Abstract:
BACKGROUND:CETP inhibitors block the transfer of cholesteryl ester from HDL-C to VLDL-C and LDL-C, thereby raising HDL-C and lowering LDL-C. In this study, we explored the effect of CETP inhibitors on hepatic LDL receptor (LDLR) and PCSK9 expression and further elucidated the underlying regulatory mechanism. RESULTS:We first examined the effect of anacetrapib (ANA) and dalcetrapib (DAL) on LDLR and PCSK9 expression in hepatic cells in vitro. ANA exhibited a dose-dependent inhibition on both LDLR and PCSK9 expression in CETP-positive HepG2 cells and human primary hepatocytes as well as CETP-negative mouse primary hepatocytes (MPH). Moreover, the induction of LDLR protein expression by rosuvastatin in MPH was blunted by cotreatment with ANA. In both HepG2 and MPH ANA treatment reduced the amount of mature form of SREBP2 (SREBP2-M). In vivo, oral administration of ANA to dyslipidemic C57BL/6J mice at a daily dose of 50 mg/kg for 1 week elevated serum total cholesterol by approximately 24.5% (p < 0.05%) and VLDL-C by 70% (p < 0.05%) with concomitant reductions of serum PCSK9 and liver LDLR/SREBP2-M protein. Finally, we examined the in vitro effect of two other strong CETP inhibitors evacetrapib and torcetrapib on LDLR/PCSK9 expression and observed a similar inhibitory effect as ANA in a concentration range of 1-10 μM. CONCLUSION:Our study revealed an unexpected off-target effect of CETP inhibitors that reduce the mature form of SREBP2, leading to attenuated transcription of hepatic LDLR and PCSK9. This negative regulation of SREBP pathway by ANA manifested in mice where CETP activity was absent and affected serum cholesterol metabolism.
journal_name
Atherosclerosisjournal_title
Atherosclerosisauthors
Dong B,Singh AB,Fung C,Kan K,Liu Jdoi
10.1016/j.atherosclerosis.2014.05.931subject
Has Abstractpub_date
2014-08-01 00:00:00pages
449-62issue
2eissn
0021-9150issn
1879-1484pii
S0021-9150(14)01181-2journal_volume
235pub_type
杂志文章相关文献
ATHEROSCLEROSIS文献大全abstract:OBJECTIVE:To analyze the possible role of arachidonic acid (AA) in macrophage cholesterol biosynthesis and in PON2 expression. METHODS AND RESULTS:We used peritoneal macrophages (MPM) from the 6-DS KO mice that were fed a diet without or with AA. Macrophage cholesterol biosynthesis rate and HMGCoA-reductase mRNA level...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2009.11.044
更新日期:2010-06-01 00:00:00
abstract::Dietary intake of long-chain n-3 polyunsaturated fatty acids (PUFA) reduces the risk for atherosclerosis. Here we examine the effect of a fish oil (FO)-rich diet on the development of atherosclerotic lesions in apolipoprotein E-deficient (apoE(-/-)) mice, which are vulnerable because of their high plasma cholesterol a...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2008.02.033
更新日期:2008-12-01 00:00:00
abstract:BACKGROUND AND AIMS:Whether carotid atherosclerosis is associated with an increased risk for ischemic stroke in patients with atrial fibrillation (AF) on anticoagulant treatment is undefined. To explore this association, patients with AF on treatment with vitamin K antagonists were included in a multicenter, prospectiv...
journal_title:Atherosclerosis
pub_type: 杂志文章,多中心研究
doi:10.1016/j.atherosclerosis.2018.02.004
更新日期:2018-04-01 00:00:00
abstract::We have previously reported that mouse peritoneal macrophages have three types of modified low density lipoprotein (LDL) receptors. One is specific for acetylated LDL (Ac-LDL), the second is for oxidized LDL (Ox-LDL), and the third recognizes both (Arai, H. et al. (1989) Biochem. Biophys. Res. Commun. 159, 1375-1382)....
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(93)90098-f
更新日期:1993-06-01 00:00:00
abstract:BACKGROUND:the extracellular matrix (ECM) is an important determinant of plaque instability. Since tissue transglutaminase (tTG) and elafin act as stabilizing factors, they might play a crucial role in the pathogenesis of acute coronary syndrome. We examined their expression in human coronary arteries and the regulatio...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/s0021-9150(01)00542-1
更新日期:2002-01-01 00:00:00
abstract:BACKGROUND & AIMS:Dysbiosis of the gut microbiota is associated with increased levels of circulating lipopolysaccharide (LPS) and subsequent activation of systemic inflammation. Diet is an important modulator of the gut microbiome. We aimed to investigate whether circulating markers of gut-related inflammation, LPS bin...
