HDL and LDL: Potential New Players in Breast Cancer Development.

Breast cancer is the most prevalent cancer and primary cause of cancer-related mortality in women. The identification of risk factors can improve prevention of cancer, and obesity and hypercholesterolemia represent potentially modifiable breast cancer risk factors. In the present work, we review the progress to date in research on the potential role of the main cholesterol transporters, low-density and high-density lipoproteins (LDL and HDL), on breast cancer development. Although some studies have failed to find associations between lipoproteins and breast cancer, some large clinical studies have demonstrated a direct association between LDL cholesterol levels and breast cancer risk and an inverse association between HDL cholesterol and breast cancer risk. Research in breast cancer cells and experimental mouse models of breast cancer have demonstrated an important role for cholesterol and its transporters in breast cancer development. Instead of cholesterol, the cholesterol metabolite 27-hydroxycholesterol induces the proliferation of estrogen receptor-positive breast cancer cells and facilitates metastasis. Oxidative modification of the lipoproteins and HDL glycation activate different inflammation-related pathways, thereby enhancing cell proliferation and migration and inhibiting apoptosis. Cholesterol-lowering drugs and apolipoprotein A-I mimetics have emerged as potential therapeutic agents to prevent the deleterious effects of high cholesterol in breast cancer

PCSK9 is expressed in human visceral adipose tissue and regulated by insulin and cardiac natriuretic peptides

open8noProprotein convertase subtilisin/kexin type 9 (PCSK9) binds to and degrades the low-density lipoprotein receptor (LDLR), contributing to hypercholesterolemia. Adipose tissue plays a role in lipoprotein metabolism, but there are almost no data about PCSK9 and LDLR regulation in human adipocytes. We studied PCSK9 and LDLR regulation by insulin, atrial natriuretic peptide (ANP, a potent lipolytic agonist that antagonizes insulin), and LDL in visceral adipose tissue (VAT) and in human cultured adipocytes. PCSK9 was expressed in VAT and its expression was positively correlated with body mass index (BMI). Both intracellular mature and secreted PCSK9 were abundant in cultured human adipocytes. Insulin induced PCSK9, LDLR, and sterol-regulatory element-binding protein-1c (SREBP-1c) and -2 expression (SREBP-2). ANP reduced insulin-induced PCSK9, especially in the context of a medium simulating hyperglycemia. Human LDL induced both mature and secreted PCSK9 and reduced LDLR. ANP indirectly blocked the LDLR degradation, reducing the positive effect of LDL on PCSK9. In conclusion, PCSK9 is expressed in human adipocytes. When the expression of PCSK9 is induced, LDLR is reduced through the PCSK9-mediated degradation. On the contrary, when the induction of PCSK9 by insulin and LDL is partially blocked by ANP, the LDLR degradation is reduced. This suggests that NPs could be able to control LDLR levels, preventing PCSK9 overexpression.openBordicchia, Marica; Spannella, Francesco; Ferretti, Gianna; Bacchetti, Tiziana; Vignini, Arianna; Di Pentima, Chiara; Mazzanti, Laura; Sarzani, RiccardoBordicchia, Marica; Spannella, Francesco; Ferretti, Gianna; Bacchetti, Tiziana; Vignini, Arianna; DI PENTIMA, Chiara; Mazzanti, Laura; Sarzani, Riccard

Mycobacterium tuberculosis-Driven Targeted Recalibration of Macrophage Lipid Homeostasis Promotes the Foamy Phenotype

SummaryUpon infection, Mycobacterium tuberculosis (Mtb) metabolically alters the macrophage to create a niche that is ideally suited to its persistent lifestyle. Infected macrophages acquire a “foamy” phenotype characterized by the accumulation of lipid bodies (LBs), which serve as both a source of nutrients and a secure niche for the bacterium. While the functional significance of the foamy phenotype is appreciated, the biochemical pathways mediating this process are understudied. We found that Mtb induces the foamy phenotype via targeted manipulation of host cellular metabolism to divert the glycolytic pathway toward ketone body synthesis. This dysregulation enabled feedback activation of the anti-lipolytic G protein-coupled receptor GPR109A, leading to perturbations in lipid homeostasis and consequent accumulation of LBs in the macrophage. ESAT-6, a secreted Mtb virulence factor, mediates the enforcement of this feedback loop. Finally, we demonstrate that pharmacological targeting of pathways mediating this host-pathogen metabolic crosstalk provides a potential strategy for developing tuberculosis chemotherapy

