Purpose of Review
Emerging data demonstrates the potential of translational applications of antibodies directed against oxidation-specific epitopes (OSE). “Biotheranostics” in cardiovascular disease (CVD) describes targeting of OSE for biomarker, therapeutic and molecular imaging diagnostic applications.
Lipid oxidation collectively yields a large variety of oxidation-specific epitopes (OSE), such as oxidized phospholipids (OxPL) and malondialdehyde (MDA) epitopes. OSE are immunogenic, pro-inflammatory, pro-atherogenic and plaque destabilizing and represent danger associated molecular patterns (DAMPs). DAMPs are recognized by the innate immune system via pattern recognition receptors, including scavenger receptors IgM natural antibodies and complement factor H (CFH), that bind, neutralize and/or facilitate their clearance. Biomarker assays measuring OxPL present on apolipoprotein B-100 lipoproteins, and particularly on lipoprotein (a), predict the development of CVD events. In contrast, OxPL on plasminogen facilitate fibrinolysis and may reduce atherothrombosis. Oxidation-specific antibodies (OSA) attached to magnetic nanoparticles image lipid-rich, oxidation-rich plaques. Infusion or overexpression of OSA reduces the progression of atherosclerosis, suggesting that they may be used in similar applications in humans.
Using the accelerating knowledge base and improved understanding of the interplay of oxidation, inflammation and innate and adaptive immunity in atherogenesis, emerging clinical applications of OSA may identify, monitor and treat CVD in humans.
biotheranostic; oxidation; innate immunity; atherogenesis; molecular imaging
Purpose of review
The phospholipase A2 (PLA2) family of proteins includes lipolytic enzymes that liberate the sn-2 fatty acyl chains from phospholipids to yield non-esterified fatty acids and lysophospholipids. The purpose of this review is to discuss recent findings showing distinct roles of several of these PLA2 enzymes in inflammatory metabolic diseases such as diabetes and atherosclerosis.
The Group 1B PLA2 (PLA2G1B) digestion of phospholipids in the intestinal lumen facilitates postprandial lysophospholipid absorption, which suppresses hepatic fatty acid oxidation leading to increased VLDL synthesis, decreased glucose tolerance, and promotion of tissue lipid deposition to accentuate diet-induced obesity, diabetes, and hyperlipidemia. Other secretory PLA2s promote inflammatory metabolic diseases by generating bioactive lipid metabolites to induce inflammatory cytokine production, whereas the major intracellular PLA2s, cPLA2α and iPLA2, generate arachidonic acid and lysophosphatic acid in response to extracellular stimuli to stimulate leukocyte chemotactic response.
Each member of the phospholipase A2 family of enzymes serves a distinct role in generating active lipid metabolites that promote inflammatory metabolic diseases including atherosclerosis, hyperlipidemia, obesity, and diabetes. The development of specific drugs that target one or more of these PLA2 enzymes may be novel strategies for treatment of these chronic inflammatory metabolic disorders.
Obesity; diabetes; hyperlipidemia; atherosclerosis; inflammation; lysophospholipid
Purpose of review
The 11 long-chain (ACSL) and very long chain acyl-coenzyme A (acyl-CoA) synthetases [(ACSVL)/fatty acid transport protein] are receiving considerable attention because it has become apparent that their individual functions are not redundant.
Recent studies have focused on the structure of the acyl-CoA synthetases, their post-translational modification, their ability to activate fatty acids of varying chain lengths, and their role in directing fatty acids into different metabolic pathways. An unsettled controversy focuses on the ACSVL isoforms and whether these have both enzymatic and transport functions. Another issue is whether conversion of a fatty acid to an acyl-CoA produces an increase in the AMP/ATP ratio that is sufficient to activate AMP-activated kinase.
