作者机构：
[Yin, WD] Department of Biochemistry and Molecular Biology, Nanhua University School of Life Sciences and Technology, Hengyang, 421001, Hunan, China. wdy20012001@yahoo.com
通讯机构：
[Yin, Weidong] Department of Biochemistry and Molecular Biology, Nanhua University School of Life Sciences and Technology, Hengyang, 421001, Hunan, China.
摘要：
The synthetic compound NO-1886 is a lipoprotein lipase activator that has been proven to be highly effective in lowering plasma triglycerides and elevating high-density lipoprotein cholesterol. Recently, we found that NO-1886 also had a plasma glucose-reducing action in high-fat/high-sucrose diet-induced diabetic rabbits. In the current study we investigated the effects of NO-1886 on the morphology of adipocytes, plasma levels of tumor necrosis factor-alpha (TNF-alpha) and free fatty acids (FFA) in miniature pigs fed a high-fat/high-sucrose diet. Our results showed that feeding a high-fat/high-sucrose diet to miniature pigs increased the size of adipocytes, and the plasma levels of TNF-alpha, FFA, and glucose. This diet also induced insulin resistance and impaired the acute insulin response to glucose loading. Supplementing 1% NO-1886 to the high-fat/high-sucrose diet inhibited adipocyte enlargement, and suppressed plasma levels of TNF-alpha, FFA, and glucose. The decrease in plasma TNF-alpha and FFA was simultaneous with the decrease in plasma glucose. We also found an increased whole body glucose clearance and an increased acute insulin response to intravenous glucose loading by NO-1886 supplementation. These data suggest that NO-1886 improves the glucose metabolism in high-fat/high-sucrose diet-induced diabetic minipigs by decreasing fat deposit, and suppressing plasma TNF-alpha and FFA levels. Therefore, NO-1886 is potentially beneficial for the treatment of insulin-resistant syndrome. (C) 2003 Elsevier Ltd. All rights reserved.
期刊：
Acta Biochimica et Biophysica Sinica,2010年42(9):635-645 ISSN：1672-9145
通讯作者：
Yuan, ZH
作者机构：
[Yuan Zhonghua; Yang Yongzong; Liu Xiaohui; Wang Zuo; Liu Zhiqiang; Liu Lushan; Yi Guanghui; Jiang Zhisheng; Liu Qingnan; Tang Chaoke] Univ S China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Peoples R China.;[Liu Qingnan] YiYang Med Coll, Dept Basic Nursing, Yiyang 413000, Peoples R China.;[Dai Zhibing] Univ S China, Inst Pathobiol, Hengyang 421001, Peoples R China.;[Dai Zhibing] Cent Hosp Yiyang, Dept B Type Ultrason Diag, Yiyang 413000, Peoples R China.
通讯机构：
[Yuan, ZH] Univ S China, Key Lab Arteriosclerol Hunan Prov, Inst Cardiovasc Dis, Hengyang 421001, Peoples R China.
关键词：
adipophilin;ERK1/2;atherosclerosis;PPARy
摘要：
It has been reported that oxidized low-density lipoprotein (Ox-LDL) can increase the expression of adipophilin. However, the detailed mechanisms are not fully understood. The aim of this study was to investigate the mechanism of Ox-LDL on adipophilin expression and the intracellular lipid droplet accumulation. A mouse macrophage-like cell line, RAW264.7, was used throughout, and it was found that Ox-LDL induced adipophilin expression in a dose-dependent manner. Moreover, Ox-LDL induced peroxisome proliferator-activated receptor-' (PPARy) expression and PPARy-specific inhibitor T0070907 abrogated Ox-LDL-induced adipophilin expression, but specific agonist GW1929 not. Furthermore, Ox-LDL induced phosphorylation of ERK1/2, and ERK1/2-specific inhibition by PD98059 suppressed the Ox-LDL-induced PPAR'y and adipophilin expression. The results showed that ERK1/2 or PPARy-specific inhibition decreased the amounts of intracellular lipid droplets. Meanwhile, the PPAR-y-specific agonist increased intracellular lipid droplets. These results suggested that Ox-LDL-induced increase in adipophilin level via ERK1/2 activation is one of the mechanisms of inducing greater amounts of intracellular lipid droplets in RAW264.7 cells, which indicated that adipophilin is involved in atherosclerotic progression
期刊：
Journal of atherosclerosis and thrombosis,2011年18(9):796-807 ISSN：1340-3478
通讯作者：
Tang, CK
作者机构：
[Xiao, Ji; Wang, Zuo; Yi, Guang-Hui; Mo, Zhong-Cheng; Tang, Ya-Ling; Liu, Xie-Hong; Hu, Yan-Wei; Li, Xiao-Xu; Tang, Chao-Ke] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.;[Liao, Duan-Fang] Hunan Univ Chinese Med, Div Stem Cell Regulat & Applicat, State Key Lab Chinese Med Powder & Med Innovat Hu, Changsha, Hunan, Peoples R China.