Cholesterol efflux in adipose tissue

Scope and Method of Study:The current studies are important to understand the reverse cholesterol transport (RCT) in vertebrates. Reverse cholesterol transport is the process by which excess unesterified cholesterol is transported from peripheral tissues to the liver for excretion from the body. Several lines of evidence suggest that defects in RCT contribute to the development of atherosclerosis. Adipose tissue constitutes a major site of cholesterol storage and it may play a role in the regulation of circulating cholesterol levels. The understanding of metabolic link between the lipolytic state (hydrolysis of triacyglycerol) of adipocytes and the mechanism of release of cellular cholesterol to external cholesterol acceptors like apolipoprotein A-I (apoA-I) and high density lipoprotein (HDL) is necessary to elucidate the role of adipose tissue in whole body cholesterol homeostasis.Findings and Conclusions:Our study shows that β-adrenergic activation of the lipolysis significantly increases the extent of cholesterol efflux to reconstituted discoidal HDL particles. The enhancement of cholesterol efflux is not due to the enrichment of plasma membrane cholesterol, or to the levels of the cholesterol transporters ABCA1 and SR-BI. The activation of lipolysis is accompanied by an increase in BFA-sensitive vesicular transport that in turn enhances cholesterol efflux to HDL. The study supports a metabolic link between the lipolytic activity of adipocytes and the rate of cellular cholesterol efflux to HDL. The activation of lipolysis does not induce a significant increase in the rate of cholesterol efflux to lipid free apoA-I. The known vesicular and non-vesicular cholesterol efflux inhibitors inhibit global cholesterol efflux significantly, but not specific cholesterol efflux to apoA-I. We have evidently presented that lipid free apoA-I undergo retroendocytosis in mouse adipose cells, human liver cells but not in human macrophage cells. The known cholesterol efflux inhibitory drugs had no effect on the uptake and recycling of apoA-I

Role of lipoproteins in the microenvironment of hormone-dependent cancers

The tumor microenvironment (TME) is an attractive target to develop novel strategies for hormone-dependent cancers. Several molecules in the TME can favor tumor development and progression, including lipoproteins. Lipoproteins are taken up by cancer cells providing them with cholesterol and fatty acids. Cholesterol regulates cell signaling and it is converted into a series of bioactive metabolites, including hormones. The conflicting results of epidemiological and interventional studies suggest that the local availability of lipoproteins in the TME is more relevant for cancer biology than their circulating levels. Thus, reducing lipoprotein uptake and stimulating cell cholesterol efflux to high density lipoproteins (HDL) can represent a novel adjuvant strategy for cancer management. HDL-like particles can also act as drug delivery systems for tumor targeting

Opposite regulation of human versus mouse apolipoprotein A-I by fibrates in human apolipoprotein A-I transgenic mice

The regulation of liver apolipoprotein (apo) A-I gene expression by fibrates was studied in human apo A-I transgenic mice containing a human genomic DNA fragment driving apo A-I expression in liver. Treatment with fenofibrate (0.5% wt/wt) for 7 d increased plasma human apo A-I levels up to 750% and HDL-cholesterol levels up to 200% with a shift to larger particles. The increase in human apo A-I plasma levels was time and dose dependent and was already evident after 3 d at the highest dose (0.5% wt/wt) of fenofibrate. In contrast, plasma mouse apo A-I concentration was decreased after fenofibrate in nontransgenic mice. The increase in plasma human apo A-I levels after fenofibrate treatment was associated with a 97% increase in hepatic human apo A-I mRNA, whereas mouse apo A-I mRNA levels decreased to 51%. In nontransgenic mice, a similar down-regulation of hepatic apo A-I mRNA levels was observed. Nuclear run-on experiments demonstrated that the increase in human apo A-I and the decrease in mouse apo A-I gene expression after fenofibrate occurred at the transcriptional level. Since part of the effects of fibrates are mediated through the nuclear receptor PPAR (peroxisome proliferator-activated receptor), the expression of the acyl CoA oxidase (ACO) gene was measured as a control of PPAR activation. Both in transgenic and nontransgenic mice, fenofibrate induced ACO mRNA levels up to sixfold. When transgenic mice were treated with gemfibrozil (0.5% wt/wt) plasma human apo A-I and HDL-cholesterol levels increased 32 and 73%, respectively, above control levels. The weaker effect of this compound on human apo A-I and HDL-cholesterol levels correlated with a less pronounced impact on ACO mRNA levels (a threefold increase) suggesting that the level of induction of human apo A-I gene is related to the PPAR activating potency of the fibrate used. Treatment of human primary hepatocytes with fenofibric acid (500 microM) provoked an 83 and 50% increase in apo A-I secretion and mRNA levels, respectively, supporting that a direct action of fibrates on liver human apo A-I production leads to the observed increase in plasma apo A4 and HDL-cholesterol

Biogenesis of the multifunctional lipid droplet: lipids, proteins, and sites

Lipid droplets (LDs) are ubiquitous dynamic organelles that store and supply lipids in all eukaryotic and some prokaryotic cells for energy metabolism, membrane synthesis, and production of essential lipid-derived molecules. Interest in the organelle's cell biology has exponentially increased over the last decade due to the link between LDs and prevalent human diseases and the discovery of new and unexpected functions of LDs. As a result, there has been significant recent progress toward understanding where and how LDs are formed, and the specific lipid pathways that coordinate LD biogenesis