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.
摘要：
Many basic and clinical studies have demonstrated that atherosclerosis is a chronic inflammatory disease. Although there are many factors affecting atherosclerosis, the role of lymphatic vessels in this disease has been neglected. Traditionally, lymphatic vessels have been considered to be passages for transporting interstitial fluid to the blood circulation. However, as early as the last century, researchers found that there are numerous lymphatic vessels surrounding sites of atherosclerosis; however, the relationship between lymphatic vessels and atherosclerosis is not clear. With further research, lymphatic vessels were determined to be involved in the induction and resolution of arterial inflammation and also to play a positive role in plaque cholesterol transport. There are abundant immune cells around atherosclerosis, and these immune cells not only have a significant impact on plaque formation but also affect local lymphangiogenesis (IAL). This promotion of IAL seems to relieve the progression of atherosclerosis. Therefore, research into the relationship between lymphatic vessels and atherosclerosis is of great importance for improving atherosclerosis treatment. This review highlights what is known about the relationship between lymphatic vessels and atherosclerosis, including the effect of immune cells on IAL, and reverse cholesterol transport. In addition, we present some of our views on the improvement of atherosclerosis treatment, which have significant clinical value in research.
作者机构：
[Jiang, Yue; Peng, Xiao-Shan; Ren, Kun; Shi, Jin-Feng; Yi, Guang-Hui; Tang, Zhen-Li] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.;[Shi, Jin-Feng; Mo, Zhong-Cheng] Univ South China, Dept Histol & Embryol, Hengyang 421001, Hunan, Peoples R China.;[Liu, Xing] Chinese Acad Med Sci, Inst Basic Med Sci, Sch Basic Med, Natl Lab Med Mol Biol,Peking Union Med Coll, Beijing 100005, 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, Guang-Hui] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang 421001, Hunan, Peoples R China.
关键词：
ApoM;TGF-β;TAK-1;JNK;C-Jun
摘要：
Apolipoprotein M (apoM) is a relatively novel apolipoprotein that plays pivotal roles in many dyslipidemia-associated diseases; however, its regulatory mechanisms are poorly understood. Many cytokines have been identified that down-regulate apoM expression in HepG2 cells, among which transforming growth factor-β (TGF-β) exerts the most potent effects. In addition, c-Jun, a member of the activated protein 1 (AP-1) family whose activity is modulated by c-Jun N-terminal kinase (JNK), decreases apoM expression at the transcriptional level by binding to the regulatory element in the proximal apoM promoter. In this study, we investigated the molecular mechanisms through which TGF-β decreases the apoM level in HepG2 cells. The results revealed that TGF-β inhibited apoM expression at both the mRNA and protein levels in a dose- and time-dependent manner and that it suppressed apoM secretion. These effects were attenuated by treatment of cells with either SP600125 (JNK inhibitor) or c-Jun siRNA. 5Z-7-oxozeaenol [(a TGF-β-activated kinase 1 (TAK-1) inhibitor)] also attenuated the TGF-β-mediated inhibition of apoM expression and suppressed the activation of JNK and c-Jun. These results have demonstrated that TGF-β suppresses apoM expression through the TAK-1-JNK-c-Jun pathway in HepG2 cells.
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：
[Jiang, Yue; Peng, Xiao-Shan; Liu, Xing; Ren, Kun; Yi, Guang-Hui; Suo, Rong; Tang, Zhen-Li] Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang City 421001, Hunan, Peoples R China.;[Xiong, Sheng-Lin] You Country Peoples Hosp, Zhuzhou 412300, Hunan, Peoples R China.;[Zhang, Qing-Hai] Univ South China, Affiliated Hosp 1, Clin Res Inst, Hengyang 421001, Hunan, Peoples R China.;[Mo, Zhong-Cheng] Univ South China, Inst Cardiovasc Res, Life Sci Res Ctr, Key Lab Atherosclerol Hunan Prov, Hengyang 421001, Hunan, Peoples R China.
通讯机构：
[Yi, Guang-Hui] U;Univ South China, Inst Cardiovasc Dis, Key Lab Arteriosclerol Hunan Prov, 28 W Changsheng Rd, Hengyang City 421001, Hunan, Peoples R 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).
期刊：
DNA AND CELL BIOLOGY,2015年34(1):6-18 ISSN：1044-5498
通讯作者：
Yi, Guang-Hui
作者机构：
[Ren, Kun; Wu, Rong; Lu, Yan-Ju; Yi, Guang-Hui] 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, Guang-Hui] U;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：
MOLECULAR MEDICINE REPORTS,2015年12(3):3599-3606 ISSN：1791-2997
通讯作者：
Yuan, Zhonghua
作者机构：
[Meng, Lei; Tang, Chaoke; Yin, Weidong; Qiao, Yuncheng; Yi, Guanghui; Guo, Dongming; Wang, Zuo; Yuan, Zhonghua] 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.;[Liu, Xiaohui] Soochow Univ, Cyrus Tang Hematol Ctr Res Partnership, Jiangsu Inst Hematol, Affiliated Hosp 1, Suzhou 215400, Jiangsu, 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, Zhonghua] U;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.
