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1.  [No title available] 
PMCID: PMC3947892  PMID: 24366230
2.  [No title available] 
PMCID: PMC4018574  PMID: 24362355
3.  Adverse metabolic effects of dietary fructose: Results from recent epidemiological, clinical, and mechanistic studies 
Current opinion in lipidology  2013;24(3):198-206.
Purpose of review
The effects of dietary sugar on risk factors and processes associated with metabolic disease remains a controversial topic, with recent reviews of the available evidence arriving at widely discrepant conclusions.
Recent findings
There are many recently published epidemiological studies that provide evidence that sugar consumption is associated with metabolic disease. Three recent clinical studies, which investigated the effects of consuming relevant doses of sucrose or high fructose corn syrup along with ad libitum diets, provide evidence that consumption of these sugars increase risk factors for cardiovascular disease (CVD) and metabolic syndrome. Mechanistic studies suggest that these effects result from the rapid hepatic metabolism of fructose catalyzed by fructokinase C, which generates substrate for de novo lipogenesis and leads to increased uric acid levels. Recent clinical studies investigating the effects of consuming less sugar, via educational interventions or by substitution of sugar-sweetened beverages for non-calorically sweetened beverages, provide evidence that such strategies have beneficial effects on risk factors for metabolic disease or on BMI in children.
The accumulating epidemiological evidence, direct clinical evidence, and the evidence suggesting plausible mechanisms support a role for sugar in the epidemics of metabolic syndrome, CVD and type 2 diabetes.
PMCID: PMC4251462  PMID: 23594708
Fructose; sucrose; high fructose corn syrup; sugar; metabolic disease
4.  Estrogens and Cardiovascular Disease Risk Revisited: the Women’s Health Initiative 
Current opinion in lipidology  2013;24(6):493-499.
Purpose of Review
In 2002 and 2004, the Women’s Health Initiative (WHI) found no evidence that hormone therapy (HT) with estrogen or estrogen with progestin (E+P) protected against cardiovascular disease (CVD). Since then, further analyses have been performed. This review summarizes current analyses on the effects of HT on CVD and CVD risk factors.
Recent Findings
The negative effects of HT vary by type of CVD event. Estrogen alone and E+P show consistent effects on CVD, but E+P has more impact on coronary heart disease (CHD) and venous thromboembolism (VTE). Women of all ethnicities, including those who are obese, have diabetes, or are taking daily aspirin or statins remain at risk for adverse effects from HT. While younger women or more recently menopausal women taking HT may be at relatively lower risk for CHD and myocardial infarction, they remain at risk for stroke, VTE, and peripheral artery disease. Adverse effects are enhanced in older women with menopausal symptoms. While HT lowers low-density lipoprotein cholesterol (LDL-C) and Lipoprotein (a) and raises high-density lipoprotein cholesterol, it has adverse effects on triglyceride, lipoprotein composition, and inflammatory and hemostatic markers. Baseline metabolic syndrome and high LDL-C increase the CHD risk with HT. Analyses of discontinuation data in the estrogen-alone and E+P trials suggest that the adverse effects of HT on CVD are reversible.
Recent analyses do not justify postmenopausal HT for CVD prevention. Further research on the role of HT-induced changes in CVD risk factors along with genetic studies may increase understanding and aid in developing safer therapies for menopausal symptoms.
PMCID: PMC4219554  PMID: 24184944
Cardiovascular disease; hormone therapy; CVD risk factors; Women’s Health Initiative
5.  Role of stearoyl-coenzyme A desaturase in regulating lipid metabolism 
Current opinion in lipidology  2008;19(3):248-256.
Purpose of review
Stearoyl-coenzyme A desaturase 1 is a δ-9 fatty acid desaturase that catalyzes the synthesis of monounsaturated fatty acids and has emerged as a key regulator of metabolism. This review evaluates the latest advances in our understanding of the pivotal role of stearoyl-coenzyme A desaturase 1 in health and disease.
