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1.  The Oxysterol 24(S),25-Epoxycholesterol Attenuates Human Smooth Muscle–Derived Foam Cell Formation Via Reduced Low-Density Lipoprotein Uptake and Enhanced Cholesterol Efflux 
Background
Foam cell formation by intimal smooth muscle cells (SMCs) inhibits the elaboration of extracellular matrix, which is detrimental to plaque stabilization. In the present study, we examined the lipoproteins and receptors involved in human SMC foam cell formation and investigated the ability of 24(S),25-epoxycholesterol [24(S),25-EC], an oxysterol agonist of the liver X receptor, to attenuate SMC foam cell formation.
Methods and Results
Incubation of human internal thoracic SMCs with atherogenic lipoproteins demonstrated that low-density lipoprotein (LDL), but not oxidized or acetylated LDL, was the primary lipoprotein taken up, resulting in marked cholesteryl ester deposition (6-fold vs 1.8-fold; P<0.05; n=4). Exposure of SMCs to exogenous or endogenously synthesized 24(S),25-EC attenuated LDL uptake (−90% and −47% respectively; P<0.05; n=3) through decreased sterol regulatory element–binding protein-2 expression (−30% and −17%, respectively; P<0.001; n=3), decreased LDL receptor expression (−75% and −40%, respectively; P<0.05; n=3) and increased liver X receptor–mediated myosin regulatory light chain interacting protein expression (7- and 3-fold, respectively; P<0.05; n=4). Furthermore, exogenous 24(S),25-EC increased adenosine triphosphate–binding cassettes A1– and G1–mediated cholesterol efflux to apolipoprotein AI (1.9-fold; P<0.001; n=5) and high-density lipoprotein3 (1.3-fold; P<0.05; n=5). 24(S),25-EC, unlike a nonsteroidal liver X receptor agonist, T0901317, did not stimulate sterol regulatory element–binding protein-1c–mediated fatty acid synthesis or triglyceride accumulation. 24(S),25-EC preserved the assembly of fibronectin and type I collagen by SMCs.
Conclusions
The oxysterol 24(S),25-EC prevented foam cell formation in human SMCs by attenuation of LDL receptor–mediated LDL uptake and stimulation of cholesterol efflux, restoring the elaboration of extracellular matrix. In contrast to T0901317, 24(S),25-EC prevented the development of a triglyceride-rich foam cell phenotype. (J Am Heart Assoc. 2012;1:e000810 doi: 10.1161/JAHA.112.000810.)
doi:10.1161/JAHA.112.000810
PMCID: PMC3487330  PMID: 23130136
vascular smooth muscle cell; lipoproteins; oxysterol; liver X receptor; cholesterol efflux
2.  Protection from Metabolic Dysregulation, Obesity, and Atherosclerosis by Citrus Flavonoids: Activation of Hepatic PGC1α-Mediated Fatty Acid Oxidation 
PPAR Research  2012;2012:857142.
Studies in a multitude of models including cell culture, animal and clinical studies demonstrate that citrus-derived flavonoids have therapeutic potential to attenuate dyslipidemia, correct hyperinsulinemia and hyperglycemia, and reduce atherosclerosis. Emerging evidence suggests the metabolic regulators, PPARα and PGC1α, are targets of the citrus flavonoids, and their activation may be at least partially responsible for mediating their metabolic effects. Molecular studies will add significantly to the concept of these flavonoids as viable and promising therapeutic agents to treat the dysregulation of lipid homeostasis, metabolic disease, and its cardiovascular complications.
doi:10.1155/2012/857142
PMCID: PMC3369495  PMID: 22701469
3.  Nobiletin Attenuates VLDL Overproduction, Dyslipidemia, and Atherosclerosis in Mice With Diet-Induced Insulin Resistance 
Diabetes  2011;60(5):1446-1457.
OBJECTIVE
Increased plasma concentrations of apolipoprotein B100 often present in patients with insulin resistance and confer increased risk for the development of atherosclerosis. Naturally occurring polyphenolic compounds including flavonoids have antiatherogenic properties. The aim of the current study was to evaluate the effect of the polymethoxylated flavonoid nobiletin on lipoprotein secretion in cultured human hepatoma cells (HepG2) and in a mouse model of insulin resistance and atherosclerosis.
RESEARCH DESIGN AND METHODS
Lipoprotein secretion was determined in HepG2 cells incubated with nobiletin or insulin. mRNA abundance was evaluated by quantitative real-time PCR, and Western blotting was used to demonstrate activation of cell signaling pathways. In LDL receptor–deficient mice (Ldlr−/−) fed a Western diet supplemented with nobiletin, metabolic parameters, gene expression, fatty acid oxidation, glucose homeostasis, and energy expenditure were documented. Atherosclerosis was quantitated by histological analysis.