通讯机构：
[Tang, CK] Univ S China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Life Sci Res Ctr, Hengyang 421001, Peoples R China.
关键词：
Advanced oxidation protein products;ATP-binding cassette transporter A1;JAK/STAT;Cholesterol efflux
摘要：
AIMS: Advanced oxidation protein products (AOPPs) are new independent risk factor for coronary artery disease. This study was to determine the effects and potential mechanisms of AOPPs on cholesterol efflux from human macrophage foam cells. METHODS: Human THP-1 monocytes were preincubated with Phorbol-12-myristate- 13-acetate (PMA) and oxidized low density lipoprotein (ox-LDL) to form foam cells. The protein and mRNA expression were examined by western immunoblotting assays and real-time quantitative PCR, respectively. Cellular cholesterol content was measured by HPLC. The cholesterol efflux was assessed by liquid scintillation counting. RESULTS: AOPPs significantly decreased the expression of ATP-binding membrane cassette transporter A-1 (ABCA1) and liver X receptor alpha (LXRalpha) and reduced cholesterol efflux from THP-1 macrophage- derived foam cells. AOPPs substantially activated NADPH oxidase and activated Janus kinase/signal transducers and activators of transcription (JAK/STAT) signal pathway in THP-1-derived foam-like cells. Inhibiting NADPH oxidase by diphenyliodonium (DPI) effectively abolished the AOPPs-induced decrease in cholesterol efflux and the expression of ABCA1. Inhibiting JAK/STAT activation by its specific inhibitor AG-490 or by siRNA could also block AOPPs action on THP-1 cells. CONCLUSIONS: AOPPs may first down-regulate the expression of LXRalpha and ABCA1 through JAK/STAT signal pathway activation and then inhibit cholesterol efflux in THP-1-derived foam-like cells; therefore, our study may be useful for understanding the critical effects of AOPPs on the pathogenesis of atherosclerosis.
期刊：
Clinica chimica acta; international journal of clinical chemistry,2012年413(3-4):384-390 ISSN：0009-8981
通讯作者：
Yi, GH
作者机构：
[Xiong, Sheng Lin] You Cty People Hosp, Zhuzhou, Hunan, Peoples R China.;[Yi, Guang-Hui; Liu, Xing] Univ S China, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res, Hengyang, Hunan, Peoples R China.
通讯机构：
[Yi, GH] Univ S China, Key Lab Atherosclerol Hunan Prov, Inst Cardiovasc Res, Hengyang, Hunan, Peoples R China.
关键词：
S1P;HDL;ABCA1;SR-BI;Sphingolipids
摘要：
Sphingosine-1-phosphate (S1P) is a zwitterionic lysophospholipid generated by the sphingosine kinase-catalyzed phosphorylation of sphingosine. A number of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface or intracellular targets. However, the synthesis and secretion of S1P require release out of cells for binding with receptors by certain transporters and carriers. High-density lipoprotein (HDL) is an important carrier of S1P in the blood, but the mechanism by which it does so is unclear. This review discusses the mechanism how S1P is transported, and focuses particularly on how the formation of HDL-associated S1P (HDL-S1P) is mediated by certain transporters and carriers. A hypothesis that the ATP-binding cassette transporter A1 (ABCA1), ABCG1, and scavenger receptor class B memberI (SR-BI) play pivotal roles in HDL-S1P formation is also described. (C) 2011 Elsevier B.V. All rights reserved.