Recent findings
scd1-deficient mice have reduced lipid synthesis and enhanced lipid oxidation, thermogenesis and insulin sensitivity in various tissues including liver, muscle and adipose tissue due to transcriptional and posttranscriptional effects. These metabolic changes protect scd1-deficient mice from a variety of dietary, pharmacological and genetic conditions that promote obesity, insulin resistance and hepatic steatosis. Stearoylcoenzyme A desaturase 1 is required to guard against dietary unsaturated fat deficiency, leptin deficiency-induced diabetes, and palmitate-induced lipotoxic insults in muscle and pancreatic β-cells. Paradoxical observations of increased muscle stearoyl-coenzyme A desaturase 1 during obesity, starvation and exercise raise questions as to the role of stearoyl-coenzyme A desaturase 1 in this tissue. Mice with a liver-specific loss of stearoyl-coenzyme A desaturase 1, and inhibition of stearoyl-coenzyme A desaturase 1 via antisense or RNA interference, recapitulate only a subset of the phenotypes observed in global Scd1 deficiency, indicating the involvement of multiple tissues.
Recent studies in humans and animal models have highlighted that modulation of stearoyl-coenzyme A desaturase 1 activity by dietary intervention or genetic manipulation strongly influences several facets of energy metabolism to affect susceptibility to obesity, insulin resistance, diabetes and hyperlipidemia.
PMCID: PMC4201499  PMID: 18460915
diabetes; insulin resistance; obesity; oleate; stearoyl-CoA desaturase
6.  Thrombospondins: Old Players, New Games 
Current opinion in lipidology  2013;24(5):401-409.
Purpose of review
Thrombospondins (TSPs) are secreted extracellular matrix (ECM) proteins from TSP family, which consists of five homologous members. They share a complex domain structure and have numerous binding partners in ECM and multiple cell surface receptors. Information that has emerged over the last decade identifies TSPs as important mediators of cellular homeostasis, assigning new important roles in cardiovascular pathology to these proteins.
Recent findings
Recent studies of the functions of TSP in the cardiovascular system, diabetes and aging, which placed several TSPs in a position of critical regulators, demonstrated the involvement of these proteins in practically every aspect of cardiovascular pathophysiology related to atherosclerosis: inflammation, immunity, leukocyte recruitment and function, function of vascular cells, angiogenesis, and responses to hypoxia, ischemia and hyperglycemia. TSPs are also critically important in the development and ultimate outcome of the complications associated with atherosclerosis – myocardial infarction and heart hypertrophy and failure. Their expression and significance increase with age and with the progression of diabetes, two major contributors to the development of atherosclerosis and its complications.
This overview of recent literature examines the latest information on the newfound functions of TSPs that emphasize the importance of ECM in cardiovascular homeostasis and pathology. The functions of TSPs in myocardium, vasculature, vascular complications of diabetes, aging and immunity are discussed.
PMCID: PMC3935726  PMID: 23892609
thrombospondin; extracellular matrix; cardiovascular system
7.  Receptor-independent fluid-phase pinocytosis mechanisms for induction of foam cell formation with native LDL particles 
Current opinion in lipidology  2011;22(5):386-393.
Purpose of review
Because early findings indicated that native low density lipoprotein (LDL) did not substantially increase macrophage cholesterol content during in vitro incubations, investigators presumed that LDL must be modified in some way to trigger its uptake by the macrophage. The purpose of this review is to discuss recent findings showing that native unmodified LDL can induce massive macrophage cholesterol accumulation mimicking macrophage foam cell formation that occurs within atherosclerotic plaques.
Recent findings
Macrophages that show high rates of fluid-phase pinocytosis also show similar high rates of uptake of native unmodified LDL through non-receptor mediated uptake within both macropinosomes and micropinosomes. Non-saturable fluid-phase uptake of LDL by macrophages converts the macrophages into foam cells. Different macrophage phenotypes demonstrate either constitutive fluid-phase pinocytosis or inducible fluid-phase pinocytosis. Fluid-phase pinocytosis has been demonstrated by macrophages within mouse atherosclerotic plaques indicating that this pathway contributes to plaque macrophage cholesterol accumulation.