RESULTS
In HepG2 cells, activation of mitogen-activated protein kinase-extracellular signal–related kinase signaling by nobiletin or insulin increased LDLR and decreased MTP and DGAT1/2 mRNA, resulting in marked inhibition of apoB100 secretion. Nobiletin, unlike insulin, did not induce phosphorylation of the insulin receptor or insulin receptor substrate-1 and did not stimulate lipogenesis. In fat-fed Ldlr−/− mice, nobiletin attenuated dyslipidemia through a reduction in VLDL-triglyceride (TG) secretion. Nobiletin prevented hepatic TG accumulation, increased expression of Pgc1α and Cpt1α, and enhanced fatty acid β-oxidation. Nobiletin did not activate any peroxisome proliferator–activated receptor (PPAR), indicating that the metabolic effects were PPAR independent. Nobiletin increased hepatic and peripheral insulin sensitivity and glucose tolerance and dramatically attenuated atherosclerosis in the aortic sinus.
CONCLUSIONS
Nobiletin provides insight into treatments for dyslipidemia and atherosclerosis associated with insulin-resistant states.
doi:10.2337/db10-0589
PMCID: PMC3292317  PMID: 21471511
4.  Naringenin Prevents Dyslipidemia, Apolipoprotein B Overproduction, and Hyperinsulinemia in LDL Receptor–Null Mice With Diet-Induced Insulin Resistance 
Diabetes  2009;58(10):2198-2210.
OBJECTIVE
The global epidemic of metabolic syndrome and its complications demands rapid evaluation of new and accessible interventions. Insulin resistance is the central biochemical disturbance in the metabolic syndrome. The citrus-derived flavonoid, naringenin, has lipid-lowering properties and inhibits VLDL secretion from cultured hepatocytes in a manner resembling insulin. We evaluated whether naringenin regulates lipoprotein production and insulin sensitivity in the context of insulin resistance in vivo.
RESEARCH DESIGN AND METHODS
LDL receptor–null (Ldlr−/−) mice fed a high-fat (Western) diet (42% calories from fat and 0.05% cholesterol) become dyslipidemic, insulin and glucose intolerant, and obese. Four groups of mice (standard diet, Western, and Western plus 1% or 3% wt/wt naringenin) were fed ad libitum for 4 weeks. VLDL production and parameters of insulin and glucose tolerance were determined.
RESULTS
We report that naringenin treatment of Ldlr−/− mice fed a Western diet corrected VLDL overproduction, ameliorated hepatic steatosis, and attenuated dyslipidemia without affecting caloric intake or fat absorption. Naringenin 1) increased hepatic fatty acid oxidation through a peroxisome proliferator–activated receptor (PPAR) γ coactivator 1α/PPARα-mediated transcription program; 2) prevented sterol regulatory element–binding protein 1c–mediated lipogenesis in both liver and muscle by reducing fasting hyperinsulinemia; 3) decreased hepatic cholesterol and cholesterol ester synthesis; 4) reduced both VLDL-derived and endogenously synthesized fatty acids, preventing muscle triglyceride accumulation; and 5) improved overall insulin sensitivity and glucose tolerance.
CONCLUSIONS
Thus, naringenin, through its correction of many of the metabolic disturbances linked to insulin resistance, represents a promising therapeutic approach for metabolic syndrome.
doi:10.2337/db09-0634
PMCID: PMC2750228  PMID: 19592617
5.  An Increased Burden of Common and Rare Lipid-Associated Risk Alleles Contributes to the Phenotypic Spectrum of Hypertriglyceridemia 
Objective
Earlier studies have suggested that a common genetic architecture underlies the clinically heterogeneous polygenic Fredrickson hyperlipoproteinemia (HLP) phenotypes defined by hypertriglyceridemia (HTG). Here, we comprehensively analyzed 504 HLP-HTG patients and 1213 normotriglyceridemic controls and confirmed that a spectrum of common and rare lipid-associated variants underlies this heterogeneity.
Methods and Results
First, we demonstrated that genetic determinants of plasma lipids and lipoproteins, including common variants associated with plasma triglyceride (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) from the Global Lipids Genetics Consortium were associated with multiple HLP-HTG phenotypes. Second, we demonstrated that weighted risk scores composed of common TG-associated variants were distinctly increased across all HLP-HTG phenotypes compared with controls; weighted HDL-C and LDL-C risk scores were also increased, although to a less pronounced degree with some HLP-HTG phenotypes. Interestingly, decomposition of HDL-C and LDL-C risk scores revealed that pleiotropic variants (those jointly associated with TG) accounted for the greatest difference in HDL-C and LDL-C risk scores. The APOE E2/E2 genotype was significantly overrepresented in HLP type 3 versus other phenotypes. Finally, rare variants in 4 genes accumulated equally across HLP-HTG phenotypes.
