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M John Chapman

Publications and source records attributed to M John Chapman.

At least 37 records · Page 2Linked to original sources
PubMed2005

The potential role of HDL- and LDL-cholesterol modulation in atheromatous plaque development.

Research into the management of dyslipidaemia has increasingly focussed on the importance of high-density lipoprotein cholesterol (HDL-C) levels. It is well known that low levels of HDL are associated with an increased risk of cardiovascular events. Recent data have highlighted the anti-atherogenic actions of HDL such as anti-inflammatory, anti-oxidative activities, and of course, reverse cholesterol transport. This latter observation may explain certain effects on atherosclerotic plaques, in particular the observation that plaque regression can occur when treatments augment HDL-C levels. This review will outline the beneficial effects of HDL, along with the detrimental effects of other lipoproteins involved in atherosclerotic processes. This manuscript will also describe the therapeutic effects of nicotinic acid, a treatment that raises HDL-C levels. Studies show that using nicotinic acid as a monotherapy or in combination with other agents halts plaque progression and translates as a significant reduction in cardiovascular events.

Atherosclerosis↗
PubMed2004

Transcription factor sterol regulatory element binding protein 2 regulates scavenger receptor Cla-1 gene expression.

OBJECTIVE: The human scavenger receptor class B type I (Cla-1) plays a key role in cellular cholesterol movement in facilitating transport of cholesterol between cells and lipoproteins. Indirect evidence has suggested that Cla-1 gene expression is under the feedback control of cellular cholesterol content. To define the molecular mechanisms underlying such putative regulation, we evaluated whether Cla-1 is a target gene of the sterol regulatory element binding protein (SREBP) transcription factor family. METHODS AND RESULTS: Transient transfections demonstrated that SREBP factors induce Cla-1 promoter activity and that SREBP-2 is a more potent inducer than the SREBP-1a isoform. The 5'-deletion analysis of 3 kb of the 5'-flanking sequence of the Cla-1 gene, combined with site-directed mutagenesis and electrophoretic mobility shift assay, allowed identification of a unique sterol responsive element. SREBP-mediated Cla-1 regulation was confirmed in stably transfected human embryonic kidney 293 cells expressing the active form of SREBP-2 at incremental levels. In these cell lines, Cla-1 mRNA and protein levels were increased in direct proportion to the level of SREBP-2 expression. CONCLUSIONS: These findings provide evidence that SREBP-2, a key regulator of cellular cholesterol uptake through modulation of the expression of the low-density lipoprotein receptor gene, may influence cellular cholesterol homeostasis via regulation of Cla-1 gene expression.

Binding Sites↗
PubMed2004

Common promoter C516T polymorphism in the ApoB gene is an independent predictor of carotid atherosclerotic disease in subjects presenting a broad range of plasma cholesterol levels.

OBJECTIVE: A common polymorphism in the promoter of the apolipoprotein B (apoB) gene, a C to T change at position -516, increases the transcription rate of apoB, resulting in elevated circulating levels of low-density lipoprotein (LDL) cholesterol. METHODS AND RESULTS: We tested the hypothesis that carriers of the -516T allele, who may display consistent elevation in plasma cholesterol over their lifetime, may present more extensive atherosclerotic disease than noncarriers. Genotyping of the apoB 516 C/T promoter polymorphism was performed in 326 subjects at low cardiovascular risk. Homozygotes for allele T displayed higher plasma levels of apoB and LDL than did heterozygotes. Furthermore, both homozygotes and heterozygotes for allele T exhibited higher plasma levels of apoB and LDL than did homozygotes for allele C (P<0.0001). In addition, homozygotes for allele T displayed higher carotid intima-media thickness (IMT) than subjects who were heterozygous. Moreover, both groups had higher carotid IMT than subjects of genotype -516C/C (P<0.001). Only age, high-density lipoprotein, and the presence of allele T were identified as independent predictors of the presence of carotid plaque. No association existed between the polymorphism and plasma concentrations of triglycerides, high-density lipoprotein, or apoAI. CONCLUSIONS: Our data indicate that a C to T change at position -516 of the apoB gene is independently associated with the presence of carotid atherosclerotic disease. Identification of the -516C/T polymorphism may therefore contribute to the estimation of overall cardiovascular risk.