Contrary to what has been believed previously, macrophages can take up large amounts of native unmodified LDL by receptor-independent, fluid-phase pinocytosis converting these macrophages into foam cells. Thus, targeting macrophage fluid-phase pinocytosis should be considered when investigating strategies to limit macrophage cholesterol accumulation in atherosclerotic plaques.
PMCID: PMC4174540  PMID: 21881499
LDL; macrophages; fluid-phase pinocytosis; cholesterol; macropinocytosis
8.  Comparative gene identification-58/α/β hydrolase domain 5: more than just an adipose triglyceride lipase activator? 
Current opinion in lipidology  2014;25(2):102-109.
Purpose of review
Comparative gene identification-58 (CGI-58) is a lipid droplet-associated protein that controls intracellular triglyceride levels by its ability to activate adipose triglyceride lipase (ATGL). Additionally, CGI-58 was described to exhibit lysophosphatidic acid acyl transferase (LPAAT) activity. This review focuses on the significance of CGI-58 in energy metabolism in adipose and nonadipose tissue.
Recent findings
Recent studies with transgenic and CGI-58-deficient mouse strains underscored the importance of CGI-58 as a regulator of intracellular energy homeostasis by modulating ATGL-driven triglyceride hydrolysis. In accordance with this function, mice and humans that lack CGI-58 accumulate triglyceride in multiple tissues. Additionally, CGI-58-deficient mice develop an ATGL-independent severe skin barrier defect and die soon after birth. Although the premature death prevented a phenotypical characterization of adult global CGI-58 knockout mice, the characterization of mice with tissue-specific CGI-58 deficiency revealed new insights into its role in neutral lipid and energy metabolism. Concerning the ATGL-independent function of CGI-58, a recently identified LPAAT activity for CGI-58 was shown to be involved in the generation of signaling molecules regulating inflammatory processes and insulin action.
Although the function of CGI-58 in the catabolism of cellular triglyceride depots via ATGL is well established, further studies are required to consolidate the function of CGI-58 as LPAAT and to clarify the involvement of CGI-58 in the metabolism of skin lipids.
PMCID: PMC4170181  PMID: 24565921
cardiomyopathy; hepatosteatosis; ichthyosis; lipid signaling; lipolysis
9.  Fructose consumption: potential mechanisms for its effects to increase visceral adiposity and induce dyslipidemia and insulin resistance 
Current opinion in lipidology  2008;19(1):16-24.
Purpose of review
Based on interim results from an ongoing study, we have reported that consumption of a high-fructose diet, but not a high-glucose diet, promotes the development of three of the pathological characteristics associated with metabolic syndrome: visceral adiposity, dyslipidemia, and insulin resistance. From these results and a review of the current literature, we present two potential sequences of events by which fructose consumption may contribute to metabolic syndrome.
Recent findings
The earliest metabolic perturbation resulting from fructose consumption is postprandial hypertriglyceridemia, which may increase visceral adipose deposition. Visceral adiposity contributes to hepatic triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance by increasing the portal delivery of free fatty acids to the liver. With insulin resistance, VLDL production is upregulated and this, along with systemic free fatty acids, increase lipid delivery to muscle. It is also possible that fructose initiates hepatic insulin resistance independently of visceral adiposity and free fatty acid delivery. By providing substrate for hepatic lipogenesis, fructose may result in a direct lipid overload that leads to triglyceride accumulation, novel protein kinase C activation, and hepatic insulin resistance.
Our investigation and future studies of the effects of fructose consumption may help to clarify the sequence of events leading to development of metabolic syndrome.
PMCID: PMC4151171  PMID: 18196982
dyslipidemia; free fatty acids; fructose consumption; hepatic steatosis; insulin resistance; metabolic syndrome
10.  Parkin in the regulation of fat uptake and mitochondrial biology emerging links in the pathophysiology of Parkinson’s Disease 
Current opinion in lipidology  2012;23(3):201-205.
