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1.  HDL-transferred microRNA-223 regulates ICAM-1 expression in endothelial cells 
Nature communications  2014;5:3292.
High-density lipoproteins (HDL) have many biological functions, including reducing endothelial activation and adhesion molecule expression. We recently reported that HDL transport and deliver functional microRNAs (miRNA). Here we show that HDL suppresses expression of intercellular adhesion molecule 1 (ICAM-1) through the transfer of miR-223 to endothelial cells. After incubation of endothelial cells with HDL, mature miR-223 levels are significantly increased in endothelial cells and decreased on HDL. However, miR-223 is not transcribed in endothelial cells and is not increased in cells treated with HDL from miR-223−/− mice. HDL inhibit ICAM-1 protein levels, but not in cells pretreated with miR-223 inhibitors. ICAM-1 is a direct target of HDL-transferred miR-223 and this is the first example of an extracellular miRNA regulating gene expression in cells where it is not transcribed. Collectively, we demonstrate that HDL’s anti-inflammatory properties are conferred, in part, through HDL-miR-223 delivery and translational repression of ICAM-1 in endothelial cells.
PMCID: PMC4189962  PMID: 24576947
2.  High Density Lipoprotein: A Therapeutic Target in Type 2 Diabetes 
Endocrinology and Metabolism  2013;28(3):169-177.
High density lipoproteins (HDLs) have a number of properties that have the potential to inhibit the development of atherosclerosis and thus reduce the risk of having a cardiovascular event. These protective effects of HDLs may be reduced in patients with type 2 diabetes, a condition in which the concentration of HDL cholesterol is frequently low. In addition to their potential cardioprotective properties, HDLs also increase the uptake of glucose by skeletal muscle and stimulate the synthesis and secretion of insulin from pancreatic β cells and may thus have a beneficial effect on glycemic control. This raises the possibility that a low HDL concentration in type 2 diabetes may contribute to a worsening of diabetic control. Thus, there is a double case for targeting HDLs in patients with type 2 diabetes: to reduce cardiovascular risk and also to improve glycemic control. Approaches to raising HDL levels include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. There is an ongoing search for HDL-raising drugs as agents to use in patients with type 2 diabetes in whom the HDL level remains low despite lifestyle interventions.
PMCID: PMC3811694  PMID: 24396675
Lipoproteins, HDL; Diabetes; Atherosclerosis
3.  Genome-wide Linkage and Association Analyses to Identify Genes Influencing Adiponectin Levels: The GEMS Study 
Obesity (Silver Spring, Md.)  2009;17(4):737-744.
Adiponectin has a variety of metabolic effects on obesity, insulin sensitivity, and atherosclerosis. To identify genes influencing variation in plasma adiponectin levels, we performed genome-wide linkage and association scans of adiponectin in two cohorts of subjects recruited in the Genetic Epidemiology of Metabolic Syndrome Study. The genome-wide linkage scan was conducted in families of Turkish and southern European (TSE, n = 789) and Northern and Western European (NWE, N = 2,280) origin. A whole genome association (WGA) analysis (500K Affymetrix platform) was carried out in a set of unrelated NWE subjects consisting of approximately 1,000 subjects with dyslipidemia and 1,000 overweight subjects with normal lipids. Peak evidence for linkage occurred at chromosome 8p23 in NWE subjects (lod = 3.10) and at chromosome 3q28 near ADIPOQ, the adiponectin structural gene, in TSE subjects (lod = 1.70). In the WGA analysis, the single-nucleotide polymorphisms (SNPs) most strongly associated with adiponectin were rs3774261 and rs6773957 (P < 10−7). These two SNPs were in high linkage disequilibrium (r2 = 0.98) and located within ADIPOQ. Interestingly, our fourth strongest region of association (P < 2 × 10−5) was to an SNP within CDH13, whose protein product is a newly identified receptor for high-molecular-weight species of adiponectin. Through WGA analysis, we confirmed previous studies showing SNPs within ADIPOQ to be strongly associated with variation in adiponectin levels and further observed these to have the strongest effects on adiponectin levels throughout the genome. We additionally identified a second gene (CDH13) possibly influencing variation in adiponectin levels. The impact of these SNPs on health and disease has yet to be determined.
