New Lipid Lowering Therapies for Cardiovascular and Metabolic Diseases: Lessons from the Past and Future Challenges

This book illustrates some of the most recent research efforts that have been made in lowering plasma cholesterol levels in patients with CVD. Selected articles aimed to illuminate advances and urgent challenges in the management of CVD, including disease management using statin-combined therapeutic strategies

Epigenetic Regulation of ATP-Binding Cassette Protein A1 (ABCA1) Gene Expression: A New Era to Alleviate Atherosclerotic Cardiovascular Disease

The most important function of high density lipoprotein (HDL) is its ability to remove cholesterol from cells and tissues involved in the early stages of atherosclerosis back to the liver for excretion. The ATP-binding cassette transporters ABCA1 and ABCG1 are responsible for the major part of cholesterol efflux to HDL in macrophage foam cells. Thus, promoting the process of reverse cholesterol transport (RCT) by upregulating mainly ABCA1 remains one of the potential targets for the development of new therapeutic agents against atherosclerosis. Growing evidence suggests that posttranscriptional regulation of HDL biogenesis as well as modulation of ABCA1 expression are under the control of several genetic and epigenetic factors such as transcription factor (TFs), microRNAs (miRNAs) and RNA-binding proteins (RBPs).These factors may act either individually or in combination to orchestrate ABCA1 expression. Complementary to our recent work, we propose an exploratory model for the potential molecular mechanism(s) underlying epigenetic signature of ABCA1 gene regulation. Such a model may hopefully provide the basic framework for understanding the epigenetic regulation of RCT and contribute to the development of novel therapeutic strategies to alleviate the burden of cardiovascular diseases (CVD)

Acknowledgement of manuscript reviewers, the underappreciated contributors

<p>Contributing reviewers</p> <p>We and the Editorial Board acknowledge and thank all reviewers for their active participation and contribution during 2012. We greatly appreciate their dedication and behind the scenes contribution. It is largely due to their support and expertise that we have been able to publish high-standard manuscripts. We would also like to thank authors for choosing Nutrition & Metabolism and contributing their cherished work.</p

Regulation of Sphingolipid Metabolism by MicroRNAs: A Potential Approach to Alleviate Atherosclerosis

The rapidly expanding field of bioactive lipids is exemplified by the many sphingolipids, which are structurally and functionally diverse molecules with significant physiologic functions. These sphingolipids are main constituents of cellular membranes and have been found associated with plasma lipoproteins, and their concentrations are altered in several metabolic disorders such as atherosclerosis, obesity, and diabetes. Understanding the mechanisms that regulate their biosynthesis and secretion may provide novel information that might be amenable to therapeutic targeting in the treatment of these diseases. Several sphingolipid synthesis genes have been targeted as potential therapeutics for atherosclerosis. In recent years, significant progress has been made in studying the role of microRNAs (miRNAs) in lipid metabolism. However, little effort has been made to investigate their role in sphingolipid metabolism. Sphingolipid biosynthetic pathways involve various enzymes that lead to the formation of several key molecules implicated in atherosclerosis, and the identification of miRNAs that regulate these enzymes could help us to understand these complex pathways better and may prove beneficial in alleviating atherosclerosis

Differential Regulation of Glucosylceramide Synthesis and Efflux by Golgi and Plasma Membrane Bound ABCC10

Glucosylceramide (GlcCer) synthesis by the enzyme glucosylceramide synthase (GCS) occurs on the cytosolic leaflet of the Golgi and is the first important step for the synthesis of complex glycosphingolipids (GSLs) that takes place inside the lumen. Apart from serving as a precursor for glycosylation, newly synthesized GlcCer is also transported to the plasma membrane and secreted onto HDL in the circulation. The mechanism by which GlcCer is transported to HDL remains unclear. Recently, we showed that ATP-binding cassette transporter protein C10 (ABCC10) plays an important role in the synthesis and efflux of GlcCer in Huh-7 cells. In this study, we found that treatment of Huh-7 cells with an ABCC10 inhibitor, sorafenib, decreased the synthesis and efflux of GlcCer. However, treatment of cells with cepharanthine reduced only the efflux, but not synthesis, of GlcCer. These results indicate that ABCC10 may regulate the synthesis and efflux of GlcCer differentially in liver cells

Reduction in Insulin Mediated ERK Phosphorylation by Palmitate in Liver Cells Is Independent of Fatty Acid Induced ER Stress

Saturated free fatty acids (FFAs) such as palmitate in the circulation are known to cause endoplasmic reticulum (ER) stress and insulin resistance in peripheral tissues. In addition to protein kinase B (AKT) signaling, extracellular signal-regulated kinase (ERK) has been implicated in the development of insulin resistance. However, there are conflicting data regarding role of ERK signaling in ER stress-induced insulin resistance. In this study, we investigated the effects of ER stress on insulin resistance and ERK phosphorylation in Huh-7 cells and evaluated how oleate prevents palmitate-mediated ER stress. Treatment with insulin resulted in an increase of 38&ndash;45% in the uptake of glucose in control cells compared to non-insulin-treated control cells, along with an increase in the phosphorylation of AKT and ERK. We found that treatment with palmitate increased the expression of ER stress genes, including the splicing of X box binding protein 1 (XBP1) mRNA. At the same time, we observed a decrease in insulin-mediated uptake of glucose and ERK phosphorylation in Huh-7 cells, without any change in AKT phosphorylation. Supplementation of oleate along with palmitate mitigated the palmitate-induced ER stress but did not affect insulin-mediated glucose uptake or ERK phosphorylation. The findings of this study suggest that palmitate reduces insulin-mediated ERK phosphorylation in liver cells and this effect is independent of fatty-acid-induced ER stress