Purpose of review
Perturbations in fatty acid levels and in regulatory proteins linked to fat and mitochondrial homeostasis are associated with modifying the risk of Parkinson Disease (PD). Findings, that are not surprising, based on the high fat content of the brain, the myriad of neurological functions dependent on polyunsaturated fatty acids and the role of mitochondria in energy supply and stress amelioration. Nevertheless, dissecting out the molecular links between lipid biology, mitochondrial regulation and PD is complicated by the divergent etiologies underpinning PD pathophysiology. Here, we summarize aspects of fatty acid biology relevant to PD; the known links between the modulation of fat and PD; and introduce mechanisms whereby the E3-ubiquitin ligase, Parkin know to be mutated as a genetic predisposing factor in PD, modulates fat uptake and mitochondrial control.
Recent Findings
Prior evidence supports that Parkin, under mitochondrial stress conditions, plays a pivotal role in the mitophagy mitochondrial housekeeping program. Recent evidence now demonstrates a broader role of Parkin in controlling fat uptake and mitochondrial regulatory programs.
The identification that Parkin has a multifunctional role in modulating cellular fatty acid uptake and mitochondrial biology further strengthens the pathophysiologic link between fat metabolism, mitochondria, and Parkinson Disease.
PMCID: PMC4151552  PMID: 22488424
Parkin; CD36; fat uptake; PGC-1α
11.  Omega-3 fatty acids: mechanisms underlying “protective effects” in atherosclerosis 
Current opinion in lipidology  2013;24(4):345-350.
Purpose of review
This article provides an updated review on mechanistic and molecular studies relating to the effects of n-3 fatty acids (FA) on inhibiting atherogenesis.
Recent findings
The effects of n-3 FA on modulating arterial lipoprotein lipase (LpL) levels link to changes in lipid deposition in the arterial wall. LpL expression in the arterial wall also relates to local macrophage-mediated inflammatory processes. Increasing evidence suggests that n-3 FA ameliorate inflammation, another key component in the development of atherosclerosis, including decreases in pro-inflammatory cytokine production. n-3 FA inhibit atherogenic signaling pathways and modulate the phenotypes of inflammatory leukocytes and their recruitment in the arterial wall.
New mechanistic insights into the anti-atherogenic action of n-3 FA have emerged. These studies may contribute to future therapeutic advances in preventing mortality and morbidity associated with atherosclerosis.
PMCID: PMC3918949  PMID: 23594712
Atherosclerosis; inflammation; lipoprotein lipase; macrophages; n-3 fatty acids
12.  New developments in selective cholesteryl ester uptake 
Current opinion in lipidology  2013;24(5):386-392.
Purpose of review
Selective lipid uptake (SLU) is known to be a major pathway of lipoprotein cholesterol metabolism in experimental animals and humans, but remains poorly understood. This review provides a brief overview of SLU mediated by the HDL receptor scavenger receptor B-type I (SR-BI), and highlights several surprising new findings related to the impact of SLU pathways in cholesterol homeostasis.
Recent findings
Under certain conditions, SR-BI-mediated SLU contributes to reverse cholesterol transport (RCT) independently of ABCG5/G8-mediated biliary cholesterol secretion, implying a novel trafficking mechanism. Hepatic SR-BI expression and RCT are decreased in diabetic mice. Farnesoid X receptor (FXR) and the microRNAs miR-185, miR-96 and miR-223 are emerging therapeutic targets for increasing SR-BI expression. SR-BI-independent selective cholesteryl ester uptake is a newly characterized pathway in macrophage foam cells.
New findings underscore the importance of SR-BI-mediated SLU in hepatic SLU and RCT, while indicating that further investigation is needed to define SLU pathways, including SR-BI-independent macrophage selective cholesteryl ester uptake. The intracellular trafficking of cholesterol in these pathways appears to be critical to their normal function and is a major subject of ongoing studies.
PMCID: PMC4096242  PMID: 23842142
HDL cholesterol; macrophage foam cell; reverse cholesterol transport; scavenger receptor B-type I; selective cholesteryl ester uptake
13.  Oxidation-specific epitopes as targets for biotheranostic applications in humans: Biomarkers, molecular imaging and therapeutics 
Current opinion in lipidology  2013;24(5):426-437.
