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(-)-Epigallocatechin-3-Gallate Ameliorates Atherosclerosis and Modulates Hepatic Lipid Metabolic Gene Expression in Apolipoprotein E Knockout Mice: Involvement of TTC39B

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      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.

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      Most cited references 44

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      Atherosclerosis--an inflammatory disease.

       R. Ross,  Paul O'Byrne (1999)
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        Biological, Clinical, and Population Relevance of 95 Loci for Blood Lipids

        Serum concentrations of total cholesterol, low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglycerides (TG) are among the most important risk factors for coronary artery disease (CAD) and are targets for therapeutic intervention. We screened the genome for common variants associated with serum lipids in >100,000 individuals of European ancestry. Here we report 95 significantly associated loci (P < 5 × 10-8), with 59 showing genome-wide significant association with lipid traits for the first time. The newly reported associations include single nucleotide polymorphisms (SNPs) near known lipid regulators (e.g., CYP7A1, NPC1L1, and SCARB1) as well as in scores of loci not previously implicated in lipoprotein metabolism. The 95 loci contribute not only to normal variation in lipid traits but also to extreme lipid phenotypes and impact lipid traits in three non-European populations (East Asians, South Asians, and African Americans). Our results identify several novel loci associated with serum lipids that are also associated with CAD. Finally, we validated three of the novel genes—GALNT2, PPP1R3B, and TTC39B—with experiments in mouse models. Taken together, our findings provide the foundation to develop a broader biological understanding of lipoprotein metabolism and to identify new therapeutic opportunities for the prevention of CAD.
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          Green tea catechin, epigallocatechin-3-gallate (EGCG): mechanisms, perspectives and clinical applications.

          An expanding body of preclinical evidence suggests EGCG, the major catechin found in green tea (Camellia sinensis), has the potential to impact a variety of human diseases. Apparently, EGCG functions as a powerful antioxidant, preventing oxidative damage in healthy cells, but also as an antiangiogenic and antitumor agent and as a modulator of tumor cell response to chemotherapy. Much of the cancer chemopreventive properties of green tea are mediated by EGCG that induces apoptosis and promotes cell growth arrest by altering the expression of cell cycle regulatory proteins, activating killer caspases, and suppressing oncogenic transcription factors and pluripotency maintain factors. In vitro studies have demonstrated that EGCG blocks carcinogenesis by affecting a wide array of signal transduction pathways including JAK/STAT, MAPK, PI3K/AKT, Wnt and Notch. EGCG stimulates telomere fragmentation through inhibiting telomerase activity. Various clinical studies have revealed that treatment by EGCG inhibits tumor incidence and multiplicity in different organ sites such as liver, stomach, skin, lung, mammary gland and colon. Recent work demonstrated that EGCG reduced DNMTs, proteases, and DHFR activities, which would affect transcription of TSGs and protein synthesis. EGCG has great potential in cancer prevention because of its safety, low cost and bioavailability. In this review, we discuss its cancer preventive properties and its mechanism of action at numerous points regulating cancer cell growth, survival, angiogenesis and metastasis. Therefore, non-toxic natural agent could be useful either alone or in combination with conventional therapeutics for the prevention of tumor progression and/or treatment of human malignancies. Copyright © 2011 Elsevier Inc. All rights reserved.
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            Author and article information

            Affiliations
            1School of Medicine, Jiangnan University , Wuxi, China
            2School of Life Sciences, Hefei Normal University , Hefei, China
            3Anhui Key Laboratory for Research and Development of Traditional Chinese Medicine, Key Laboratory of Xin’an Medicine, Ministry of Education, School of Pharmacy, Anhui University of Chinese Medicine , Hefei, China
            4State Key Laboratory of Tea Plant Biology and Utilization, Anhui Agricultural University , Hefei, China
            Author notes

            Edited by: Wenliang Song, Vanderbilt University Medical Center, United States

            Reviewed by: Jesus Osada, University of Zaragoza, Spain; Carole L. Wilson, Medical University of South Carolina, United States; Soon Yew Tang, University of Pennsylvania, United States

            *Correspondence: Wei Wang, wangwei_sir@ 123456126.com Zheng-Zhu Zhang, zzz@ 123456ahau.edu.cn

            This article was submitted to Inflammation Pharmacology, a section of the journal Frontiers in Pharmacology

            Contributors
            Journal
            Front Pharmacol
            Front Pharmacol
            Front. Pharmacol.
            Frontiers in Pharmacology
            Frontiers Media S.A.
            1663-9812
            09 March 2018
            2018
            : 9
            5854642
            10.3389/fphar.2018.00195
            Copyright © 2018 Pan, Wu, Wang, Chen, Chen, Zhang, Chen, Geng, Xu, Dai, Li, Wang and Zhang.

            This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

            Counts
            Figures: 4, Tables: 1, Equations: 0, References: 44, Pages: 10, Words: 0
            Categories
            Pharmacology
            Original Research

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