FuturestudiesarerequiredtodeterminethesubcellularlocationofeachACSLandACSVL isoform and the functional importance of phosphorylation and acetylation. Purification and crystallization of mammalian ACSL and ACSVL isoforms is needed to confirm the mechanism of action and discover how these enzymesdiffer in their affinity for fatty acids of differentchainlengths.Functionally,itwillbeimportanttolearnhowtheACSLisoformscan direct their acyl-CoA products toward independent downstream pathways.
β-oxidation; acyl-CoA synthetase; AMP-activated kinase; fatty acid; fatty acid transport protein; glycerolipid synthesis
Purpose of review
The accumulation of macrophages in the vascular wall is a hallmark of atherosclerosis. The biological properties of atherosclerotic plaque macrophages determine lesion size, composition and stability. In atherosclerotic plaques, macrophages encounter a microenvironment that is comprised of a variety of lipid oxidation products, each of which has diverse biological effects. In this review, we summarize recent advances in our understanding of the effects of plaque lipids on macrophage phenotypic polarization.
Atherosclerotic lesions in mice and in humans contain various macrophage phenotypes, which play different roles in mediating inflammation, the clearance of dead cells, and possibly resolution. Macrophages alter their phenotype and biological function in response to plaque lipids through the upregulation of specific sets of genes. Interaction of oxidized lipids with pattern recognition receptors and activation of the inflammasome by cholesterol crystals drive macrophages towards an inflammatory M1 phenotype. A new phenotype, Mox, develops when oxidized phospholipids activate stress response genes via Nrf2. Other lipid mediators such as nitrosylated-fatty acids and omega-3 fatty acid-derived products polarize plaque macrophages towards anti-inflammatory and proresolving phenotypes.
A deeper understanding of how lipids that accumulate in atherosclerotic plaques affect macrophage phenotype and function and thus atherosclerotic lesion development and stability will help to devise novel strategies for intervention.
Macrophages; oxidized lipids; atherosclerosis; inflammation
Purpose of review
With the advent of whole-transcriptome sequencing, or RNA-seq, we now know that
alternative splicing is a generalized phenomenon, with nearly all multi-exonic genes subject to
alternative splicing. In this review we highlight recent studies examining alternative splicing as a
modulator of cellular cholesterol homeostasis, and as an underlying mechanism of dyslipidemia.
A number of key genes involved in cholesterol metabolism are known to undergo
functionally relevant alternative splicing. Recently, we have identified coordinated changes in
alternative splicing in multiple genes in response to alteration in cellular sterol content. We and
others have implicated several splicing factors as regulators of lipid metabolism. Furthermore, a
number of cis-acting human gene variants that modulate alternative splicing have been implicated in
a variety of human metabolic diseases.
Alternative splicing is of importance in various types of genetically influenced
dyslipidemias, and in the regulation of cellular cholesterol metabolism.
PTBP1; HMGCR; LDLR; statin; SFRS10
Purpose of review
Obesity, dyslipidemia and cardiovascular disease are complex and determined by both genetic and environmental factors and their inter-relationships. Many associations from genome-wide association studies and candidate gene approaches have described a multitude of polymorphisms associating with lipid and obesity phenotypes but identified genetic variants account for only a small fraction of phenotypic variation.
That many genotype–phenotype associations involve variants under positive selection and that those variants respond to environmental cues together suggest prominent roles for both genetic adaptation and their interactions with the environment. Adaptive genetic variations interacting with environment modulate disease susceptibility but the level to which those variants contribute to dyslipidemia and obesity and how environmental factors, especially diet, alter the genetic association is not yet completely known.
It is evident that genetic variants under positive selection make important contributions to obesity and heart disease risk. Advances in resequencing the entire human genome will enable accurate identification of adaptive variants. Considering interactions between environmental factors and genotypes will empower both genome-wide association studies and characterization of the relationship between positive selection and the obese and dyslipidemic conditions.
dyslipidemia; gene–environment interaction; obesity; positive selection
Purpose of review
Raising HDL cholesterol (HDL-C) has become an attractive therapeutic target to lower cardiovascular risk in addition to statins. Inhibition of the cholesteryl ester transfer protein (CETP), which mediates the transfer of cholesteryl esters from HDL to apolipoprotein B-containing particles, leads to a substantial increase in HDL-C levels. Various CETP inhibitors are currently being evaluated in phase II and phase III clinical trials. However, the beneficial effect of CETP inhibition on cardiovascular outcome remains to be established.