期刊：
Advanced Drug Delivery Reviews,2016年106:132-147 ISSN：0169-409X
通讯作者：
Yi, GH
作者机构：
[Mo, Zhong-Cheng; Tang, Zhen-Li; Ren, Kun; Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang City;[Mo, Zhong-Cheng; Tang, Zhen-Li; Ren, Kun; Yi, Guang-Hui] Hunan Province;[Mo, Zhong-Cheng; Tang, Zhen-Li; Ren, Kun; Yi, Guang-Hui] 421001, China;[Mo, Zhong-Cheng] Department of Histology and Embryology, University of South China, Hengyang;[Mo, Zhong-Cheng] Hunan
通讯机构：
[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang City 421001, Hunan Province, China. Electronic address:
摘要：
High-density lipoprotein (HDL) is a comparatively dense and small lipoprotein that can carry lipids as a multifunctional aggregate in plasma. Several studies have shown that increasing the levels or improving the functionality of HDL is a promising target for treating a wide variety of diseases. Among lipoproteins, HDL particles possess unique physicochemical properties, including naturally synthesized physiological components, amphipathic apolipoproteins, lipid-loading and hydrophobic agent-incorporating characteristics, specific protein protein interactions, heterogeneity, nanoparticles, and smaller size. Recently, the feasibility and superiority of using HDL particles as drug delivery vehicles have been of great interest. In this review, we summarize the structure, constituents, biogenesis, remodeling, and reconstitution of HDL drug delivery systems, focusing on their delivery capability, characteristics, applications, manufacturing, and drug-loading and drug-targeting characteristics. Finally, the future prospects are presented regarding the clinical application and challenges of using HDL as a pharmacodelivery carrier. (C) 2016 Elsevier B.V. All rights reserved.
摘要：
AIMS AND OBJECTIVES: The purpose of this study was to describe knowledge about stroke warning signs and risk factors in patients with previous stroke or transient ischaemic attacks in China and to investigate the relationship between socio-demographic characteristics & health status and patients' knowledge about stroke. BACKGROUND: Stroke is the leading cause of death and functional impairment in China. Survivors are at high risk of new vascular events. Secondary prevention after stroke or transient ischaemic attacks is not satisfactory. Previous research suggests that awareness of stroke plays an important role in facilitating secondary prevention. However, little is known about knowledge of stroke warning signs and risk factors among patients with previous stroke/transient ischaemic attacks. DESIGN: A cross-sectional questionnaire study. METHODS: This study was conducted in Hunan Province, China, between July and December in 2010. Subjects were recruited using a cluster sampling method. A questionnaire was administered to 1600 patients with stroke/transient ischaemic attacks diagnose from eight hospitals, and 1200 patients (75%) responded. Patients' knowledge about stroke warning signs and risk factors were collected and analysed. Results. Patients' knowledge about stroke warning signs was very poor (only 3.3% identified all warning signs and 28.3% identified three). Patients' knowledge about important risk factors (e.g. atrial fibrillation, diabetes, metabolic syndrome, etc.) was also very poor (<30%). Patients' action in emergency was extremely poor (only 9.2% reported to call emergency service). The age, education, stroke-related diagnoses and family history of cardiovascular disease were significantly associated with patients' knowledge about stroke. CONCLUSIONS: Knowledge about stroke warning signs and risk factors was very poor in patients with previous stroke or transient ischaemic attacks in China. RELEVANCE TO CLINICAL PRACTICE: Dissemination of stroke knowledge should be a core responsibility for Chinese clinical nurse. Future clinical education to improve patient's knowledge about stroke and further intervention to manage cardiovascular risk factors are indicated.