Apolipoproteins↗
PubMed2004

Impaired intravascular triglyceride lipolysis constitutes a marker of clinical outcome in patients with stable angina undergoing secondary prevention treatment: a long-term follow-up study.

OBJECTIVES: We sought to verify whether the intravascular metabolism of chylomicron-like emulsion may predict the clinical evolution of patients with coronary artery disease (CAD) undergoing secondary prevention therapy of CAD. BACKGROUND: Case-control studies have suggested an association between impaired intravascular catabolism of triglyceride (TG)-rich lipoproteins and CAD. However, evidence is lacking with respect to the potential clinical relevance of this metabolic disorder in CAD patients. METHODS: During a period of 4.5 +/- 0.9 years, we followed up 63 stable CAD patients (mean age 60 +/- 10 years) undergoing secondary prevention therapy (low-density lipoprotein cholesterol <100 mg/dl) in whom kinetic studies of the in vivo catabolism of chylomicron-like emulsions were performed. At enrollment into the study, fasting patients were injected intravenously with a chylomicron-like emulsion labeled with radioactive triglyceride (3H-TG) and cholesteryl esters (14C-CE) to evaluate the efficacy of intravascular TG lipolysis. RESULTS: At baseline, CAD patients displayed a diminished fractional clearance rate (FCR) for 3H-TG (-26%; p = 0.027), for 14C-CE (-37%; p = 0.015), and for delipidation index (DI) (-26%; p = 0.02) as compared with 35 control subjects. During follow-up of secondary prevention therapy, 33% of CAD patients (n = 21) presented with clinically refractory angina and aggravated coronary angiographic severity. The FCR for 3H-TG (-44%; p = 0.005) and DI (-41%; p = 0.006) in those patients with refractory angina was significantly lower than that observed in those with stable evolution. Moreover, in a Cox multivariate regression analysis, the presence of a DI less than the median value was an independent predictor of an unfavorable clinical evolution (adjusted hazard ratio 3.32; 95% confidence interval 1.21 to 9.14; p = 0.020). CONCLUSIONS: The current study establishes that delayed intravascular TG lipolysis is a strong and independent predictor of evolution to severe angina among patients undergoing secondary prevention therapy of CAD.

Adult↗
PubMed2004

Antioxidative activity of HDL particle subspecies is impaired in hyperalphalipoproteinemia: relevance of enzymatic and physicochemical properties.

OBJECTIVE: Hyperalphalipoproteinemia (HALP) is characterized by elevated plasma levels of high-density lipoprotein (HDL) particles with altered composition, metabolism, and function. The impact of such modification on antioxidative activities of HDL subfractions is indeterminate. METHODS AND RESULTS: Gradient fractionation revealed that buoyant HDL2b and 2a and small dense HDL3b and 3c levels were elevated up to 2.0-fold in HALP subjects (n=9; mean plasma HDL cholesterol, 79 mg/dL) with low hepatic lipase activity. HDL2a, 3a, 3b, and 3c displayed lower specific antioxidative activity (sAA) during low-density lipoprotein (LDL) oxidation (-15% to -86%, on a unit particle mass basis) than their normolipidemic counterparts (n=13). LDL oxidation was delayed by control HDL3a, 3b, and 3c (up to -79%) but specifically by HDL3c (-54%) in HALP. Paraoxonase activity was deficient in all HALP HDL subfractions. Paraoxonase, PAF-AH, and LCAT activities together accounted for approximately 50% of variation in sAA. Abnormal chemical composition of HDL3b and 3c (cholesterol-deficient, triglyceride-enriched) in HALP was associated with impaired sAA. Systemic oxidative stress (as plasma 8-isoprostanes) tended to be elevated (1.5-fold) in HALP and negatively correlated with sAA (as TBARS). CONCLUSIONS: Intrinsic antioxidative activity of HDL subspecies is impaired in HALP, reflecting altered enzymatic and physicochemical properties.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2004

Rosuvastatin reduces MMP-7 secretion by human monocyte-derived macrophages: potential relevance to atherosclerotic plaque stability.

