Resveratrol administration or SIRT1 overexpression does not increase LXR signaling and macrophage-to-feces reverse cholesterol transport in vivo.

The natural polyphenol resveratrol has cardiometabolic protective properties. Resveratrol has been reported to be an activator of NAD+-dependent deacetylase sirtuin 1 (SIRT1), which may regulate liver X receptor (LXR) activity, thereby upregulating the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, the effects of resveratrol and SIRT1 overexpression on RCT from macrophages-to-feces in vivo in C57BL/6 mice were determined.

Acute psychological stress accelerates reverse cholesterol transport via corticosterone-dependent inhibition of intestinal cholesterol absorption.

Rationale: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood.

Objective: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion.

Phytosterols inhibit the tumor growth and lipoprotein oxidizability induced by a high-fat diet in mice with inherited breast cancer.

Dietary phytosterol supplements are readily available to consumers since they effectively reduce plasma low-density lipoprotein cholesterol. Several studies on cell cultures and xenograft mouse models suggest that dietary phytosterols may also exert protective effects against common cancers. We examined the effects of a dietary phytosterol supplement on tumor onset and progression using the well-characterized mouse mammary tumor virus polyoma virus middle T antigen transgenic mouse model of inherited breast cancer.

Genetic ablation of Cav1 differentially affects melanoma tumor growth and metastasis in mice: role of Cav1 in Shh heterotypic signaling and transendothelial migration.

Both cell-autonomous and non-cell-autonomous factors contribute to tumor growth and metastasis of melanoma. The function of caveolin-1 (Cav1), a multifunctional scaffold protein known to modulate several biologic processes in both normal tissue and cancer, has been recently investigated in melanoma cancer cells, but its role in the melanoma microenvironment remains largely unexplored. Here, we show that orthotopic implantation of B16F10 melanoma cells in the skin of Cav1KO mice increases tumor growth, and co-injection of Cav1-deficient dermal fibroblasts with melanoma cells is sufficient to recapitulate the tumor phenotype observed in Cav1KO mice.

The cholesterol content of Western diets plays a major role in the paradoxical increase in high-density lipoprotein cholesterol and upregulates the macrophage reverse cholesterol transport pathway.

Objective: A high-saturated fatty acid- and cholesterol-containing (HFHC) diet is considered to be a major risk factor for cardiovascular disease. The present study aimed to determine the effects of this Western-type diet on high-density lipoprotein (HDL) metabolism and reverse cholesterol transport (RCT) from macrophages to feces.

Methods And Results: Experiments were carried out in mice fed a low-fat, low-cholesterol diet, an HFHC diet, or an HFHC diet without added cholesterol (high-saturated fatty acid and low-cholesterol [HFLC]).

ATP-binding cassette G5/G8 deficiency causes hypertriglyceridemia by affecting multiple metabolic pathways.

Mutations in ABCG5 or ABCG8 transporters are responsible for sitosterolemia, an autosomal recessive disease characterized by the accumulation of plant sterols. The aim of this study was to investigate the effects of ABCG5 and ABCG8 deficiency on TG metabolism in mice. Experiments were carried out in wild-type (G5/G8+/+) mice, mice heterozygous for ABCG5 and ABCG8 deficiency (G5/G8+/-) and ABCG5/G8-deficient (G5/G8-/-) mice fed a chow diet.

Role of cholesterol in the development and progression of breast cancer.

Diet and obesity are important risk factors for cancer development. Many studies have suggested an important role for several dietary nutrients in the progression and development of breast cancer. However, few studies have specifically addressed the role of components of a Western diet as important factors involved in breast cancer initiation and progression.

Seeking novel targets for improving in vivo macrophage-specific reverse cholesterol transport: translating basic science into new therapies for the prevention and treatment of atherosclerosis.

Epidemiologic studies have demonstrated that increased high-density lipoprotein cholesterol (HDL-C) is a protective factor against cardiovascular disease. However, the beneficial therapeutic effects of raising HDL-C are proving difficult to confirm in humans. Macrophage-specific reverse cholesterol transport (RCT) is thought to be one of the most important HDL-mediated cardioprotective mechanisms.

Effect of atorvastatin on lipoprotein (a) and interleukin-10: a randomized placebo-controlled trial.

Aim: This study aimed to determine the effect of atorvastatin therapy on plasma lipoprotein (a) [Lp(a)] and biomarkers of inflammation in hypercholesterolaemic patients free of cardiovascular disease.