Torcetrapib, the first CETP inhibitor tested in a phase III clinical trial (ILLUMINATE), failed in 2006 because of an increase in all-cause mortality and cardiovascular events that subsequently were attributed to nonclass-related off-target effects (particularly increased blood pressure and low serum potassium) related to the stimulation of aldosterone production. Anacetrapib, another potent CETP inhibitor, raises HDL-C levels by approximately 138% and decreases LDL cholesterol (LDL-C) levels by approximately 40%, without the adverse off-targets effects of torcetrapib (DEFINE study). The CETP modulator dalcetrapib raises HDL-C levels by approximately 30% (with only minimal effect on LDL-C levels) and proved safety in the dal-VESSEL and dal-PLAQUE trials involving a total of nearly 600 patients. Evacetrapib, a relatively new CETP inhibitor, exhibited favorable changes in the lipid profile in a phase II study.
The two ongoing outcome trials, dal-OUTCOMES (dalcetrapib) and REVEAL (anacetrapib), will provide more conclusive answers for the concept of reducing cardiovascular risk by raising HDL-C with CETP inhibition.
atherosclerosis; cholesteryl ester transfer protein; inhibitor; lipid metabolism
Purpose of review
Lipase maturation factor 1 (LMF1) is a membrane-bound protein located in the endoplasmic reticulum (ER). It is essential to the folding and assembly (i.e., maturation) of a select group of lipases that include lipoprotein lipase (LPL), hepatic lipase (HL) and endothelial lipase (EL). The purpose of this review is to examine recent studies that have begun to elucidate the structure and function of LMF1, and to place it in the context of lipase folding and assembly.
Recent studies identified mutations in LMF1 that cause combined lipase deficiency and hypertriglyceridemia in humans. These mutations result in the truncation of a large, evolutionarily conserved domain called DUF1222, which is essential for interaction with lipases and their attainment of enzymatic activity. The structural complexity of LMF1 has been further characterized by solving its topology in the ER membrane. Recent studies indicate that in addition to LPL and HL, the maturation of EL is also dependent on LMF1. Based on its apparent specificity for dimeric lipases, LMF1 is proposed to play an essential role in the assembly and/or stabilization of head-to-tail lipase homodimers.
LMF1 functions in the maturation of a select group of secreted lipases that assemble into homodimers in the ER. These dimeric lipases include LPL, HL and EL, all of which contribute significantly to plasma triglyceride and HDL cholesterol levels in human populations. Future studies involving genetically engineered mouse models will be required to fully elucidate the role of LMF1 in normal physiology and disease.
Protein folding; endoplasmic reticulum; lipase maturation factor 1; lipoprotein lipase; hepatic lipase; endothelial lipase
Purpose of review
The global prevalence of obesity is increasing epidemically. Obesity causes an array of health problems, reduces life expectancy, and costs over US$100 billion annually. More than a quarter of the population suffers from an aggregation of co-morbidities, including obesity, atherosclerosis, insulin resistance, dyslipidemias, coagulopathies, hypertension, and a pro-inflammatory state known as the metabolic syndrome. Patients with metabolic syndrome have high risk of atherosclerosis as well as type 2 diabetes and other health problems. Like obesity, atherosclerosis has very limited therapeutic options.
Fatty acid binding proteins integrate metabolic and immune responses and link the inflammatory and lipid-mediated pathways that are critical in the metabolic syndrome. This review will highlight recent studies on fatty acid binding protein-deficient models and several fatty acid binding protein-mediated pathways specifically modified in macrophages, cells that are paramount to the initiation and persistence of cardiovascular lesions.
