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
Purpose of review
Although the role for microRNAs (miRNAs) in regulating multiple physiological processes including apoptosis, cell differentiation, and cancer is well established, the importance of these tiny RNAs in regulating lipid metabolism has only recently been uncovered. This review summarizes the evidence for a critical role of miRNAs in regulating lipid metabolism.
Lipid metabolism is tightly regulated at the cellular level. In addition to classic transcriptional regulation of cholesterol metabolism (e.g. by SREBP and LXR), members of a class of noncoding RNAs termed miRNAs have now been identified to be potent post-transcriptional regulators of lipid metabolism genes involved in cholesterol homeostasis and fatty acid oxidation. Several reports have recently shown that miR-33 regulates cholesterol efflux and HDL biogenesis by downregulating the expression of the ABC transporters, ABCA1 and ABCG1. In addition, miR-33 also inhibits the translation of several transcripts encoding proteins involved in fatty acid β-oxidation including CPT1a, CROT, and HADHB, thereby reducing fatty acid degradation. Other miRNAs including miR-122, miR-370, miR-335, and miR-378/378*, miR-27 and miR-125a-5p have been implicated in regulating cholesterol homeostasis, fatty acid metabolism and lipogenesis.
Recent advances in the understanding of the regulation of lipid metabolism indicate that miRNAs play major roles in regulating cholesterol and fatty acid metabolism. These new findings may open new avenues for the treatment of dyslipidemias.
cholesterol homeostasis; HDL; microRNAs
Purpose of review
The metabolic syndrome has become a leading health concern in developed countries. In the search for strategies to combat this growing problem, stearoyl-CoA desaturase 1 (SCD1) inhibition has been proposed as an attractive therapeutic strategy. However, recent studies warn of potentially harmful consequences of SCD1 inhibition. The purpose of this review is to discuss recent insights into the potential for SCD1 inhibitors as viable metabolic syndrome therapeutics.
SCD1 converts saturated fatty acids (SFAs) to monounsaturated fatty acids (MUFAs). Although SCD1 inhibition protects against diet-induced obesity, hepatic steatosis, and insulin resistance, recent studies have demonstrated that the accumulation of SCD1 substrates (SFA) can promote inflammation, atherosclerosis, steatohepatitis, and pancreatic beta cell dysfunction in preclinical rodent models. This suggests SCD1 may play a critical role in suppressing inflammatory diseases by shuttling proinflammatory SFAs into less biologically active MUFA-enriched neutral lipids. Given this, SCD1 inhibitors given in conjunction with anti-inflammatory agents may provide a useful strategy to prevent the metabolic syndrome without deleterious side-effects seen with SCD1 inhibition alone.
SCD1 inhibitors continue to hold promise as metabolic syndrome therapeutics; yet consideration must be taken to avoid the proinflammatory side-effects secondary to accumulation SCD1 substrates (SFAs).
inflammation; metabolic syndrome; saturated fatty acids; stearoyl-CoA desaturase
Purpose of review
Dietary saturated fatty acids (SFAs) have been implicated in promoting the metabolic syndrome and atherosclerotic cardiovascular disease. Recent evidence suggests that SFAs promote the metabolic syndrome by activating Toll-like receptor 4 (TLR4). Here we examine emerging molecular evidence that SFAs directly engage pathways of innate immunity, thereby promoting inflammatory aspects of the metabolic syndrome.
Accumulation of SFA in the body is tightly regulated by stearoyl-CoA desaturase 1, an enzyme that converts endogenous SFA to monounsaturated fatty acids. Recent studies have demonstrated that the accumulation of SFA seen with genetic deletion or inhibition stearoyl-CoA desaturase 1 promotes inflammation, TLR4 hypersensitivity, and accelerated atherosclerosis. Therefore, stearoyl-CoA desaturase 1 may play an unexpected role in suppressing inflammation by preventing excessive accumulation of endogenous SFA-derived TLR4 agonists. In parallel, several independent laboratories have demonstrated that TLR4 is necessary for dietary SFAs to induce obesity, insulin resistance, and vascular inflammation in rodent models.
The metabolic syndrome and atherosclerotic cardiovascular disease have long been linked to dietary SFA intake and inflammation. Recent mechanistic insights into how SFAs and downstream metabolites can potentiate inflammation-driven metabolic disease are discussed here.
atherosclerosis; insulin resistance; obesity; polyunsaturated fatty acids; saturated fatty acids; Toll-like receptor 4
Purpose of review
The purpose of this review is to summarize recent advances in investigations of interactions between established genetic and dietary risk factors for type 2 diabetes (T2D).