期刊：
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY,2016年72(4):657-667 ISSN：1138-7548
通讯作者：
Yi, Guang-Hui
作者机构：
[Tang, Zhen-Li; Suo, Rong; Ren, Kun; Liu, Xing; Peng, Xiao-Shan; Jiang, Yue] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China;[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China. ghyi6108@163.com;[Mo, Zhong-Cheng] Institute of Cardiovascular Research, Key Laboratory for Atherosclerology of Hunan Province, Life Science Research Center, University of South China, Hengyang, Hunan, 421001, China;[Zhang, Qing-Hai] Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China;[Xiong, Sheng-Lin] You Country People's Hospital, Zhuzhou, 412300, Hunan, China
通讯机构：
[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang City, 421001, Hunan Province, China.
关键词：
S1P;SR-BI;ABCA1;SphK;S1P receptors;Release
摘要：
Sphingosine-1-phosphate (S1P), which has emerged as a pivotal signaling mediator that participates in the regulation of multiple cellular processes, is derived from various cells, including vascular endothelial cells. S1P accumulates in lipoproteins, especially HDL, and the majority of free plasma S1P is bound to HDL. We hypothesized that HDL-associated S1P is released through mechanisms associated with the HDL maturation process. ApoA-I, a major HDL apolipoprotein, is a critical factor for nascent HDL formation and lipid trafficking via ABCA1. Moreover, apoA-I is capable of promoting bidirectional lipid movement through SR-BI. In the present study, we confirmed that apoA-I can facilitate the production and release of S1P by HUVECs. Furthermore, we demonstrated that ERK1/2 and SphK activation induced by apoA-I is involved in the release of S1P from HUVECs. Inhibitor and siRNA experiments showed that ABCA1 and SR-BI are required for S1P release and ERK1/2 phosphorylation induced by apoA-I. However, the effects triggered by apoA-I were not suppressed by inhibiting ABCA1/JAK2 or the SR-BI/Src pathway. S1P released due to apoA-I activation can stimulate the (ERK1/2)/SphK1 pathway through S1PR (S1P receptor) 1/3. These results indicated that apoA-I not only promotes S1P release through ABCA1 and SR-BI but also indirectly activates the (ERK1/2)/SphK1 pathway by releasing S1P to trigger their receptors. In conclusion, we suggest that release of S1P induced by apoA-I from endothelial cells through ABCA1 and SR-BI is a self-positive-feedback process: apoA-I-(ABCA1 and SR-BI)-(S1P release)-S1PR-ERK1/2-SphK1-(S1P production)-(more S1P release induced by apoA-I).
摘要：
AIM: To study the effect of oxidized low density lipoprotein (ox-LDL) on ATP binding cassette transporter A1 (CA1) in THP-1 macrophages. METHODS: After exposing the cultured THP-1 macrophages to ox-LDL for different periods, cholesterol efflux was determined by FJ-2107P type liquid scintillator. CA1 mRNA and protein level were determined by reverse trancriptase-polymerase chain reaction (RT-PCR) and Western blot, respectively. The cholesterol level in THP-1 macrophage foam cells was detected by high performance liquid chromatography. RESULTS: ox-LDL elevated CA1 in both protein and mRNA levels and increased apolipoprotein (apo) A-I-mediated cholesterol efflux in a time- and dose-dependent manner. 22(R)-hydroxycholesterol and 9-cis-retinoic acid did significantly increase cholesterol efflux in THP-1 macrophage foam cells (P<0.05), respectively. Both of them further promoted cholesterol efflux (P<0.01). As expected, liver X receptor (LXR) agonist decreased content of esterified cholesterol in the macrophage foam cells compared with control, whereas only a slight decrease of free cholesterol was observed. LXR activity was slightly increased by oxidized LDL by 12 % at 12 h compared with 6 h. However, LXR activity was increased about 1.8 times at 24 h, and oxidized LDL further increased LXR activity by about 2.6 times at 48 h. CONCLUSION: CA1 gene expression was markedly increased in cholesterol-loaded cells as a result of activation of LXR/RXR. CA1 plays an important role in the homeostasis of cholesterol in the macrophages.