Adipocyte/macrophage fatty acid binding proteins, aP2 and mal1, act at the interface of metabolic and inflammatory pathways. These fatty acid binding proteins are involved in the formation of atherosclerosis predominantly through the direct modification of macrophage cholesterol trafficking and inflammatory responses. In addition to atherosclerosis, these fatty acid binding proteins also exert a dramatic impact on obesity, insulin resistance, type 2 diabetes and fatty liver disease. The creation of pharmacological agents to modify fatty acid binding protein function will provide tissue or cell-type-specific control of these lipid signaling pathways, inflammatory responses, atherosclerosis, and the other components of the metabolic syndrome, therefore offering a new class of multi-indication therapeutic agents.
atherosclerosis; fatty acid binding protein; fatty acids; lipomics; macrophage
Purpose of review
The paraoxonase (PON) gene family includes 3 members, PON1, PON2, and PON3. In vitro and mouse studies have demonstrated that all three PONs are athero-protective. Some but not all human epidemiologic studies have observed associations between PON gene polymorphisms and risk of cardiovascular disease (CVD). In this review, we summarize studies published within the past year elucidating involvement of PON1 and PON2 in oxidative stress, cardiovascular disease, and innate immune responses.
In a prospective study, the PON1 192QQ genotype and low PON1 activity were associated with increased systemic oxidative stress and increased risk for cardiovascular disease. PON1 expression protected against Pseudomonas aeruginosa lethality in Drosophila, suggesting that PON1 can interfere with quorum sensing in vivo. PON2 attenuated macrophage triglyceride accumulation via inhibition of diacylglycerol acyltransferase 1. Over-expression of PON2 protected against endoplasmic reticulum (ER) stress-induced apoptosis when the stress was induced by interference with protein modification but not when ER stress was induced by Ca ++ deregulation.
Both mouse and human studies have demonstrated the anti-oxidative and athero-protective effects of PON1. The mechanisms by which PON2 exerts its athero-protective effects are emerging. Large-scale epidemiologic studies are needed to further examine the relationship between PON2 genetic polymorphisms and risk for CVD. Elucidation of the physiological substrates of the PON proteins is of particular importance to further advance this field.
Atherosclerosis; high density lipoprotein; paraoxonases; oxidative stress; quorum sensing
Purpose of review
Elevated plasma triglyceride and reduced HDL concentrations are prominent features of metabolic syndrome and type 2 diabetes. Individuals with Tangier disease also have elevated plasma triglyceride concentrations and very low HDL, resulting from mutations in ATP-binding cassette transporter A1 (ABCA1), an integral membrane protein that facilitates nascent HDL particle assembly. Past studies attributed the inverse relationship between plasma HDL and triglyceride to intravascular lipid exchange and catabolic events. However, recent studies also suggest that hepatic signaling and lipid mobilization and secretion may explain how HDL affects plasma triglyceride concentrations.
Hepatocyte-specific ABCA1 knockout mice have markedly reduced plasma HDL and a two-fold increase in triglyceride due to failure to assemble nascent HDL particles by hepatocytes, causing increased catabolism of HDL apolipoprotein A-I and increased hepatic production of triglyceride-enriched VLDL. In-vitro studies suggest that nascent HDL particles may induce signaling to decrease triglyceride secretion. Inhibition of microRNA 33 expression in nonhuman primates augments hepatic ABCA1, genes involved in fatty acid oxidation, and decreases expression of lipogenic genes, causing increased plasma HDL and decreased triglyceride levels.
New evidence suggests potential mechanisms by which hepatic ABCA1-mediated nascent HDL formation regulates VLDL–triglyceride production and contributes to the inverse relationship between plasma HDL and triglyceride.