3-Hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) have been shown to reduce cardiovascular morbidity and mortality by their actions on atherogenic lipid profiles and by pleiotropic effects. In this study, we have investigated the effect of a new statin, rosuvastatin (Crestor), on sterol synthesis and the expression of metalloproteinases (MMPs) in human monocyte-derived macrophages (HMDM). Rosuvastatin dose-dependently inhibited sterol synthesis from acetate with an IC(50) of 70 nM. In addition, MMP-7 levels were reduced in a dose-dependent manner with maximal inhibition of 50% (P < 0.01) at 1 microM. Also, addition of isoprenoids such as farnesyl pyrophosphate (Fpp) or geranylgeranyl pyrophosphate (GGpp) fully overcame the inhibitory effect of rosuvastatin on MMP-7. Neither quantitative PCR nor transient transfection of HMDM with a luciferase reporter construct under the control of human MMP-7 promoter (2300 bp of the 5' region on MMP-7 gene) showed a decrease in MMP-7 mRNA following treatment with rosuvastatin (10(-6)M). However, the inhibitory effect of the statin occurred at the post-transcriptional level as determined by actinomycin D experiment. In conclusion, several studies have reported a high expression of active MMP-7 in human atherosclerotic plaques indicating a potential role in the weakening of the fibrous cap, predisposing it to rupture. The effect of rosuvastatin in reducing MMP-7 might protect fibrous caps from degradation and in turn stabilize atheromatous plaques.

Arteriosclerosis↗
PubMed2004

Pharmacological modulation of cholesteryl ester transfer protein, a new therapeutic target in atherogenic dyslipidemia.

In mediating the transfer of cholesteryl esters (CE) from antiatherogenic high density lipoprotein (HDL) to proatherogenic apolipoprotein (apo)-B-containing lipoprotein particles (including very low density lipoprotein [VLDL], VLDL remnants, intermediate density lipoprotein [IDL], and low density lipoprotein [LDL]), the CE transfer protein (CETP) plays a critical role not only in the reverse cholesterol transport (RCT) pathway but also in the intravascular remodeling and recycling of HDL particles. Dyslipidemic states associated with premature atherosclerotic disease and high cardiovascular risk are characterized by a disequilibrium due to an excess of circulating concentrations of atherogenic lipoproteins relative to those of atheroprotective HDL, thereby favoring arterial cholesterol deposition and enhanced atherogenesis. In such states, CETP activity is elevated and contributes significantly to the cholesterol burden in atherogenic apoB-containing lipoproteins. In reducing the numbers of acceptor particles for HDL-derived CE, both statins (VLDL, VLDL remnants, IDL, and LDL) and fibrates (primarily VLDL and VLDL remnants) act to attenuate potentially proatherogenic CETP activity in dyslipidemic states; simultaneously, CE are preferentially retained in HDL and thereby contribute to elevation in HDL-cholesterol content. Mutations in the CETP gene associated with CETP deficiency are characterized by high HDL-cholesterol levels (>60 mg/dL) and reduced cardiovascular risk. Such findings are consistent with studies of pharmacologically mediated inhibition of CETP in the rabbit, which argue strongly in favor of CETP inhibition as a valid therapeutic approach to delay atherogenesis. Consequently, new organic inhibitors of CETP are under development and present a potent tool for elevation of HDL in dyslipidemias involving low HDL levels and premature coronary artery disease, such as the dyslipidemia of type II diabetes and the metabolic syndrome. The results of clinical trials to evaluate the impact of CETP inhibition on premature atherosclerosis are eagerly awaited.