期刊：
Clinica chimica acta; international journal of clinical chemistry,2015年446:21-29 ISSN：0009-8981
通讯作者：
Yi, GH
作者机构：
[Tang, Zhen-Li; Tan, Yan-Mei; Ren, Kun; Jiang, Yue] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang City 421001 Hunan Province, China;[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang City 421001 Hunan Province, China. Electronic address: ghyi6108@163.com
通讯机构：
[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, Hengyang City 421001 Hunan Province, China. Electronic address:
关键词：
Apolipoprotein M;Regulation;Function
摘要：
Apolipoprotein M (ApoM) is a novel apolipoprotein that was discovered in 1999 and is bound primarily to high-density lipoproteins (HDLs) in the plasma. Multiple factors may influence its expression at both the post-transcriptional and the transcriptional levels both in vivo and ex vivo as follows: hepatocyte nuclear factor-1 alpha, 4 alpha (HNF-1 alpha, 4 alpha), liver receptor homolog-1 (LRH-1), forkhead box A2 (Foxa2) and platelet activating factor (PAF) upregulate its expression; liver X receptor (LXR), retinoid X receptor (RXR), famesoid X receptor (FXR), small heterodimer partner (SHP) and the majority of cytokines downregulate its expression. However, mechanisms underlying these processes remain unknown. Structurally, there exists a characterized hydrophobic binding pocket within the apoM protein, which enables it to bind functional lipids such as Sphingosine-1-Phosphate (S1P). Functionally, it facilitates the formation of pre beta-HDL and enhances an avalanche of atheroprotective effects exerted by HDL. Moreover, in patients with diabetes, the levels of plasma apoM may decrease, whereas the augmentation of apoM decreases plasma glucose levels and magnifies the secretion of insulin. This article offers a panorama of the progress made in the research regarding the characteristics of apoM, particularly the regulation of its expression and its functions. (C) 2015 Elsevier B.V. All rights reserved.
摘要：
Sphingosine-1-phosphate (S1P), which is generated from the sphingosine kinase-catalyzed phosphorylation of sphingosine, is now recognized as a critical regulator of many kinds of physiological and pathological processes, including cancer, cardiovascular function, and diabetes. It can also trigger a wide variety of biological effect, such as cell movement, differentiation, survival, inflammation, immunity, calcium homeostasis, and angiogenesis. As we know, a number of the biological effects of S1P are mediated by its binding to five specific G protein-coupled receptors located on the cell surface or intracellular targets. However, the synthesis and the secretion of S1P are regulated by various endogenetic or ectogenous stimuli and involve many kinds of enzymes and transporters. In this review, we discuss the regulation of S1P synthesis by many kinds of enzymes and mainly introduce the process of ceramide to S1P. Moreover, S1P deterioration is important balance in physiologic adjustment. We also describe the role of verified or potential transporters in S1P release in detail.
摘要：
OBJECTIVES: The aim of the study was to elucidate the possible role and mechanism of NO-1886 (ibrolipim, a lipoprotein lipase activator) in ameliorating insulin resistance induced by high palmitate. METHODS: HepG2 cells were cultured in RPMI 1640 medium and were treated with palmitate to induce insulin resistance. Free fatty acids (FFAs), glucose, glycogen, cell viability and mRNA and protein levels were analysed separately. KEY FINDINGS: We found that HepG2 cells treated with 0.5 mm palmitate for 48 h led to a significant decrease of insulin-induced glucose consumption (from 2.89 +/- 0.85 mm in the control to 0.57 +/- 0.44 mm in palmitate). Insulin resistance (IR) of HepG2 cells was induced by 0.5 mm palmitate for 48 h. NO-1886 stimulated glucose consumption, glycogen synthesis and FFA absorption in insulin-resistant HepG2 cells. Maximum stimulation effects were observed with 10 microm NO-1886 for 24 h. Compared with the dimethyl sulfoxide-treated group, 2.5 microm NO-1886 or higher could induce the mRNA expression of lipoprotein lipase. Meanwhile, NO-1886 increased the protein content of P-GSK-3betaser(9) and decreased the protein level of GSK-3beta in insulin-resistant HepG2 cells, but NO-1886 didn't change the protein levels of PI3-Kp85 and Akt2. CONCLUSION: Lipoprotein lipase activator NO-1886 could increase glycogen synthesis in HepG2 cells and could ameliorate the insulin resistance, which was associated with GSK-3 signalling.