Several studies reported that dietary factors related with carbohydrate quality and quantity, such as whole grains and glycemic load, might interact with TCF7L2 variants in relation to T2D risk. The genetic predisposition defined by the combination of ten established T2D risk alleles was found to modulate the association between Western dietary pattern (high intakes of red meat, processed meat, and low fiber) and T2D; a stronger association was observed in those with high-risk genetic profile. Variants in genes HHEX, CDKN2A/2B, JAZF1, and IGF2BP2 were found to interact with prenatal nutrition in relation to T2D risk and glucose levels in later life.
The available data provide preliminary support for the gene-diet interactions in determining T2D. However, most findings have yet to be validated. Future studies will need agreed standards of study design and statistical power, dietary measurement, analytical methods, and replication strategies.
gene; diet; interaction; diabetes
Purpose of review
To review the recent studies on intensive glucose control and the risk of cardiovascular disease (CVD) in type 2 diabetes, to discuss potential reasons for discordant results among recent trials, and to comment on implications for clinical practice.
Three large randomized controlled trials on the effect of tight glycemic control (TGC) on CVD in patients with type 2 diabetes have been published within the last year, along with the cardiovascular outcomes from the long-term follow-up of the UKPDS study. This narrative review of the methods and results of these trials reveals cardiovascular benefit from early institution of TGC, and lack of benefit or potential harm with intensification of glucose control late in the course of type 2 diabetes or after CVD has developed. Also, the benefits of TGC may be outweighed by weight gain and hypoglycemia. All trials had fewer cardiovascular events than anticipated due to improvements in other cardiovascular risk factors.
In addition to controlling cardiovascular risk factors, patients with type diabetes should aim for good glycemic control (HbA1c<7%) soon after the diagnosis of diabetes to prevent macrovascular as well as microvascular complications. Glycemic targets should be individualized as diabetes progresses, comorbidities develop, and to avoid having the side effects of therapy (hypoglycemia and weight gain) predominate.
Diabetes mellitus; cardiovascular disease; glucose control
Purpose of review
Despite that statin treatment substantially reduces cardiovascular morbidity and mortality, many treated patients still experience a high residual risk. Statins lower LDL-cholesterol (LDL-C), with limited effects on other lipid parameters. Fibrates improve atherogenic dyslipidemia characterized by high triglyceride and/or low HDL-C levels and elevated concentrations of small dense LDL particles, with or without high LDL-C levels. Fibrates decrease cardiovascular morbidity especially in patients with the metabolic syndrome. The purpose of this review is to provide a rationale for the combined use of statins and fibrates in the management of patients with high residual cardiovascular risk related to atherogenic dyslipidemia and persisting after single therapy.
A meta-analysis from 14 randomised trials conducted in high-risk patients reported that statin therapy is effective in reducing the proportional risk for major vascular events by 21% for each mmol/L lowering of LDL-C. However, on average 14% of patients still experienced an event despite being allocated to statin. Beyond LDL-C, other factors, including triglycerides, non-HDL-C, HDL-C and apolipoprotein B, have been identified as factors determining residual risk, and normalization of these parameters may further decrease cardiovascular disease in patients treated with statins. Data from fibrate trials indicate that these drugs are particularly effective in reducing cardiovascular morbidity in patients with atherogenic dyslipidemia.
Reducing the residual cardiovascular risk in patients treated with statins requires addressing multiple lipid goals. In this context, future therapeutic interventions based on combination therapy, such as statins and fibrates, appears particularly promising.
Antilipemic Agents; therapeutic use; Cardiovascular Diseases; blood; drug therapy; Cholesterol, LDL; blood; Clofibric Acid; therapeutic use; Drug Therapy, Combination; Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; therapeutic use; Meta-Analysis as Topic; Randomized Controlled Trials as Topic; Treatment Outcome; Cardiovascular risk factors; Residual risk; Statins; Fibrates; Dyslipoproteinemia
Purpose of review
This review summarizes recent research implicating Forkhead box (Fox)O1, a key transcription factor in glucose metabolism, in the regulation of hepatic lipid metabolism. Insulin dysregulation leading to hypertriglyceridemia is associated with increased hepatic VLDL secretion. FoxO1 is integrated in action with other regulatory factors in VLDL metabolism. The role of FoxO1 is defined in context of recent controversies.