journal_title:Atherosclerosis
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.atherosclerosis.2019.05.004
更新日期:2019-07-01 00:00:00
abstract::Atherosclerotic plaque rupture and erosions precipitate thrombus formation and may lead to an acute ischemic syndrome. Lipids and lipoproteins modulate the expression and/or function of thrombotic, fibrinolytic and rheologic factors, and thereby influence hemostasis and potential tissue damage resulting from vascular ...
journal_title:Atherosclerosis
pub_type: 杂志文章,评审
doi:10.1016/s0021-9150(98)00144-0
更新日期:1998-10-01 00:00:00
abstract::Plasma cholesterol was lower in spontaneously hypertensive rats (SHR), while plasma triglyceride and free fatty acid were increased in comparison with control normotensive Wistar-Kyoto (WK) rats. Correspondingly, [1-14C]-acetate incorporation into liver cholesterol was clearly decreased in SHR as compared with WK. As ...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(77)90171-x
更新日期:1977-11-01 00:00:00
abstract:BACKGROUND AND AIMS:Chronic intermittent hypoxia (CIH) exposure causes atherosclerosis, although the underlying mechanisms are poorly understood. This study defines the role of endothelial intrinsic NF-κB signaling in the atherogenic response to CIH. METHODS:We created ApoE-ECI-κBmt mice that are deficient in the apol...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2018.01.027
更新日期:2018-03-01 00:00:00
abstract::Copper mediated oxidative modification of high density lipoprotein (HDL) diminishes its capacity to promote cholesterol efflux from cells in culture. In the present study, HDL was isolated from eight subjects before and after a 10 day administration of the antioxidant vitamins C and E. After incubation HDL (1.25 mg pr...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/s0021-9150(96)05928-x
更新日期:1996-11-15 00:00:00
abstract:OBJECTIVE:We examined the association between increasing serum GGT levels and PAD in the US general population. METHODS:Cross-sectional study among 3941 National Health and Nutrition Examination Survey 1999-2002 participants aged >or=40 years. Main outcome-of-interest was PAD defined as ankle-brachial index <0.9 (n=21...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2007.10.009
更新日期:2008-07-01 00:00:00
abstract:BACKGROUND AND PURPOSE:It has not been fully determined whether non-high-density lipoprotein cholesterol (non-HDLC) levels are involved in vascular events, especially stroke, in general Asian populations. We evaluated the association between non-HDLC levels and the risk of type-specific cardiovascular disease in a pros...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2014.01.005
更新日期:2014-04-01 00:00:00
abstract::Activation of the renin-angiotensin-aldosterone system plays an important role in the pathogenesis of endothelial dysfunction and atherosclerosis. Studies evaluating the effect of AT1-receptor blockers on endothelial dysfunction in patients with coronary artery disease (CAD) revealed mixed results. Studies addressing ...
journal_title:Atherosclerosis
pub_type: 杂志文章,随机对照试验
doi:10.1016/j.atherosclerosis.2006.08.034
更新日期:2007-10-01 00:00:00
abstract::Serum total and HDL cholesterol concentrations were measured in schoolboy populations from 16 countries. Total and HDL cholesterol concentrations were determined in one laboratory to reduce methodological variability as much as possible. A standardized protocol was used for the drawing of blood, preparation, storage a...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(80)90245-2
更新日期:1980-08-01 00:00:00
abstract:AIMS:To assess efficacy and safety of HMG-CoA reductase inhibitor (statin) treatment in children and adolescents with heterozygous familial hypercholesterolaemia. METHODS:MEDLINE, EMBASE, COCHRANE and Current Controlled Trials databases were searched. Study design, efficacy, and safety outcome-measures were extracted....
journal_title:Atherosclerosis
pub_type: 杂志文章,meta分析,评审
doi:10.1016/j.atherosclerosis.2006.09.030
更新日期:2007-12-01 00:00:00
abstract:BACKGROUND AND AIMS:Early detection of atrial fibrillation after stroke is important for secondary prevention in stroke patients without known atrial fibrillation (AF). We aimed to compare the performance of CHADS2, CHA2DS2-VASc and HATCH scores in predicting AF detected after stroke (AFDAS) and to test whether adding ...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2018.03.024
更新日期:2018-05-01 00:00:00
abstract::The newly identified apoprotein AV (apoAV) gene was suggested to have a significant effect on triglyceride (TG) metabolism in Caucasians. We studied the genetic effect of this gene on serum TG in a Japanese population. Participants (481 male and 412 female) were recruited at a health examination. A T/C single nucleoti...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/s0021-9150(02)00252-6
更新日期:2002-12-01 00:00:00
abstract::Bezafibrate in a dosage of 200 mg 3 times daily was given to 24 patients with type II A (n = 8), II B (n = 1) and IV (n = 15) hyperlipoproteinaemia for 4.5 years. In type II A the content of total cholesterol and that of low density lipoprotein in serum decreased by 10-23 and 11-34 percent over the years compared to p...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(85)90098-x
更新日期:1985-05-01 00:00:00
abstract:OBJECTIVE:To examine the associations of maternal smoking in pregnancy with development of cholesterol levels from childhood to adulthood. METHODS:Total cholesterol, high-density lipoprotein (HDL) cholesterol and low-density lipoprotein (LDL) cholesterol were measured annually from 1975 to 1993 and in 2002 in 350 subj...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2007.01.032
更新日期:2008-01-01 00:00:00
abstract::Over 200 risk factors for cardiovascular disease (CVD) have now been identified. Among these, the three most important are (1) abnormal lipids, including the fact that there are more than 15 types of cholesterol-containing lipoproteins and four different types of triglyceride-rich particles, some of which are very ath...