Animals↗
PubMed2004

Raising high-density lipoprotein cholesterol with reduction of cardiovascular risk: the role of nicotinic acid--a position paper developed by the European Consensus Panel on HDL-C.

Reduction of low-density lipoprotein cholesterol (LDL-C) is presently the primary focus of lipid-lowering therapy for prevention and treatment of coronary heart disease (CHD). However, the high level of residual risk among statin-treated patients in recent coronary prevention studies indicates the need for modification of other major components of the atherogenic lipid profile. There is overwhelming evidence that a low plasma level of high-density lipoprotein cholesterol (HDL-C) is an important independent risk factor for CHD. Moreover, a substantial proportion of patients with or at risk of developing premature CHD typically exhibit distinct lipid abnormalities, including low HDL-C levels. Thus, therapeutic intervention aimed at raising HDL-C, within the context of reducing global cardiovascular risk, would benefit such patients, a viewpoint increasingly adopted by international treatment guidelines. Therapeutic options for patients with low HDL-C include treatment with statins, fibrates and nicotinic acid, either as monotherapy or in combination. Of these options, nicotinic acid is not only the most potent agent for raising HDL-C but is also effective in reducing key atherogenic lipid components including triglyceride-rich lipoproteins (mainly very low-density lipoproteins [VLDL] and VLDL remnants), LDL-C, and lipoprotein(a). The principal features of the atherogenic lipid profile in type 2 diabetes and the metabolic syndrome make them logical targets for nicotinic acid therapy, either alone or in combination with a statin. The lack of comprehensive European data on the prevalence of low HDL-C levels highlights a critical need for education on the importance of raising HDL-C in CHD prevention and treatment. The development of a reliable and accurate assay for HDL-C, as well as clarification of criteria for low and optimal levels of HDL-C in both men and women, constitute critical factors in the reliable identification and treatment of patients at elevated risk of CHD due to low HDL-C. Based on the available evidence, the European Consensus Panel recommends that the minimum target for HDL-C should be 40 mg/dL (1.03 mmol/L) in patients with CHD or with a high level of risk for CHD, including patients at high global risk with type 2 diabetes or the metabolic syndrome.

Cholesterol, HDL↗
PubMed2004

Metabolic syndrome is associated with elevated oxidative stress and dysfunctional dense high-density lipoprotein particles displaying impaired antioxidative activity.

A metabolic syndrome (MetS) phenotype is characterized by insulin-resistance, atherogenic dyslipidemia, oxidative stress, and elevated cardiovascular risk and frequently involves subnormal levels of high-density lipoprotein (HDL) cholesterol. We evaluated the capacity of physicochemically distinct HDL subfractions from MetS subjects to protect low-density lipoprotein against oxidative stress.MetS subjects presented an insulin-resistant phenotype, with central obesity and elevation in systolic blood pressure and plasma triglyceride, LDL-cholesterol, apolipoprotein B, glucose, and insulin levels. Systemic oxidative stress, assessed as plasma 8-isoprostanes, was significantly higher (3.7-fold) in MetS subjects (n = 10) compared with nonobese normolipidemic controls (n = 11). In MetS, small, dense HDL3a, 3b, and 3c subfractions possessed significantly lower specific antioxidative activity (up to -23%, on a unit particle mass basis) than their counterparts in controls. In addition, HDL2a and 3a subfractions from MetS patients possessed lower total antioxidative activity (up to -41%, at equivalent plasma concentrations). The attenuated antioxidative activity of small, dense HDL subfractions correlated with systemic oxidative stress and insulin resistance and was associated with HDL particles exhibiting altered physicochemical properties (core triglyceride enrichment and cholesteryl ester depletion). We conclude that antioxidative activity of small, dense HDL subfractions of altered chemical composition is impaired in MetS and associated with elevated oxidative stress and insulin resistance. Induction of selective increase in the circulating concentrations of dense HDL subfractions may represent an innovative therapeutic approach for the attenuation of high cardiovascular risk in MetS.