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.
Recent findings
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.
PMCID: PMC4085330  PMID: 23995232
biotheranostic; oxidation; innate immunity; atherogenesis; molecular imaging
14.  Phospholipase A2 enzymes in metabolic and cardiovascular diseases 
Current opinion in lipidology  2012;23(3):235-240.
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.
Recent findings
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.
PMCID: PMC4062387  PMID: 22327613
Obesity; diabetes; hyperlipidemia; atherosclerosis; inflammation; lysophospholipid
15.  Acyl-coenzyme A synthetases in metabolic control 
Current opinion in lipidology  2010;21(3):212-217.
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 findings
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.
PMCID: PMC4040134  PMID: 20480548
β-oxidation; acyl-CoA synthetase; AMP-activated kinase; fatty acid; fatty acid transport protein; glycerolipid synthesis
16.  Phenotypic modulation of macrophages in response to plaque lipids 
Current opinion in lipidology  2011;22(5):335-342.
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.
Recent findings
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.
PMCID: PMC3979355  PMID: 21841486
Macrophages; oxidized lipids; atherosclerosis; inflammation
17.  Alternative splicing in regulation of cholesterol homeostasis 
Current opinion in lipidology  2013;24(2):147-152.
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.
Recent findings
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.
PMCID: PMC3667406  PMID: 23314925
PTBP1; HMGCR; LDLR; statin; SFRS10
18.  Adaptive genetic variation and heart disease risk 
Current opinion in lipidology  2010;21(2):116-122.
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.
Recent findings
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.
PMCID: PMC3936255  PMID: 20154611
dyslipidemia; gene–environment interaction; obesity; positive selection
19.  Rationale for cholesteryl ester transfer protein inhibition 
Current opinion in lipidology  2012;23(4):372-376.
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.
Recent findings
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.
PMCID: PMC3924318  PMID: 22517614
atherosclerosis; cholesteryl ester transfer protein; inhibitor; lipid metabolism
20.  Lipase Maturation Factor 1 (Lmf1): Structure and Role in Lipase Folding and Assembly 
Current opinion in lipidology  2010;21(3):198-203.
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 findings
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.
PMCID: PMC3924775  PMID: 20224398
Protein folding; endoplasmic reticulum; lipase maturation factor 1; lipoprotein lipase; hepatic lipase; endothelial lipase
21.  The role of fatty acid binding proteins in metabolic syndrome and atherosclerosis 
Current opinion in lipidology  2005;16(5):543-548.
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.
Recent findings
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.
PMCID: PMC3904771  PMID: 16148539
atherosclerosis; fatty acid binding protein; fatty acids; lipomics; macrophage
22.  The roles of PON1 and PON2 in cardiovascular disease and innate immunity 
Current opinion in lipidology  2009;20(4):10.1097/MOL.0b013e32832ca1ee.
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.
Recent findings
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.
PMCID: PMC3869948  PMID: 19474728
Atherosclerosis; high density lipoprotein; paraoxonases; oxidative stress; quorum sensing
23.  Hepatic ABC transporters and triglyceride metabolism 
Current opinion in lipidology  2012;23(3):196-200.
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.
Recent findings
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.
PMCID: PMC3793202  PMID: 22488425
ATP-binding cassette transporter A1; high-density lipoprotein formation; mRNA; Tangier disease; very low-density lipoprotein production
24.  Biliary and Non-Biliary Contributions to Reverse Cholesterol Transport 
Current opinion in lipidology  2012;23(2):85-90.
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).
Recent Findings
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.
PMCID: PMC3711548  PMID: 22262055
cholesterol; lipoprotein; bile; reverse cholesterol transport
25.  Finding genes and variants for lipid levels after genome-wide association analysis 
Current opinion in lipidology  2012;23(2):98-103.
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.
Recent findings
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.
PMCID: PMC3666174  PMID: 22418572
genome-wide association study; lipids; cholesterol; next-generation sequencing

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