journal_title:Atherosclerosis
pub_type: 杂志文章,评审
doi:10.1016/0021-9150(96)05851-0
更新日期:1996-07-01 00:00:00
abstract::Glycoprotein VI is a platelet collagen receptor binding to subendothelial collagen after a rupture of an atherosclerotic plaque. The GPVI gene is polymorphic with several SNPs and the T13254C polymorphism predicting amino acid substitution (serine to proline) has been associated with the risk of MI in a preliminary st...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2004.03.021
更新日期:2004-09-01 00:00:00
abstract:BACKGROUND AND AIMS:Oxidative stress-induced endothelial dysfunction is considered to exert a vital role in the development of atherosclerotic coronary heart disease (CHD). NRF2 is a key transcriptional factor against oxidative stress through activation of multiple ARE-mediated genes. Z-Lig is derived from the Ligustic...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2019.02.010
更新日期:2019-05-01 00:00:00
abstract:BACKGROUND AND AIMS:Inhibition of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduces atherogenic lipoproteins and could lead to reduction of cardiovascular (CV) events. However, it is unclear whether blood PCSK9 levels predict future CV events. We performed a meta-analysis of all longitudinal studies to dete...
journal_title:Atherosclerosis
pub_type: 杂志文章,meta分析,评审
doi:10.1016/j.atherosclerosis.2016.07.922
更新日期:2016-09-01 00:00:00
abstract:BACKGROUND AND AIMS:Overt atherosclerotic cardiovascular disease (ASCVD) warrants aggressive lipid lowering. Imaging for ambiguous symptoms suggesting ischemia or for clarification of CV risk in asymptomatic individuals often uncovers previously unknown ASCVD. Guidelines do not provide clear recommendations for aggress...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2017.06.006
更新日期:2017-08-01 00:00:00
abstract:BACKGROUND AND AIMS:Bone marrow (BM)-derived progenitor cells are functionally impaired in patients with ischemic heart disease (IHD), thereby hampering the outcome of autologous stem cell therapy. In search for underlying mechanisms for this BM dysfunction, accelerated cellular senescence was explored. METHODS:We ana...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2017.03.023
更新日期:2017-05-01 00:00:00
abstract::Quantitative assessment of atherosclerosis during its natural history and following therapeutic interventions is important, as cardiovascular disease remains the most significant cause of morbidity and mortality in industrial societies. While coronary angiography delineates the vessel lumen, permitting only the indire...
journal_title:Atherosclerosis
pub_type: 杂志文章,评审
doi:
更新日期:1995-12-01 00:00:00
abstract::Although triglycerides (TG) are a major risk factor for coronary artery disease (CAD), their exact role is still controversial. Recently, a T/C polymorphism in the promoter region of the apoA5 gene at position 1131 has been found that is associated with an increased plasma TG concentration. We investigated the role of...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2003.12.003
更新日期:2004-03-01 00:00:00
abstract::An organ culture technique was used to investigate the removal of fatty acids incorporated into various lipid fractions in intimal segments of atherosclerotic rabbit aorta. Segments of aorta were pulse-labelled in vitro with [9,10-3H]oleic acid and [1-14C]linoleic acid for 24 h. The incubation medium was replaced with...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(77)90069-7
更新日期:1977-12-01 00:00:00
abstract::Lack of physical activity appears to have deleterious effects on serum lipoproteins. Twenty-three patients who were completely immobilised by traumatic fracture of the spine had significantly lower (P < 0.001) plasma high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I levels than normally mobile paired...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/0021-9150(80)90151-3
更新日期:1980-11-01 00:00:00
abstract:OBJECTIVES:To analyze the relationship between office and ambulatory heart rate, and its variability, and arterial stiffness in patients with primary arterial hypertension. METHODS:A cross-sectional study was conducted in a primary care setting, with the inclusion of 356 hypertensive patients aged 30-80 years. Office ...
journal_title:Atherosclerosis
pub_type: 杂志文章
doi:10.1016/j.atherosclerosis.2011.03.037
更新日期:2011-08-01 00:00:00