Adult↗
PubMed2004

Matrix metalloproteinases, inflammation and atherosclerosis: therapeutic perspectives.

Matrix metalloproteinases (MMPs), also called matrixins, are proteinases that participate in extracellular matrix remodelling and degradation. Under normal physiological conditions, the activities of MMPs are precisely regulated at the level of transcription, of activation of the pro-MMP precursor zymogens and of inhibition by endogenous inhibitors (tissue inhibitors of metalloproteinases; TIMPs). Alteration in the regulation of MMP activity is implicated in diseases such as cancer, fibrosis, arthritis and atherosclerosis. The pathological effects of MMPs and TIMPs in cardiovascular diseases involve vascular remodelling, atherosclerotic plaque instability and left ventricular remodelling after myocardial infarction. Since excessive tissue remodelling and increased matrix metalloproteinase activity have been demonstrated during atherosclerotic lesion progression (including plaque disruption), MMPs represent a potential target for therapeutic intervention aimed at modification of vascular pathology by restoring the physiological balance between MMPs and TIMPs. This review describes the members of the MMP and TIMP families and discusses the structure, function and regulation of MMP activity; finally, pharmacological approaches to MMP inhibition are highlighted.

Animals↗
PubMed2003

Small, dense HDL particles exert potent protection of atherogenic LDL against oxidative stress.

OBJECTIVE: The relationship of the structural and functional heterogeneity of HDL particles to protection of LDL against oxidative stress is indeterminate. METHODS AND RESULTS: HDL subfractions of defined physicochemical properties were isolated by density gradient ultracentrifugation from normolipidemic human serum (n=8), and their capacity to protect LDL from oxidation was evaluated. Under mild oxidative stress induced by AAPH or Cu(II), HDL subfractions (at equal cholesterol or protein concentration or equal particle number) significantly decreased LDL oxidation rate (-20% to -85%) in the propagation phase (234 nm), which was prolonged by up to 82% with decreased maximal diene formation. Antioxidative activity of HDL subfractions increased with increment in density, as follows: HDL2b<HDL2a<HDL3a<HDL3b<HDL3c (confirmed by thiobarbituric acid-reactive substance content and LDL electrophoretic mobility). Concordantly, antioxidative activity of small HDL prepared by FPLC was significantly higher (+56%) than that of large HDL. Antioxidative action of HDL subfractions was primarily associated with inactivation of LDL lipid hydroperoxides. The potent protective activity of small HDL could not be accounted for exclusively by enzymatic activities (PON1, platelet-activating factor acetylhydrolase, and lecithin-cholesterol acyltransferase). CONCLUSIONS: Small, dense HDL exhibit potent antioxidant activity, which may arise from synergy in inactivation of oxidized LDL lipids by enzymatic and nonenzymatic mechanisms, in part reflecting distinct intrinsic physicochemical properties.

Antioxidants↗
PubMed2003

Regulation of the expression of the apolipoprotein(a) gene: evidence for a regulatory role of the 5' distal apolipoprotein(a) transcription control region enhancer in yeast artificial chromosome transgenic mice.