ATP-binding cassette transporter A1; high-density lipoprotein formation; mRNA; Tangier disease; very low-density lipoprotein production
Purpose of Review
The process of reverse cholesterol transport (RCT) is critical for disposal of excess cholesterol from the body. Although it is generally accepted that RCT requires biliary secretion, recent studies show that RCT persists in genetic or surgical models of biliary insufficiency. Discovery of this non-biliary pathway has opened new possibilities of targeting the intestine as an inducible cholesterol excretory organ. In this review we highlight the relative contribution and therapeutic potential for both biliary and non-biliary components of reverse cholesterol transport (RCT).
Recently, the proximal small intestine has gained attention for its underappreciated ability to secrete cholesterol in a process called transintestinal cholesterol efflux (TICE). Although this intestinal pathway for RCT is quantitatively smaller than the biliary route under normal physiological conditions, the TICE pathway is highly inducible, providing a novel therapeutic opportunity for treatment of atherosclerotic cardiovascular disease (ASCVD). In fact, recent studies show that intestine-specific activation of RCT protects against ASCVD in mice.
It is well known that the small intestine plays a gatekeeper role in the maintenance of cholesterol balance. Through integrated regulation of cholesterol absorption and TICE, the small intestine is a key target for new therapies against ASCVD.
cholesterol; lipoprotein; bile; reverse cholesterol transport
Purpose of review
We review the main findings from genome-wide association studies (GWAS) for levels of HDL-cholesterol, LDL-cholesterol and triglycerides, including approaches to identify the functional variant(s) or gene(s). We discuss study design and challenges related to whole genome or exome sequencing to identify novel genes and variants.
GWAS have detected ~100 loci associated with one or more lipid trait. Fine-mapping of several loci for LDL-c demonstrated that the trait variance explained may double when the variants responsible for the association signals are identified. Experimental follow-up of three loci identified by GWAS has identified functional genes at GALNT2, TRIB1, and SORT1, and a functional variant at SORT1.
The goal of genetic studies for lipid levels is to improve treatment and ultimately reduce the prevalence of heart disease. Many signals identified by GWAS have modest effect sizes, useful for identifying novel biologically-relevant genes, but less useful for personalized medicine. Whole genome or exome sequencing studies may fill this gap by identifying rare variants of larger effect associated with lipid levels and heart disease.
genome-wide association study; lipids; cholesterol; next-generation sequencing
Purpose of the review
PGC-1α has been extensively described as a master regulator of mitochondrial biogenesis. However, PGC-1α activity is not constant, and can be finely tuned in response to different metabolic situations. From this point of view, PGC-1α could be described as a mediator of the transcriptional outputs triggered by metabolic sensors, providing the idea that these sensors, together with PGC-1α, might be weaving a network controlling cellular energy expenditure. In this review we will focus on how pathologies such as type 2 diabetes and the metabolic syndrome might be related to an abnormal and improper function of this network.
Two metabolic sensors, AMPK and SIRT1 have been described to directly affect PGC-1α activity through phosphorylation and deacetylation, respectively. While the physiological relevance of these modifications and their molecular consequences are still largely unknown, recent insight from different in vivo transgenic models clearly suggests that AMPK, SIRT1 and PGC-1α might act as an orchestrated network to improve metabolic fitness.
Metabolic sensors such as AMPK and SIRT1, gatekeepers of the activity of the master regulator of mitochondria, PGC1α, are vital links in a regulatory network for metabolic homeostasis. Together these players explain many of the beneficial effects of physical activity and dietary interventions in our battle against type 2 diabetes and related metabolic disorders. Hence, understanding the mechanisms by which they act could guide us to identify and improve preventive and therapeutic strategies for metabolic diseases.
energy expenditure; PGC-1α; SIRT1; AMPK
Purpose of review
CREB-H is a transcription factor that is highly and selectively expressed in liver and small intestine. Here I summarize recent findings on the role of CREB-H in lipid metabolism.