期刊：
DNA AND CELL BIOLOGY,2015年34(1):6-18 ISSN：1044-5498
通讯作者：
Yi, GH
作者机构：
[Yi, Guang-Hui; Lu, Yan-Ju; Wu, Rong; Ren, Kun] Univ South China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.;[Zhang, Qing-Hai] Univ South China, Affiliated Hosp 1, Clin Res Inst, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Yi, GH] Univ South China, Inst Cardiovasc Res, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
摘要：
The X-box binding protein 1 (XBP1) is not only an important component of the unfolded protein response (UPR), but also an important nuclear transcription factor. Upon endoplasmic reticulum stress, XBP1 is spliced by inositol-requiring enzyme 1 (IRE1), thereby generating functional spliced XBP1 (XBP1s). XBP1s functions by translocating into the nucleus to initiate transcriptional programs that regulate a subset of UPR- and non-UPR-associated genes involved in the pathophysiological processes of various diseases. Recent reports have implicated XBP1 in metabolic diseases. This review summarizes the effects of XBP1-mediated regulation on lipid metabolism, glucose metabolism, obesity, and atherosclerosis. Additionally, for the first time, we present XBP1s-dependent transcriptional reprogramming in metabolic diseases under different conditions, including pathology and physiology. Understanding the function of XBP1 in metabolic diseases may provide a basic knowledge for the development of novel therapeutic targets for ameliorating these diseases.
期刊：
JOURNAL OF PHYSIOLOGY AND BIOCHEMISTRY,2017年73(2):287-296 ISSN：1138-7548
通讯作者：
Yi, GH
作者机构：
[Tang, Zhen-Li; Ren, Kun; Peng, Xiao-Shan; Jiang, Yue] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China;[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China. ghyi6108@163.com;[Mo, Zhong-Cheng] Department of Histology and Embryology, University of South China, Hengyang, Hunan, 421001, China;[Liu, Xing] National Laboratory of Medical Molecular Biology, Institute of Basic Medical Sciences, Chinese Academy of Medical Sciences, School of Basic Medicine, Peking Union Medical College, Beijing, 100005, China;[Zhang, Qing-Hai] Clinical Research Institution, The First Affiliated Hospital, University of South China, Hengyang, Hunan, 421001, China
通讯机构：
[Yi, Guang-Hui] Institute of Cardiovascular Disease, Key Lab for Arteriosclerology of Hunan Province, University of South China, 28 W Changsheng Road, Hengyang, Hunan, 421001, China.
关键词：
HDL;S1P/S1PR2;apoA-I/SR-BI;Inflammation
摘要：
Endothelial dysfunction plays a vital role during the initial stage of atherosclerosis. Oxidized low-density lipoprotein (ox-LDL) induces vascular endothelial injury and vessel wall inflammation. Sphingosine-1-phosphate (S1P) exerts numerous vasoprotective effects by binding to diverse S1P receptors (S1PRs; S1PR1-5). A number of studies have shown that in endothelial cells (ECs), S1PR2 acts as a pro-atherosclerotic mediator by stimulating vessel wall inflammation through the phosphatidylinositol 3-kinase (PI3K)/Akt signaling pathway. Scavenger receptor class B member I (SR-BI), a high-affinity receptor for apolipoprotein A-I (apoA-I)/high-density lipoprotein (HDL), inhibits nuclear factor-kappa B (NF-kappa B) translocation and decreases the plasma levels of inflammatory mediators via the PI3K/Akt pathway. We hypothesized that the inflammatory effects of S1P/S1PR2 on ECs may be regulated by apoA-I/SR-BI. The results showed that ox-LDL, a pro-inflammatory factor, augmented the S1PR2 level in human umbilical vein endothelial cells (HUVECs) in a dose- and time-dependent manner. In addition, S1P/S1PR2 signaling influenced the levels of inflammatory factors, including tumor necrosis factor-alpha (TNF-alpha), interleukin-1 beta (IL-1 beta), and IL-10, aggravating inflammation in HUVECs. Moreover, the pro-inflammatory effects induced by S1P/S1PR2 were attenuated by SR-BI overexpression and enhanced by an SR-BI inhibitor, BLT-1. Further experiments showed that the PI3K/Akt signaling pathway was involved in this process. Taken together, these results demonstrate that apoA-I/SR-BI negatively regulates S1P/S1PR2-mediated inflammation in HUVECs by activating the PI3K/Akt signaling pathway.