FoxO1 regulates transcription of microsomal triglyceride transfer protein and apolipoprotein (apo)CIII involved in hepatic assembly and postsecretory catabolism of VLDL. Insulin activation of Akt leads to the phosphorylation of FoxO1 with nuclear exclusion and loss of transcriptional activity. Reduced insulin action increases FoxO1 activity and induces microsomal triglyceride transfer protein favoring VLDL assembly and induces apoCIII reducing peripheral triglyceride catabolism. This new mechanistic link between insulin resistance and VLDL overproduction and hypertriglyceridemia compounds effects of other known VLDL regulatory factors.
This review highlights recent advances in research of insulin regulation of hepatic VLDL metabolism. Formation of VLDL requires lipid, apoB structural protein, and microsomal triglyceride transfer protein. FoxO1 is a major factor in hepatic microsomal triglyceride ransfer protein regulation. A unifying hypothesis is presented linking regulation of the three necessary hepatic components for VLDL assembly with insulin action and insulin resistance.
Akt; apoB; forkhead transcription factor; FoxO; lipoproteins; microsomal triglyceride transfer protein; very low-density lipoprotein
Purpose of review
Low-grade inflammation is characteristic of the metabolic syndrome (MetS). C-reactive protein (CRP), the best characterized biomarker of inflammation, is also an independent predictor of future cardiovascular events. The purpose of this review is to outline the role of inflammation and high sensitivity CRP in the MetS.
Emerging laboratory and epidemiological data now link inflammation and high sensitivity CRP to insulin resistance and adiposity and other features of MetS. Furthermore, in large prospective studies, increased high sensitivity CRP levels in MetS confer greater cardiovascular risk. CRP has been shown to impair insulin signaling and contributes to atherothrombosis.
Thus, although a high CRP level predisposes to increased cardiovascular risk in MetS, future investigation is warranted on the in-vivo role of CRP in mediating vascular effects and resulting in increased cardiovascular events in MetS patients.
C-reactive protein; inflammation; metabolic syndrome; vascular cells
Purpose of review
This review summarizes recent data indicating that glycosylphosphatidylinositol-anchored high density lipoprotein–binding protein 1 (GPIHBP1) plays a key role in the lipolytic processing of chylomicrons.
Lipoprotein lipase (LpL) hydrolyzes triglycerides in chylomicrons at the luminal surface of the capillaries in heart, adipose tissue, and skeletal muscle. However, the endothelial cell molecule that facilitates the lipolytic processing of chylomicrons has never been clearly defined. Mice lacking GPIHBP1 manifest chylomicronemia, with plasma triglyceride levels as high as 5,000 mg/dl. In wild-type mice, GPIHBP1 is expressed on the luminal surface of capillaries in heart, adipose tissue, and skeletal muscle. Cells transfected with GPIHBP1 bind both chylomicrons and LpL avidly.
The chylomicronemia in Gpihbp1-deficient mice, the fact that GPIHBP1 is located within the lumen of capillaries, and the fact that GPIHBP1 binds LpL and chylomicrons suggest that GPIHBP1 is a key platform for the lipolytic processing of triglyceride-rich lipoproteins.
Chylomicronemia; lipoprotein lipase; hypertriglyceridemia; GPI-anchored proteins
Purpose of review
Over the last few years ApoE receptors, also known as LDL receptor related proteins, have distinguished themselves as functionally diverse signaling receptors with pivotal roles not only in the vascular system, but also in the nervous system and during development.
The expanding roles of ApoE receptors for cellular signal transduction at the same time transcend and integrate their lipid transport roles into a larger biological and clinical context. ApoE receptors are essential for the development of the nervous system, the regulation of synaptic plasticity, neuroprotection, and the innervation of the muscle. They also regulate the metabolism of the amyloid precursor protein on multiple levels, implicating them in the pathogenesis of Alzheimer's disease (AD).
ApoE, a common ligand for all members of the evolutionarily ancient LDL receptor gene family, is the major genetic modifier of the age of onset of Alzheimer's disease. The underlying molecular mechansims remain shrouded in mystery, but the numerous critical functions of ApoE receptors within and outside the nervous system that have recently emerged make it likely that these multifunctional signal modulators participate in AD pathogenesis. This review attempts to summarize the most recent and relevant findings in this area.
LDL receptor family; dementia; synaptic plasticity; neuronal survival