OBJECTIVE: The apolipoprotein(a) [apo(a)] gene locus is the major determinant of the circulating concentration of the atherothrombogenic lipoprotein Lp(a). In vitro analysis of the intergenic region between the apo(a) and plasminogen genes revealed the presence of a putative apo(a) transcription control region (ACR) approximately 20 kb upstream of the apo(a) gene that significantly increases the minimal promoter activity of the human apo(a) gene. METHODS AND RESULTS: To examine the function of the ACR in its natural genomic context, we used the Cre-loxP recombination system to generate 2 nearly identical apo(a)-yeast artificial chromosome transgenic mouse lines that possess a single integration site for the human apo(a) transgene in the mouse genome but differ by the presence or absence of the ACR enhancer. Analysis of the 2 groups of animals revealed that the deletion of the ACR was associated with 30% reduction in plasma and mRNA apo(a) levels. Apo(a)-yeast artificial chromosome transgenic mice with and without the ACR sequence were similar in all other aspects of apo(a) regulation, including liver-specific apo(a) expression and alteration in expression levels in response to sexual maturation and a high-fat diet. CONCLUSIONS: This study provides the first experimental in vivo evidence for a functional role of the ACR enhancer in determining levels of apo(a) expression.

5' Untranslated Regions↗
PubMed2003

Regulation of human CETP gene expression: role of SP1 and SP3 transcription factors at promoter sites -690, -629, and -37.

Cholesteryl ester transfer protein (CETP) is a key factor in plasma reverse cholesterol transport and is implicated in the pathophysiology of atherogenic dyslipidemia. Variations observed in plasma CETP mass and activity in both normolipidemic and dyslipidemic individuals may reflect differences in CETP gene expression. We evaluated the respective roles of the Sp1 and Sp3 transcription factors on the promoter activity of the human CETP gene at a new Sp1/Sp3 site identified at position -690, and at two previously described Sp1/Sp3 sites at positions -37 and -629. In transient transfection in HepG2 cells, site-directed mutagenesis using luciferase reporter constructs containing a promoter fragment from +32 to -745 indicated that the new -690 site acts as a repressive element in reducing CETP promoter activity (-22%; P < 0.05); equally, this site exerts an additive effect with the -629 site, inducing marked repression (-42%; P < 0.005). In contrast, in NCTC cells that display a 16-fold lower level of Sp3, the repressive effect at the -690 site was enhanced 2-fold (-45%; P < 0.05), whereas the -629 site exerted no effect. Cotransfection of Sp1 and/or Sp3 in SL2 insect cells lacking endogenous Sp factors demonstrated that Sp1 and Sp3 act as activators at the -690 and -37 sites, whereas Sp3 acts as a repressor at the -629 site. Taken together, our data demonstrate that Sp1 and Sp3 regulate human CETP promoter activity through three Sp1/Sp3 binding sites in a distinct manner, and that the Sp1/Sp3 ratio is a key factor in determining the relative contribution of these sites to total promoter activity.

Animals↗
PubMed2003

Fenofibrate induces HDL-associated PAF-AH but attenuates enzyme activity associated with apoB-containing lipoproteins.

Human plasma platelet-activating factor acetylhydrolase (PAF-AH) is an enzyme associated mainly with the apolipoprotein B (apoB)-containing lipoproteins and primarily with LDL. A small proportion of enzymatic activity is also associated with HDL. Plasma paraoxonase 1 (PON1) is an esterase exclusively associated with HDL. The effect of fenofibrate on PAF-AH and PON1 activities in patients with dyslipidemias of Types IIA, IIB, and IV were studied. Fenofibrate reduced plasma PAF-AH activity in all patient groups. In Type IIA patients, this reduction was mainly due to a fall in enzyme activity associated with the dense LDL subspecies, whereas in Type IIB and Type IV patients, it was due to the decrease in PAF-AH activity associated with both the VLDL+IDL and dense LDL subspecies. Drug therapy in Type IIB and Type IV patients significantly increased the HDL-associated PAF-AH activity due to the increase in enzyme activity associated with the HDL-3c subfraction. Fenofibrate did not affect serum PON1 activities toward paraoxon and phenylacetate in either patient group. The fenofibrate-induced elevation of HDL-associated PAF-AH activity in dyslipidemic patients of Type IIB and Type IV, as well as the reduction in enzyme activity associated with atherogenic apoB-containing lipoproteins in all patient groups, may represent a new and important antiatherogenic effect of this potent lipid-modulating agent.