Recent studies have demonstrated that hepatic CREB-H is transcriptionally activated by fasting, and induces lipid metabolism genes, such as Apoa4, Apoa5, and Apoc2 apolipoproteins which exhibit stimulatory effects on lipoprotein lipase (LPL). Consistent with the essential role of LPL in TG clearance, CREB-H deficient mice showed hypertriglyceridemia, associated with defective production of these apolipoproteins and decreased LPL activity. DNA sequencing of the CREB3L3 gene (encoding CREB-H) identified multiple nonsynonymous mutations in CREB3L3 in individuals with extreme hypertriglyceridemia.
Recent studies uncover a novel function of CREB-H in the regulation of TG metabolism in rodents and humans. In liver and small intestine, CREB-H induces LPL coactivators, Apoa4, Apoa5, and Apoc2 that facilitate TG clearance from plasma.
CREB-H; CREB3L3; transcription factor; triglyceride; apolipoprotein
Purpose of review
Despite a strong correlation between obesity and insulin resistance, 25% of severely obese (BMI >40) individuals are insulin sensitive. In this review, we will examine the factors in adipose tissue that distinguish the two groups, as well as reasons for believing the insulin-sensitive group will be less disease prone.
Obesity has been linked to the metabolic syndrome with an increase in visceral (intra-abdominal) compared to subcutaneous fat. Recent studies in which adipose tissue of insulin-sensitive and insulin-resistant patients with severe obesity were compared indicate that the insulin-resistant group is also distinguished by increases in oxidative stress and decreases in AMP-activated protein kinase (AMPK) activity. In contrast, changes in the expression of genes for SIRT1, inflammatory cytokines, mitochondrial biogenesis and function, and the two α-isoforms of AMPK showed more depot variation. Studies of how these and other changes in adipose tissue respond to bariatric surgery are still in their infancy.
Available data suggest that increases in oxidative stress, decreases in AMPK activity and SIRT1 gene expression, depot-specific changes in inflammatory, mitochondrial and other genes distinguish adipose tissue of insulin resistant from insulin-sensitive individuals with severe obesity.
AMP-activated protein kinase; inflammation; insulin resistance; oxidative stress; SIRT1
Purpose of review
To discuss recent findings on the role and regulation of macrophage polarization in obesity and atherosclerosis.
Macrophages infiltrate the vascular wall during atherosclerosis and adipose tissue during obesity. At least two distinct sub-populations with different functions, the classically (M1) and the alternatively (M2) activated macrophages, have been found in these tissues. Reciprocal skewing of macrophage polarization between the M1 and M2 states is a process modulated by diet, humoral and transcription factors, such as the nuclear receptor Peroxisome Proliferator-Activated Receptor gamma (PPARγ).
Recent literature highlights the importance not only of the number of infiltrated macrophages, but also their activation in the maintenance of the inflammation state. Identifying mechanisms and molecules able to modify the balance between M1 and M2 represents a promising field of research.
Adipose Tissue; immunology; Animals; Humans; Inflammation; immunology; Macrophages; cytology; metabolism; Metabolic Diseases; immunology; macrophages; obesity; atherosclerosis; nuclear receptors
Review aberrations of insulin signaling to atypical protein kinase C (aPKC) in muscle and liver that generate cardiovascular risk factors, including, obesity, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in type 2 diabetes mellitus (T2DM), and obesity-associated metabolic syndrome (MetSyn).
aPKC and/or Akt mediate insulin effects on glucose transport in muscle, and synthesis of lipids, cytokines and glucose in liver. In T2DM, whereas Akt and aPKC activation are diminished in muscle, and hepatic Akt activation is diminished, hepatic aPKC activation is conserved. Imbalance between muscle and hepatic aPKC activation (and expression of PKC-ι in humans) by insulin results from differential downregulation of insulin receptor substrates that control phosphatidylinositol 3-kinase. Conserved activation of hepatic aPKC in hyperinsulinemic states of T2DM, obesity and MetSyn is problematic as excessive activation of aPKC-dependent lipogenic, gluconeogenic and proinflammatory pathways increases cardiovascular risk factors. Indeed, selective inhibition of hepatic aPKC by adenoviral-mediated expression of kinase-inactive aPKC, or newly-developed small-molecule biochemicals, dramatically improves abdominal obesity, hepatosteatosis, hypertriglyceridemia, hypercholesterolemia, insulin resistance and glucose intolerance in murine models of obesity and T2DM.