Conclusion
HTG susceptibility and phenotypic heterogeneity are both influenced by accumulation of common and rare TG-associated variants.
doi:10.1161/ATVBAHA.111.226365
PMCID: PMC3562702  PMID: 21597005
lipoproteins; genetic risk scores; genetic variation; hypertriglyceridemia; pleiotropy
6.  Excess of Rare Variants in Non-GWAS Candidate Genes in Patients with Hypertriglyceridemia 
Background
Rare variant accumulation studies can implicate genes in disease susceptibility when a significant burden is observed in patients versus controls. Such analyses might be particularly useful for candidate genes that are selected based on experiments other than genome-wide association studies (GWAS). We sought to determine whether rare variants in non-GWAS candidate genes identified from mouse models and human Mendelian syndromes of hypertriglyceridemia (HTG) accumulate in patients with polygenic adult-onset HTG.
Methods and Results
We resequenced protein coding regions of 3 genes with established roles (APOC2, GPIHBP1, LMF1) and 2 genes recently implicated (CREB3L3 and ZHX3) in TG metabolism. We identified 41 distinct heterozygous rare variants, including 29 singleton variants, in the combined sample; in total, we observed 47 rare variants in 413 HTG patients versus 16 in 324 controls (OR=2.3; P=0.0050). Post hoc assessment of genetic burden in individual genes using three different tests suggested that the genetic burden was most prominent in the established genes LMF1 and APOC2, and also in the recently identified CREB3L3 gene.
Conclusions
These extensive resequencing studies show a significant accumulation of rare genetic variants in non-GWAS candidate genes among patients with polygenic HTG, and indicate the importance of testing specific hypotheses in large-scale resequencing studies.
doi:10.1161/CIRCGENETICS.111.960864
PMCID: PMC3288444  PMID: 22135386
hyperlipoproteinemia; genetics; apolipoproteins; lipoproteins; cardiovascular diseases
7.  Mutation skew in genes identified by genome-wide association study of hypertriglyceridemia 
Nature genetics  2010;42(8):684-687.
Genome-wide association studies (GWAS) have replicably identified multiple loci associated with population-based plasma lipid concentrations1-5. Common genetic variants at these loci together explain <10% of the total variation of each lipid trait4,5. Rare variants of individually large effect may contribute additionally to the “missing heritability” of lipid traits6,7, however it remains to be shown to what extent rare variants will affect lipid phenotypes. Here, we demonstrate a significant accumulation of rare variants in GWAS-identified genes in patients with an extreme phenotype of abnormal plasma triglyceride (TG) metabolism. A GWAS of hypertriglyceridemia (HTG) patients revealed that common variants in APOA5, GCKR, LPL and APOB genes were associated with the HTG phenotype at genome-wide significance. We subsequently resequenced protein coding regions of these genes and found a significant burden of 154 rare missense or nonsense variants in 438 HTG patients, in contrast to 53 variants in 327 controls (P=6.2X10-8); this corresponds to a carrier frequency of 28.1% of HTG patients and 15.3% of controls (P=2.6X10-5). Many rare variants were predicted in silico to have compromised function; additionally some had previously demonstrated dysfunctionality in vitro. Rare variants in these 4 genes explained 1.1% of total variation in HTG diagnoses. Our study demonstrates a marked mutation skew that likely contributes to disease pathophysiology in patients with HTG.
doi:10.1038/ng.628
PMCID: PMC3017369  PMID: 20657596
8.  Canadian global village reality 
Canadian Family Physician  2010;56(5):e174-e182.
ABSTRACT
OBJECTIVE
To test the appropriateness of body mass index (BMI) and waist circumference (WC) cutoff points derived in largely white populations (ie, those of European descent) for detecting obesity-related metabolic abnormalities among East Asian and South Asian Canadians.
DESIGN
Cross-sectional survey.
SETTING
Primary care and community settings in Ontario.
PARTICIPANTS
Canadians of East Asian (n = 130), South Asian (n = 113), and European (n = 111) descent.
MAIN OUTCOME MEASURES
Variables for metabolic syndromes, including BMI, WC, body fat percentage, blood pressure, lipid profile, and fasting blood glucose and insulin levels, were measured. Receiver operating characteristics curve analysis was used to generate BMI and WC cutoff points based on various criteria for metabolic syndromes.
RESULTS
Adjusting for sex and age, East Asian Canadians had a significantly lower mean BMI (23.2 kg/m2) and mean WC (79.6 cm) than did those of South Asian (26.1 kg/m2 and 90.3 cm) and European (26.5 kg/m2 and 89.3 cm) descent (P < .05). The BMI cutoffs for an increased risk of metabolic abnormalities ranged from 23.1 to 24.4 kg/m2 in East Asian Canadians; 26.6 to 26.8 kg/m2 in South Asian Canadians; and 26.3 to 28.2 kg/m2 in European Canadians. Waist circumference cutoffs for increased risk of metabolic abnormalities were relatively low in East Asian men (83.3 to 85.2 cm) and women (74.1 to 76.7 cm), compared with South Asian men (98.8 cm) and women (90.1 to 93.5 cm), as well as European men (91.6 to 95.2 cm) and women (82.8 to 88.3 cm).