1-Alkyl-2-acetylglycerophosphocholine Esterase↗
PubMed2003

VLDL-induced triglyceride accumulation in human macrophages is mediated by modulation of LPL lipolytic activity in the absence of change in LPL mass.

Mixed dyslipidemia of phenotype IIB is characterized by elevated levels of very low density lipoprotein (VLDL)-1 and VLDL-2 subfractions and of low density lipoprotein (LDL), which are associated with premature formation of atherosclerotic plaques, characterized by the presence of lipid-rich macrophage foam cells. Lipoprotein lipase (LPL) is a key factor in mediating macrophage lipid accumulation and foam-cell formation from native VLDL particles. The action of macrophage-derived LPL in the induction of intracellular lipid accumulation from triglyceride-rich lipoprotein (TRL) subfractions (VLDL-1, VLDL-2) is, however, indeterminate, as is the potential role of VLDL-1 and VLDL-2 in modulating macrophage LPL expression. We evaluated the role of LPL in the interaction of type IIB VLDL-1 and VLDL-2 with human macrophages. Both VLDL-1 and VLDL-2 subfractions induced significant accumulation of triglyceride (9.8-fold, P<0.0001, and 4.8-fold, P<0.0001, respectively) and of free cholesterol content (1.4-fold, P<0.001, and 1.2-fold, P=0.02, respectively). Specific inhibition (90%) of the lipolytic activity of endogenous LPL by tetrahydrolipstatin (THL) in the presence of VLDL-1 or VLDL-2 resulted in marked reduction in cellular loading of both triglycerides (-89%, P=0.008, and -89%, P=0.015, respectively) and free cholesterol (-76%, P=0.02, and -55%, P=0.06 respectively). Furthermore, VLDL-1 and VLDL-2 induced marked increase in macrophage-derived LPL enzyme activity (+81%, P=0.002, and +45%, P=0.02), but did not modulate macrophage-derived LPL mRNA and protein expression; consequently, LPL specific activity was significantly increased from 1.6 mU/microg at baseline to 4.1 mU/microg (P=0.01) and 3.1 mU/microg (P=0.05), in the presence of VLDL-1 and VLDL-2, respectively. We conclude that type IIB VLDL-1 and VLDL-2 induce triglyceride accumulation in human monocyte-macrophages primarily via the lipolytic action of LPL, which may involve stabilization and activation of the macrophage-secreted enzyme, rather than via modulation of enzyme production.

Cells, Cultured↗
PubMed2003

A CYP7A promoter binding factor site and Alu repeat in the distal promoter region are implicated in regulation of human CETP gene expression.

The cholesteryl ester transfer protein (CETP) plays a key role in reverse cholesterol transport in mediating the transfer of cholesteryl ester from HDL to atherogenic apolipoprotein B-containing lipoproteins (VLDL, IDL, and LDL). Variation in plasma CETP mass in both normolipidemic and dyslipidemic individuals may reflect differences in CETP gene expression. As the 5' flanking sequence up to 3.4 kb of the human CETP gene contributes to transcriptional activity and tissue-specific gene expression, we evaluated the role of the distal promoter region in the modulation of CETP gene expression. In transfection experiments in HepG2 cells, we presently demonstrate that an Alu repeat (-2,153/-2,414) acts as a repressive element, whereas a binding site for the orphan nuclear receptor CYP7A promoter binding factor (CPF), at position -1,042, facilitates activation of human CETP promoter activity. Cotransfection of liver receptor homolog, the mouse homologue of CPF in HEK293 cells that lack CPF, indicated that the -1,042 CPF site is sufficient to induce CPF-mediated activation of CETP promoter activity. Taken together, our results indicate that the distal-promoter region is a major component in the modulation of human CETP promoter activity, and that it may contribute to the liver-specific expression of the CETP gene.

Alu Elements↗