摘要：
Background and aims: Liver scavenger receptor class B type I (SR-BI) exerts atheroprotective effects through selective lipid uptake (SLU) from high-density lipoprotein cholesterol (HDL-C). Low hepatic SRBI expression leads to high HDL-C levels in the circulation and an increased risk of atherosclerosis. Furthermore, macrophage SR-BI mediates bidirectional cholesterol flux and may protect against atherogenesis. Previous studies have revealed that miR-24 is closely related to cardiovascular disease (CVD) progression. We aimed to investigate the molecular mechanisms by which miR-24 participates in SR-BI-mediated selective HDL cholesteryl ester (HDL-CE) uptake and further atherogenesis in apoE(-/-) mice. Methods: Bioinformatic predictions and luciferase reporter assays were utilized to detect the association between miR-24 and the SR-BI 30 untranslated region (30 UTR), and RT-PCR and western blotting were used to evaluate SR-BI mRNA and protein expression, respectively. The effects of miR-24 on Dil-HDL uptake were determined by flow cytometry assay. Double-radiolabeled HDL (I-125-TC-/[H-3] CEt-HDL) was utilized to measure the effects of miR-24 on HDL and CE binding and SLU in HepG2 and PMAtreated THP-1 cells. In addition, total cholesterol (TC) levels in HepG2 cells were analyzed using enzymatic methods, and macrophage lipid content was evaluated by high-performance liquid chromatography (HPLC) assay. Small interfering RNA (siRNA) and pcDNA3.1(-)-hSR-BI plasmid transfection procedures were utilized to confirm the role of SR-BI in the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels in both cell types. Hepatic SR-BI level in apoE(-/-) mice was measured by western blotting. Liver TC, FC and CE levels and plasma triglycerides (TG), TC and HDL-C levels were evaluated enzymatically using commercial test kits. Atherosclerotic lesion sizes were measured using Oil Red O and hematoxylin-eosin staining. Results: miR-24 directly repressed SR-BI expression by targeting its 30UTR. In addition, miR-24 decreased Dil-HDL uptake and SLU in HepG2 and THP-1 macrophages. In the presence of HDL, miR-24 decreased TC levels in HepG2 cells and TC, free cholesterol (FC) and CE levels in macrophages. Overexpression and down-regulation assays showed that SR-BI mediated the effects of miR-24 on Dil-HDL uptake, SLU and cholesterol levels. Lastly, miR-24 administration decreased hepatic SR-BI expression and promoted atheromatous plaque formation in apoE(-/-) mice, findings in line with those of our in vitro studies. Conclusions: These findings indicate that miR-24 accelerates atherogenesis by repressing SR-BI-mediated SLU from HDL-C. (c) 2018 Elsevier B.V. All rights reserved.