PMCID: PMC4028785  PMID: 19165155
4.  The Relationship between Total Bilirubin Levels and Total Mortality in Older Adults: The United States National Health and Nutrition Examination Survey (NHANES) 1999-2004 
PLoS ONE  2014;9(4):e94479.
Due to its anti-oxidant and anti-inflammatory properties, bilirubin has been associated with reduced cardiovascular risk. A recent study demonstrated an L-shaped association of pre-treatment total bilirubin levels with total mortality in a statin-treated cohort. We therefore investigated the association of total bilirubin levels with total mortality in a nationally representative sample of older adults from the general population.
A total of 4,303 participants aged ≥60 years from the United States National Health and Nutrition Examination Survey 1999–2004 with mortality data followed up through December 31, 2006 were included in this analysis, with a mean follow-up period of 4.5 years.
Participants with total bilirubin levels of 0.1–0.4 mg/dl had the highest mortality rate (19.8%). Compared with participants with total bilirubin levels of 0.5–0.7 mg/dl and in a multivariable regression model, a lower total bilirubin level of 0.1–0.4 mg/dl was associated with higher risk of total mortality (hazard ratios, 1.36; 95% confidence interval, 1.07–1.72; P = 0.012), while higher levels (≥0.8 mg/dl) also tended to be associated with higher risk of total mortality, but this did not reach statistical significance (hazard ratios, 1.24; 95% confidence interval, 0.98–1.56; P = 0.072).
In this nationally representative sample of older adults, the association of total bilirubin levels with total mortality was the highest among those with a level between 0.1 and 0.4 mg/dl. Further studies are needed to investigate whether higher total bilirubin levels could be associated with a higher mortality risk, compared to a level of 0.5–0.7 mg/dl.
PMCID: PMC3984185  PMID: 24728477
5.  High density lipoproteins improve insulin sensitivity in high-fat diet-fed mice by suppressing hepatic inflammation[S] 
Journal of Lipid Research  2014;55(3):421-430.
Obesity-induced liver inflammation can drive insulin resistance. HDL has anti-inflammatory properties, so we hypothesized that low levels of HDL would perpetuate inflammatory responses in the liver and that HDL treatment would suppress liver inflammation and insulin resistance. The aim of this study was to investigate the effects of lipid-free apoAI on hepatic inflammation and insulin resistance in mice. We also investigated apoAI as a component of reconstituted HDLs (rHDLs) in hepatocytes to confirm results we observed in vivo. To test our hypothesis, C57BL/6 mice were fed a high-fat diet (HFD) for 16 weeks and administered either saline or lipid-free apoAI. Injections of lipid-free apoAI twice a week for 2 or 4 weeks with lipid-free apoAI resulted in: i) improved insulin sensitivity associated with decreased systemic and hepatic inflammation; ii) suppression of hepatic mRNA expression for key transcriptional regulators of lipogenic gene expression; and iii) suppression of nuclear factor κB (NF-κB) activation. Human hepatoma HuH-7 cells exposed to rHDLs showed suppressed TNFα-induced NF-κB activation, correlating with decreased NF-κB target gene expression. We conclude that apoAI suppresses liver inflammation in HFD mice and improves insulin resistance via a mechanism that involves a downregulation of NF-κB activation.
PMCID: PMC3934727  PMID: 24347528
insulin resistance; apolipoprotein AI; cellular signalling
6.  The Causes and Consequences of Low Levels of High Density Lipoproteins in Patients with Diabetes 
Diabetes & Metabolism Journal  2011;35(2):101-106.