Methods: In this three-month randomized double-blind placebo-controlled trial, 63 hypercholesterolaemic patients were randomly treated with either placebo or atorvastatin (10 or 40 mg/day) for 12 weeks. Lp(a) and biomarkers of inflammation (C-reactive protein [CRP], interleukin [IL]-6 and -10, and tumour necrosis factor-alpha receptors [TNF-Rs]) were measured at study entry, and at four and 12 weeks of follow-up.

Differential effects of gemfibrozil and fenofibrate on reverse cholesterol transport from macrophages to feces in vivo.

Gemfibrozil and fenofibrate, two of the fibrates most used in clinical practice, raise HDL cholesterol (HDLc) and are thought to reduce the risk of atherosclerotic cardiovascular disease. These drugs act as PPARα agonists and upregulate the expression of genes crucial in reverse cholesterol transport (RCT). In the present study, we determined the effects of these two fibrates on RCT from macrophages to feces in vivo in human apoA-I transgenic (hApoA-ITg) mice.

A Western-type diet accelerates tumor progression in an autochthonous mouse model of prostate cancer.

Epidemiological studies have provided evidence suggesting an important role for diet and obesity in the development of cancer. Specifically, lipid nutrients of the diet have been identified as important regulators of tumor development and progression. In the present study, we have examined the role of dietary fat and cholesterol in the initiation and progression of prostate cancer using the well-characterized TRAMP mouse model.

Monocyte gene-expression profile in men with familial combined hyperlipidemia and its modification by atorvastatin treatment.

Aim: The genetic origin of familial combined hyperlipidemia (FCH) is not well understood. We used microarray profiling of peripheral blood monocytes to search novel genes and pathways involved in FCH.

Methods: Fasting plasma for determination of lipid profiles, inflammatory molecules and adipokines was obtained and peripheral blood monocytes were isolated from male FCH patients basally and after 4 weeks of atorvastatin treatment.

Caveolin-1 and regulation of cellular cholesterol homeostasis.

Caveolae are 50- to 100-nm cell surface plasma membrane invaginations present in terminally differentiated cells. They are characterized by the presence of caveolin-1, sphingolipids, and cholesterol. Caveolin-1 is thought to play an important role in the regulation of cellular cholesterol homeostasis, a process that needs to be properly controlled to limit and prevent cholesterol accumulation and eventually atherosclerosis.

Effects of rosiglitazone and atorvastatin on the expression of genes that control cholesterol homeostasis in differentiating monocytes.

We studied the effects of 5 microM atorvastatin, 2 microM rosiglitazone and their combination on intracellular cholesterol levels and on the expression of genes controlling cholesterol trafficking in human monocytes during their differentiation into macrophages. Our results show that treatment with rosiglitazone caused an increase in CD36 mRNA and protein levels (2.7- and 2.

Leptin down-regulates peroxisome proliferator-activated receptor gamma (PPAR-gamma) mRNA levels in primary human monocyte-derived macrophages.

Increased leptin levels are associated with cardiovascular disease in obesity although the mechanism is unknown. Peroxisome proliferator-activated receptor gamma (PPARgamma) is a key regulator of macrophage lipid metabolism and its activation by thiazolidinediones protects against atherosclerosis. The aim of this study was to assess the effects of human recombinant leptin on PPARgamma mRNA levels in primary human macrophages and macrophage-derived foam cells.

Cholesterol regulation of genes involved in sterol trafficking in human THP-1 macrophages.

Modulation of the expression of genes involved in the control of cholesterol homeostasis by sterols in macrophages is crucial to foam cell formation. To characterize this regulation in THP-1 macrophages, we examined the effect of sterol loading and unloading on the expression of a number of genes that participate in lipoprotein uptake and cholesterol efflux. Sterol loading by exposure to acetylated LDL for 24 h resulted in an increase in free and esterified cholesterol of 1.

Aspirin increases CD36, SR-BI, and ABCA1 expression in human THP-1 macrophages.

Objective: CD36 is a receptor, whose expression increases during the differentiation of monocytes to macrophages, playing a key role in the phagocytosis of apoptotic cells and in the formation of foam cells during atherosclerosis. Recently, it has been described that ligands of PPARgamma induce CD36 expression and inhibit cyclooxygenase expression in macrophages. Our aim was to study whether the reduction of endogenous prostaglandin production could modify CD36 expression in macrophages and to outline the potential mechanism.

Acyl coenzyme A:cholesterol acyltransferase inhibitors as hypolipidemic and antiatherosclerotic drugs.