Hepatic aPKC is a unifying target for treating multiple clinical abnormalities that increase cardiovascular risk in insulin-resistant states of obesity, MetSyn and T2DM.
Atypical Protein Kinase C; Obesity; Metabolic Syndrome; Type 2 Diabetes Mellitus; Insulin Signaling in Liver and Muscle
Purpose of Review
The regulatory lipids are a class of bioactive lipids which regulate various important biological processes. Profiling these regulatory lipids is an attractive method to understand the role of these metabolites. This is especially true since most of these regulatory lipids are derived from several important pharmacological targets: cyclooxygenase (COX), lipoxygenase (LOX), and cytochrome P450 enzymes. This review highlights the development of methods to profile these regulatory lipids and the recent publications employing these profiling methods.
The recent development of methods for the profiling of regulatory lipids target two different directions: to expand coverage for discovery studies (fingerprinting) and to make the quantitative method more accurate, sensitive, and faster for diagnostic or more detailed studies. Recent applications of these profiling methods including assessment of in vivo drug engagement, pathways crosstalk, and possible mechanisms for side effects of a withdrawn anti-inflammatory drug-Rofecoxib are also reviewed here.
The profiling of regulatory lipids is a useful tool for many investigations. The breadth of coverage, throughput limits with detection, and reproducibility of quantitation are being improved. The resulting data will assist with fundamental investigation, disease biomarker discovery, drug discovery and drug development.
Regulatory lipids; profiling; Lipidomics; oxylipins; eicosanoids
Purpose of review
We summarize recent progress on GPIHBP1, a molecule that transports lipoprotein lipase (LPL) to the capillary lumen, and discuss several newly studied molecules that appear important for the regulation of LPL activity.
LPL, the enzyme responsible for the lipolytic processing of triglyceride-rich lipoproteins, interacts with multiple proteins and is regulated at multiple levels. Several regulators of LPL activity have been known for years and have been investigated thoroughly, but several have been identified only recently, including an endothelial cell protein that transports LPL to the capillary lumen, a microRNA that reduces LPL transcript levels, a sorting protein that targets LPL for uptake and degradation, and a transcription factor that increases the expression of apolipoproteins that regulate LPL activity.
Proper regulation of LPL is important for controlling the delivery of lipid nutrients to tissues. Recent studies have identified GPIHBP1 as the molecule that transports LPL to the capillary lumen, and have also identified other molecules that are potentially important for regulating LPL activity. These new discoveries open new doors for understanding basic mechanisms of lipolysis and hyperlipidemia.
diabetes mellitus; gene regulation; lipoproteins; triglyceride metabolism
Purpose of Review
In December of 2003, two seminal articles describing the presence of macrophages in obese adipose tissue (AT) were published. These AT macrophages (ATMs) are inflammatory and promote local and systemic insulin resistance. Due to the continuing rise in obesity around the world, understanding how these ATMs contribute to metabolic disorders is of much interest.
Chemokines have been extensively studied for their role in ATM recruitment. Deficiency or antagonism of chemokine receptors that interact with multiple chemokine ligands reduces ATM accumulation. ATMs are now defined as either classically (M1) or alternatively (M2) activated. PPAR activation and adiponectin promote an M2 polarized state resulting in improved insulin sensitivity. Finally, recent studies have provided evidence that T lymphocytes, NKT cells, mast cells, and B cells also enter AT and may interact with macrophages and adipocytes.
Literature published during the past year has shown that macrophage recruitment to AT is only one of the important mediators of obesity-related insulin resistance. The phenotype of ATMs and recruitment of other immune cells to the AT play key roles in the overall contribution of AT to systemic metabolic outcomes of obesity.
macrophages; chemokines; T lymphocytes; polarization; PPAR
Purpose of review
Comparative genomics allows researchers to combine genome wide association data from humans with studies in animal models in order to assist in the identification of the genes and the genetic variants that modify susceptibility to dyslipidemia and atherosclerosis.