Type 2 diabetes is commonly accompanied by a low level of high density lipoprotein cholesterol (HDL-C) that contributes to the increased cardiovascular risk associated with this condition. Given that HDLs have the ability to improve increase the uptake of glucose by skeletal muscle and to stimulate the secretion of insulin from pancreatic beta cells the possibility arises that a low HDL concentration in type 2 diabetes may also contribute to a worsening of diabetic control. Thus, there is a double case for raising the level of HDL-C in patients with type 2 diabetes: to reduce cardiovascular risk and to improve glycemic control. Approaches to raising HDL-C include lifestyle factors such as weight reduction, increased physical activity and stopping smoking. Of currently available drugs, the most effective is niacin. Newer formulations of niacin are reasonably well tolerated and have the ability to increase HDL-C by up to 30%. The effect of niacin on cardiovascular events in type 2 diabetes is currently being tested in a large-scale clinical outcome trial.
PMCID: PMC3122896  PMID: 21738891
Diabetes mellitus, type 2; High density lipoprotein; Insulin secretion; Insulin resistance; Lifestyle
7.  The apolipoprotein A-I mimetic peptide, ETC-642, reduces chronic vascular inflammation in the rabbit 
High-density lipoproteins (HDL) and their main apolipoprotein, apoA-I, exhibit anti-inflammatory properties. The development of peptides that mimic HDL apolipoproteins offers a promising strategy to reduce inflammatory disease. This study aimed to compare the anti-inflammatory effects of ETC-642, an apoA-I mimetic peptide, with that of discoidal reconstituted HDL (rHDL), consisting of full-length apoA-I complexed with phosphatidylcholine, in rabbits with chronic vascular inflammation.
New Zealand White rabbits (n = 10/group) were placed on chow supplemented with 0.2% (w/w) cholesterol for 6-weeks. The animals received two infusions of saline, rHDL (8 mg/kg apoA-I) or ETC-642 (30 mg/kg peptide) on the third and fifth days of the final week. The infusions of rHDL and ETC-642 were able to significantly reduce cholesterol-induced expression of intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in the thoracic aorta (p < 0.05). When isolated rabbit HDL was pre-incubated with human coronary artery endothelial cells (HCAECs), prior to stimulation with TNF-α, it was found that HDL from ETC-642 treated rabbits were more effective at inhibiting the TNF-α-induced increase in ICAM-1, VCAM-1 and p65 than HDL isolated from saline treated rabbits (p < 0.05). There were, however, no changes in HDL lipid composition between treatment groups.
Infusion of ETC-642 causes anti-inflammatory effects that are comparable to rHDL in an animal model of chronic vascular inflammation and highlights that apoA-I mimetic peptides present a viable strategy for the treatment of inflammatory disease.
PMCID: PMC3276454  PMID: 22128776
High-density lipoproteins; apolipoproteinA-I; apolipoproteinA-I mimetic peptides; vascular inflammation; rabbits; intracellular cell adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1)
8.  Genetic Association and Interaction Analysis of USF1 and APOA5 on Lipid Levels and Atherosclerosis 
USF1 is a ubiquitous transcription factor governing the expression of numerous genes of lipid and glucose metabolism. APOA5 is a well-established candidate gene regulating triglyceride (TG) levels and has been identified as a downstream target of upstream stimulatory factor. No detailed studies about the effect of APOA5 on atherosclerotic lesion formation have been conducted, nor has its potential interaction with USF1 been examined.
Methods and Results
We analyzed allelic variants of USF1 and APOA5 in families (n=516) ascertained for atherogenic dyslipidemia and in an autopsy series of middle-aged men (n=300) with precise quantitative measurements of atherosclerotic lesions. The impact of previously associated APOA5 variants on TGs was observed in the dyslipidemic families, and variant rs3135506 was associated with size of fibrotic aortic lesions in the autopsy series. The USF1 variant rs2516839, associated previously with atherosclerotic lesions, showed an effect on TGs in members of the dyslipidemic families with documented coronary artery disease. We provide preliminary evidence of gene-gene interaction between these variants in an autopsy series with a fibrotic lesion area in the abdominal aorta (P=0.0028), with TGs in dyslipidemic coronary artery disease subjects (P=0.03), and with high-density lipoprotein cholesterol (P=0.008) in a large population cohort of coronary artery disease patients (n=1065) in which the interaction for TGs was not replicated.
