive Akt activation, whereas the increased expression of the nuclear factor ?B subset promoted by adenoviral vinexin ? was dramatically suppressed by inhibition of AKT.ConclusionsVinexin ? deficiency attenuates atherogenesis primarily by suppressing vascular inflammation and inactivating Akt-nuclear factor ?B signaling. Our data suggest that vinexin ? could be a therapeutic target for the treatment of atherosclerosis.

Dataset Information

Functional interplay between liver X receptor and AMP-activated protein kinase ? inhibits atherosclerosis in apolipoprotein E-deficient mice - a new anti-atherogenic strategy.

Publications

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

Similar Datasets

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