期刊：
MOLECULAR MEDICINE REPORTS,2015年12(3):3599-3606 ISSN：1791-2997
通讯作者：
Yuan, ZH
作者机构：
[Liu, Xiaohui] Soochow Univ, Cyrus Tang Hematol Ctr Res Partnership, Jiangsu Inst Hematol, Affiliated Hosp 1, Suzhou 215400, Jiangsu, Peoples R China.;[Yuan, Zhonghua; Wang, Zuo; Guo, Dongming; Yi, Guanghui; Qiao, Yuncheng; Yin, Weidong; Tang, Chaoke; Meng, Lei] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan, Hengyang 421001, Hunan, Peoples R China.;[Qiao, Yuncheng] Pingyu Renmin Hosp, Dept Cardiovasc Med, Pingyu 463400, Henan, Peoples R China.;[Liu, Qingnan] Yiyang Med Coll, Dept Basic Nursing, Yiyang 413000, Hunan, Peoples R China.;[Tian, Guoping] Univ South China, Dept Cardiovasc Med, Affiliated Hosp 2, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Yuan, ZH] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan, 28 West Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
small interfering RNA;adipophilin;acyl-coenzyme A;cholesterol acyltransferse 1;retrovirus;lipid
摘要：
Oxidized low-density lipoprotein (ox-LDL) can increase the expression of adipophilin and the accumulation of intracellular lipid droplets. However, the detailed mechanisms remain to be fully elucidated. The present study aimed to investigate the mechanism underlying the effect of ox-LDL on the expression of adipophilin and the accumulation of intracellular cholesterol esters. The results revealed that ox-LDL increased the activation of protein kinase C alpha (PKC alpha), expression of adipophilin and acyl-coenzymeA: cholesterol acyltransferse 1 (ACAT1) and increased accumulation of intracellular cholesterol esters. In addition, PKCa siRNA abrogated ox-LDL-induced adipophilin, expression of ATAC1 and accumulation of cholesterol esters. Furthermore, ox-LDL increased the accumulation of intracellular cholesterol esters and expression of ACAT1, and this effect were reversed by transfection with adipophilin siRNA. Taken together, these results demonstrated that ox-LDL induces the accumulation of cholesterol esters, which is mediated by the PKC alpha-adipophilin-ACAT1 pathway.
关键词：
High-density lipoprotein;Sphingosine kinase;Sphingosine 1-phosphate;Cyclooxygenase-2;Protein kinase C
摘要：
High-density lipoprotein (HDL) has a significant cardioprotective effects. HDL induces cyclooxygenase-2 (COX-2) expression and prostacyclin I-2 (PGI-2) release in vascular endothelial cells, which contributes to its anti-atherogenic effects. However, the underlying mechanisms are not fully understood. In the present study, we observed that HDL-stimulated COX-2 expression and PGI-2 production in human umbilical vein endothelial cells (HUVECs) in a time- and dose-dependent manner. These effects triggered by HDL were inhibited by pertussis toxin (PTX), protein kinase C (PKC) inhibitor GF109203X, and ERK inhibitor PD98059, suggesting that G alpha i/G alpha o-coupled GPCR, PKC, and ERK pathways are involved in HDL-induced COX-2/PGI-2 activation. More importantly, we found that silencing of sphingosine kinase 2 (SphK-2) also blocked HDL-induced COX-2/PGI-2 activation. In addition, HDL-activated SphK-2 phosphorylation accompanied by increased S1P level in the nucleus. Our ChIP data demonstrated that SphK-2 is associated with CREB at the COX-2 promoter region. Collectively, these results indicate that HDL induces COX-2 expression and PGI-2 release in endothelial cells through activation of PKC, ERK1/2, and SphK-2 pathways. These findings implicate a novel mechanism underlying anti-atherothrombotic effects of HDL.
摘要：
ATP citrate lyase (ACL or ACLY) is an extra-mitochondrial enzyme widely distributed in various human and animal tissues. ACL links glucose and lipid metabolism by catalyzing the formation of acetyl-CoA and oxaloacetate from citrate produced by glycolysis in the presence of ATP and CoA. ACL is aberrantly expressed in many immortalized cells and tumors, such as breast, liver, colon, lung and prostate cancers, and is correlated reversely with tumor stage and differentiation, serving as a negative prognostic marker. ACL is an upstream enzyme of the long chain fatty acid synthesis, providing acetyl-CoA as an essential component of the fatty acid synthesis. Therefore, ACL is a key enzyme of cellular lipogenesis and potent target for cancer therapy. As a hypolipidemic strategy of metabolic syndrome and cancer treatment, many small chemicals targeting ACL have been designed and developed. This review article provides an update for the research and development of ACL inhibitors with a focus on their patent status, offering a new insight into their potential application.