Association and linkage studies in human and rodent species have been successful in identifying genetic loci associated with complex traits, but have been less robust in identifying and validating the responsible gene and/or genetic variants. Recent technological advancements have assisted in the development of comparative genomic approaches, which rely on the combination of human and rodent datasets and bioinformatics tools, followed by the narrowing of concordant loci and improved identification of candidate genes and genetic variants. Additionally, candidate genes and genetic variants identified by these methods have been further validated and functionally investigated in animal models, a process that is not feasible in humans.
Comparative genomic approaches have lead to the identification and validation of several new genes, including a few not previously implicated, as modifiers of plasma lipid levels and atherosclerosis, yielding new insights into the biological mechanisms of these complex traits.
comparative genomics; cross-species QTLs; cross-species eQTLs; dyslipidemia; atherosclerosis
Purpose of review
This review summarizes the recent data on the ‘Autoimmune Concept of Atherosclerosis’, according to which the first stage of this disease is due to an autoimmune reaction against arterial endothelial cells expressing heat shock protein 60 (HSP60) and adhesion molecules when stressed by classical atherosclerosis risk factors. Special emphasis is put on oxidized low-density lipoproteins as early endothelial stressors.
Plasma cholesterol and LDL levels considered ‘normal’ by the medical community are possibly too high from an evolutionary viewpoint. The proinflammatory milieu at sites of early atherosclerotic lesions could be conducive to oxidation of LDL in situ. LDL oxidation can also take place at nonvascular sites or in the circulation under general proinflammatory conditions explaining its proatherosclerotic role in ‘normocholesterolemic’ individuals.
We hypothesize that the plasma cholesterol and LDL levels currently considered normal are evolutionarily too high. Cholesterol and/or oxidized low-density lipoprotein, even as a mild HSP60-inducing endothelial stressor, function as a ubiquitous risk factor. If this hypothesis is true, most members of developed societies might be at risk to develop atherosclerotic plaques at anti-HSP60-immunity-triggered intimal inflammatory foci, irrespective of the primary risk-factor(s).
atherosclerosis; cholesterol; classical atherosclerosis risk factors; heat shock protein; oxidized low-density lipoprotein; vascular-associated dendritic cells
Purpose of review
HDL is a cardioprotective lipoprotein, at least in part, because of its ability to mediate reverse cholesterol transport (RCT). It is becoming increasingly clear that the antiatherogenic effects of HDL are not only dependent on its concentration in circulating blood but also on its biological ‘quality’. This review summarizes our current understanding of how the biological activities of individual subclasses of HDL particles contribute to overall HDL performance in RCT.
Recent work indicates that apolipoprotein A-I-containing nascent HDL particles are heterogeneous and that such particles exert different effects on the RCT pathway. RCT from macrophages has been examined in detail in mice and the roles of plasma factors (lecithin-cholesterol acyltransferase, cholesterol ester transfer protein, phospholipid transfer protein) and cell factors (ATP-binding cassette transporter A1, ATP-binding cassette transporter G1, scavenger receptor class B type 1) have been evaluated. Manipulation of such factors has consistent effects on RCT and atherosclerosis, but the level of plasma HDL does not reliably predict the degree of RCT. Furthermore, HDL cholesterol or apolipoprotein A-I levels do not necessarily correlate with the magnitude of cholesterol efflux from macrophages; more understanding of the contributions of specific HDL subspecies is required.
The antiatherogenic quality of HDL is defined by the functionality of HDL subspecies. In the case of RCT, the rate of cholesterol movement through the pathway is critical and the contributions of particular types of HDL particles to this process are becoming better defined.
apolipoprotein A-I; atherosclerosis; cholesterol efflux; HDL; reverse cholesterol transport