Our findings in these unique samples reinforce the roles of APOA5 and USF1 variants on cardiovascular phenotypes and suggest that both genes contribute to lipid levels and aortic atherosclerosis individually and possibly through epistatic effects.
PMCID: PMC3224996  PMID: 19910639
genes; USF1; APOA5; lipids; atherosclerosis; epistasis
9.  Non-Enzymatic Glycation Impairs the Anti-Inflammatory Properties of Apolipoprotein A-I 
To investigate the effects of non-enzymatic glycation on the anti-inflammatory properties of apolipoprotein (apo) A-I.
Methods and Results
Rabbits were infused with saline, lipid-free apoA-I from normal subjects (apoA-IN), lipid-free apoA-I non-enzymatically glycated by incubation with methylglyoxal (apoA-IGlyc in vitro), non-enzymatically glycated lipid-free apoA-I from subjects with diabetes (apoA-IGlyc in vivo), discoidal reconstituted HDL containing phosphatidylcholine and apoA-IN, (A-IN)rHDL, or apoA-IGlyc in vitro, (A-IGlyc in vitro)rHDL. At 24 h post-infusion, acute vascular inflammation was induced by inserting a non-occlusive, periarterial carotid collar. The animals were sacrificed 24 h post-collar insertion. The collars caused intima/media neutrophil infiltration and increased endothelial expression of vascular cell adhesion molecule-1 (VCAM-1) and intercellular adhesion molecule-1 (ICAM-1). ApoA-IN infusion decreased neutrophil infiltration and VCAM-1 and ICAM-1 expression by 89, 90 and 66%, respectively. The apoA-IGlyc in vitro infusion decreased neutrophil infiltration by 53%, but did not reduce VCAM-1 or ICAM-1 expression. ApoA-IGlyc in vivo did not inhibit neutrophil infiltration or adhesion molecule expression. (A-IGlyc in vitro)rHDL also inhibited vascular inflammation less effectively than (A-IN)rHDL. The reduced anti-inflammatory properties of non-enzymatically glycated apoA-I were attributed to a reduced ability to inhibit nuclear factor-κB activation and reactive oxygen species formation.
Non-enzymatic glycation impairs the anti-inflammatory properties of apoA-I.
PMCID: PMC3038672  PMID: 20110571
apoA-I; inflammation; HDL; adhesion molecules; neutrophils; NF-κB; reactive oxygen species
10.  The 5A apolipoprotein A-I mimetic peptide displays anti-inflammatory and antioxidant properties in vivo and in vitro 
The apolipoprotein (apo) A-I mimetic peptide 5A is highly specific for ABCA1-transporter mediated cholesterol efflux. We investigated whether the 5A peptide shares other beneficial features of apoA-I, such as protection against inflammation and oxidation.
New-Zealand White rabbits received an infusion of apoA-I, reconstituted HDL containing apoA-I ((A-I)rHDL) or the 5A peptide complexed with phospholipids (PLPC), prior to inserting a collar around the carotid artery. Human coronary artery endothelial cells (HCAECs) were incubated with (A-I)rHDL or 5A/PLPC prior to TNFa stimulation.
ApoA-I, (A-I)rHDL and 5A/PLPC reduced the collar mediated increase in (i) endothelial expression of cell adhesion molecules VCAM-1 and ICAM-1, (ii) O2− production as well as the expression of the Nox4 catalytic subunits of the NADPH oxidase, and (iii) infiltration of circulating neutrophils into the carotid intima-media. In HCAECs, both 5A/PLPC and (A-I)rHDL inhibited TNFa induced ICAM-1 and VCAM-1 expression as well as the NF-κB signalling cascade and O2− production. The effects of the 5A/PLPC complex were no longer apparent in HCAECs knocked down for ABCA1.
