Abstract
Background: Aberrant chronic inflammation and excess accumulation of lipids play a pivotal role in the occurrence and progression of atherosclerosis. (–)-Epigallocatechin-3-gallate (EGCG), the major catechins in green tea, displayed anti-atherosclerotic properties in vivo and in vitro. However, the effects and underlying mechanism of EGCG on atherosclerosis remain unclear.Methods: Male apolipoprotein E-knockout (ApoE-/-) mice (7 weeks old) fed with high-fat diet (HFD) were treated with normal saline or EGCG (40 mg/kg/d, i.g.) for 18 weeks. Atherosclerotic plaque and liver lipid accumulation were measured by Oil Red staining. Plasma lipids and cytokines were detected using commercial kits. The expression of protein and mRNA was analyzed by western blot and quantitative real-time reverse transcription-polymerase chain reaction, respectively.Results: EGCG administration markedly attenuated atherosclerotic plaque formation in HFD-fed ApoE-/- mice, which were accompanied by increased plasma interleukin-10 (IL-10) level and decreased plasma IL-6 and tumor necrosis factor-α (TNF-α) levels. In addition, EGCG modulated high-fat-induced dyslipidemia, evidencing by decreased total cholesterol (TC) and low-density lipoprotein levels and increased high-density lipoprotein level. Meanwhile, EGCG treatment alleviated high-fat-mediated liver lipid accumulation and decreased liver TC and triglyceride. Mechanistically, EGCG significantly modulated high-fat-induced hepatic tetratricopeptide repeat domain protein 39B (TTC39B) expression and its related genes (Lxrβ, Abcg5, Abcg8, Abca1, Srebf1, Scd1, Scd2, Fas, Elovl5, Mylip) expression in liver from ApoE-/- mice. Notably, EGCG remarkably induced hepatic liver X receptor α (LXRα) and LXRβ expression and inhibited both precursor and mature sterol regulatory element binding transcription factor-1 (SREBP-1) expression.Conclusion: Taken together, our data for the first time suggested that TTC39B was involved in EGCG-mediated anti-atherosclerotic effects through modulation of LXR/SREBP-1 pathway.
Highlights
Atherosclerosis is a highly prevalent disease that can significantly increase the risk of major vascular events, such as myocardial or cerebral infarctions (Koon et al, 2011)
EGCG administration markedly attenuated atherosclerotic plaque formation in highfat diet (HFD)-fed ApoE−/− mice, which were accompanied by increased plasma interleukin10 (IL-10) level and decreased plasma IL-6 and tumor necrosis factor-α (TNF-α) levels
Taken together, our data for the first time suggested that tetratricopeptide repeat domain protein 39B (TTC39B) was involved in EGCG-mediated anti-atherosclerotic effects through modulation of liver X receptors (LXRs)/sterol regulatory element-binding protein 1 (SREBP-1) pathway
Summary
Atherosclerosis is a highly prevalent disease that can significantly increase the risk of major vascular events, such as myocardial or cerebral infarctions (Koon et al, 2011). There is growing evidence that both chronic inflammation and hyperlipidemia are key risk factors for the development of vascular diseases including atherosclerosis [reviewed in Back and Hansson (2015)]. The nuclear receptor liver X receptors (LXRs) upregulated a series of genes, including Abcg, Abcg, Abca, and so on, which promote coordinated mobilization of excess cholesterol from cells and from the body [Reviewed in Calkin and Tontonoz (2012)], making it a potentially therapeutic target for the treatment of metabolic and atherosclerotic diseases. Inhibition of T39, and stabilization of endogenous LXRs, provided insights into treating metabolic diseases, including atherosclerosis and fatty liver [reviewed in Loaiza et al (2017) and Tran and Wang (2017)]. The expression of protein and mRNA was analyzed by western blot and quantitative real-time reverse transcription-polymerase chain reaction, respectively
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