Acyl coenzyme A:cholesterol acyltransferase (ACAT) is the enzyme that catalyzes the conversion of intracellular cholesterol into cholesteryl esters. Two ACAT isoforms, termed ACAT1 and ACAT2, have been described. ACAT1 is ubiquitously found, with high expression levels in macrophages, adrenals, sebaceous glands and foam cells from human atherosclerotic lesions.

Rosiglitazone upregulates caveolin-1 expression in THP-1 cells through a PPAR-dependent mechanism.

Peroxisome proliferator-activated receptor gamma (PPARgamma) activation or overexpression induces caveolin-1 (cav-1) expression in several cell types. The objective of this study was to investigate if PPAR agonists could also regulate the cav-1 gene in macrophages and to explore the mechanisms involved. Our experiments demonstrated that rosiglitazone dose- and time-dependently increased cav-1 mRNA and protein in THP-1 macrophages.

Reduction of intracellular cholesterol accumulation in THP-1 macrophages by a combination of rosiglitazone and atorvastatin.

Rosiglitazone and atorvastatin combination therapy has beneficial effects on both glycemic control and plasma lipid levels in type 2 diabetic patients. In the present study, we sought to determine whether this combination can also exert direct antiatherosclerotic effects in macrophages. Our results show that 2 microM rosiglitazone, alone or combined with 5 microM atorvastatin, significantly upregulated the expression of the ATP-binding cassette transporter ABCA1 and of the class B scavenger receptor CLA-1 (CD36 and LIMPII analog), both involved in cholesterol efflux from macrophages.

Atorvastatin reduces CD68, FABP4, and HBP expression in oxLDL-treated human macrophages.

With the aim of identifying new target genes that could contribute to limit foam cell formation, we analyzed changes in the pattern of gene expression in human THP-1 macrophages treated with atorvastatin and oxidized-LDL (oxLDL). To this end, we used a human cDNA array containing 588 cardiovascular-related cDNAs. Exposure to oxLDL resulted in differential expression of 26 genes, while coincubation with atorvastatin modified the expression of 29 genes, compared to treatment with oxLDL alone.

Differential effects of peroxisome proliferator-activated receptor activators on the mRNA levels of genes involved in lipid metabolism in primary human monocyte-derived macrophages.

Peroxisome proliferator-activated receptors (PPARs) are key regulators of macrophage lipid metabolism. We compared the effects of three PPAR activators (bezafibrate, fenofibrate, and troglitazone) on the mRNA levels of genes involved in lipid metabolism in primary human macrophages and macrophage-derived foam cells. Treatment of human macrophages for 24 hours with 100 micro mol/L bezafibrate, a nonselective drug that activates the 3 PPAR subtypes (PPARalpha, PPARbeta/delta, and PPARgamma), caused an 87% (P <.

Pharmacology of the ACAT inhibitor avasimibe (CI-1011).

Avasimibe is a novel orally bioavailable ACAT inhibitor, currently under clinical development (phase III trials). It was safe when administered to rats, dogs, and humans. In vitro studies in human macrophages demonstrated that avasimibe reduces foam cell formation not only by enhancing free cholesterol efflux, but also by inhibiting the uptake of modified LDL.

Avasimibe and atorvastatin synergistically reduce cholesteryl ester content in THP-1 macrophages.

Evidence suggests that the inhibition of both acyl-CoA:cholesterol acyltransferase and hydroxymethyl glutaryl-CoA reductase causes a synergistic direct antiatherosclerotic effect on the vessel wall. To investigate this synergism in a single cell type and to avoid the confounding effect of plasma cholesterol lowering by these drugs, we have used an in vitro model of human macrophages (phorbol ester-treated THP-1 cells). In macrophages incubated simultaneously with acetyl low-density lipoproteins, the novel acyl-CoA:cholesterol acyltransferase inhibitor avasimibe (0.

Uncoupling protein-3 mRNA levels are increased in white adipose tissue and skeletal muscle of bezafibrate-treated rats.

Fibrates are hypolipidemic drugs that are also able to improve glucose tolerance in animals and diabetic patients through an unknown mechanism. Since uncoupling proteins (UCP) seem to play an important role in the pathogenesis of non-insulin-dependent diabetes mellitus (NIDDM), we examined whether treatment of rats with bezafibrate for 3, 7, or 15 days modified UCP mRNA levels. Using RT-PCR, we observed a weak ectopic expression of UCP-1 and a 2-fold increase in UCP-3 mRNA levels in white adipose tissue after 7 and 15 days of treatment.