Like apoA-I, the 5A peptide inhibits acute inflammation and oxidative stress in rabbit carotids and HCAECs. In vitro, the 5A peptide exerts these beneficial effects through interaction with ABCA1.
PMCID: PMC2828392  PMID: 19965776
HDL; apoA-I; mimetic peptide; inflammation; oxidation
11.  Precursor-Product Relationship between Pools of Very Low Density Lipoprotein Triglyceride 
Journal of Clinical Investigation  1972;51(1):174-180.
The process of removal of triglyceride from the plasma may involve a sequential conversion of larger to smaller glyceride-rich lipoproteins. This has been studied within the species of lipoproteins comprising the very low density lipoproteins (VLDL) which transport the bulk of endogenously formed triglyceride. Palmitic acid-14C which was used to label the plasma glycerides was administered either as a prolonged constant infusion or as a pulse label. The specific activity-time curves of triglyceride fatty acids (TGFA) were analyzed both in total VLDL and in two subfractions of VLDL. The nature of the curves for total VLDL that were observed during the constant infusions were consistent with slow isotopic equilibration of precursors of VLDL-TGFA or with the presence of a precursor-product relationship between different components of VLDL-TGFA. The curves did not indicate any detectable differences in (fractional) turnover rates of independently metabolized pools of VLDL-TGFA. Differences in the specific activity-time curves of TGFA in two subfractions of VLDL (Sf > 100 and Sf 20-100) were consistent with a precursor-product relationship between TGFA in the two subfractions; again there was no indication of significant differences in (fractional) turnover rates. The specific activity-time curves of TGFA in the two subfractions of VLDL that were obtained with single injections of radio-palmitate showed a consistent difference in the rates at which TGFA became labeled in the two subfractions, being slower in the Sf 20-100 fraction. The findings from all experiments when considered together, were compatible with a precursor-product relationship that suggested that larger VLDL were converted to progressively smaller species as triglyceride was being removed.
PMCID: PMC332943  PMID: 5007049
12.  Diurnal fluctuations in triglyceride, free fatty acids, and insulin during sucrose consumption and insulin infusion in man 
Journal of Clinical Investigation  1971;50(3):583-591.
Serial changes in circulating triglyceride, free fatty acids (FFA), insulin, and glucose have been measured in human subjects fed sucrose as the sole source of calories for 2- or 3-day periods. The sucrose was given either during the day with overnight fasting (19 subjects) or as continual 3-hour meals during the day and night (seven subjects). Insulin was infused overnight in five additional subjects on the day-feeding regimen to determine the effect on triglyceride concentration.
The concentration of triglyceride increased during the study in all subjects, but there was a clear diurnal pattern in the response which was present even in the continual feeding studies. The rise in triglyceride occurred mainly overnight, and during the day there was frequently a fall in the concentration. The overnight increase was significantly less when insulin was infused. There were also diurnal fluctuations in FFA and insulin in both daytime and continual feeding regimens. The plasma FFA, like triglyceride, rose during the night and fell during the day while the insulin rose during the day and fell overnight.
Separate statistical analysis of the daytime and overnight changes revealed that the changes in triglyceride were significantly but negatively correlated with changes in insulin during both periods. The changes in triglyceride and FFA were positively correlated during the day but not significantly related during the night. The data show that when sucrose is eaten for 2 or 3 days, there is a general increase in triglyceride concentration upon which are superimposed major diurnal fluctuations in the concentrations of triglyceride, insulin, and FFA. It is suggested that the highly significant inverse relationship between changes in triglyceride and insulin may be mediated through an effect of insulin on triglyceride removal.
PMCID: PMC291966  PMID: 5101782

Results 1-12 (12)