CONCLUSION
The BMI and WC cutoffs used for defining risk of metabolic abnormalities should be lowered for East Asian Canadians but not for South Asian Canadians. The World Health Organization ethnic-specific BMI and WC cutoffs should be used with caution, particularly with Asian migrants who have resided in Canada for a long period of time.
PMCID: PMC2868628  PMID: 20463258
9.  A polygenic basis for four classical Fredrickson hyperlipoproteinemia phenotypes that are characterized by hypertriglyceridemia 
Human Molecular Genetics  2009;18(21):4189-4194.
Numerous single nucleotide polymorphisms (SNPs) have been found in recent genome wide association studies (GWAS) to be associated with subtle plasma triglyceride (TG) variation in normolipidemic subjects. However, since these GWAS did not specifically evaluate patients with rare disorders of lipoprotein metabolism—‘hyperlipoproteinemia’ (HLP)—it remains largely unresolved whether any of these SNP determinants of modest physiological changes in TG are necessarily also determinants of most HLP phenotypes. To address this question, we evaluated 28 TG-associated SNPs from GWAS in 386 unrelated adult patients with one of five Fredrickson phenotypes (HLP types 2A, 2B, 3, 4 and 5) and 242 matched normolipidemic controls. We found that several SNPs associated with TG in normolipidemic samples, including APOA5 p.S19W and -1131T>C, TRIB1 rs17321515, TBL2 rs17145738, GCKR rs780094, GALNT2 rs4846914 and ANGPTL3 rs12130333, were significantly associated with HLP types 2B, 3, 4 and 5. The findings indicate that: (i) the TG-associated Fredrickson HLP types 2B, 3, 4 and 5 are polygenic traits; (ii) these Fredrickson HLP types share numerous genetic determinants among themselves; and (iii) genetic determinants of modest TG variation in normolipidemic population samples also underlie—to an apparently even greater degree—susceptibility to these rare HLP phenotypes. Thus, the TG-associated Fredrickson HLP types 2B, 3, 4 and 5, although historically considered to be distinct are actually complex traits sharing among them several common genetic determinants seen in GWAS of normolipidemic population samples.
doi:10.1093/hmg/ddp361
PMCID: PMC2758142  PMID: 19656773
10.  Association between the FTO rs9939609 polymorphism and the metabolic syndrome in a non-Caucasian multi-ethnic sample 
Background
The rs9939609 T>A single-nucleotide polymorphism (SNP) in the FTO gene has previously been found to be associated with obesity in European Caucasian samples. The objective of this study is to examine whether this association extends to metabolic syndrome (MetS) and applies in non-Caucasian samples.
Methods
The FTO rs9939609 SNP was genotyped in 2121 subjects from four different non-Caucasian geographical ancestries. Subjects were classified for the presence or absence of MetS according to the International Diabetes Federation (IDF) and National Cholesterol Education Program Adult Treatment Panel (NCEP ATP) III definitions.
Results
Carriers of ≥ 1 copy of the rs9939609 A allele were significantly more likely to have IDF-defined MetS (35.8%) than non-carriers (31.2%), corresponding to a carrier odds ratio (OR) of 1.23 (95% confidence interval [CI] 1.01 to 1.50), with a similar trend for the NCEP ATP III-defined MetS. Subgroup analysis showed that the association was particularly strong in men. The association was related to a higher proportion of rs9939609 A allele carriers meeting the waist circumference criterion; a higher proportion also met the HDL cholesterol criterion compared with wild-type homozygotes.
Conclusion
Thus, the FTO rs9939609 SNP was associated with an increased risk for MetS in this multi-ethnic sample, confirming that the association extends to non-Caucasian population samples.
doi:10.1186/1475-2840-7-5
PMCID: PMC2275229  PMID: 18339204
11.  Association between the -455T>C promoter polymorphism of the APOC3 gene and the metabolic syndrome in a multi-ethnic sample 
BMC Medical Genetics  2007;8:80.
Background
Common polymorphisms in the promoter of the APOC3 gene have been associated with hypertriglyceridemia and may impact on phenotypic expression of the metabolic syndrome (MetS). The rs7566605 marker, located near the INSIG2 gene, has been found to be associated with obesity, making it also a potential genetic determinant for MetS. The objective of this study is to examine the APOC3 -455T>C and the INSIG2 rs7566605 polymorphisms as potential genetic determinants for MetS in a multi-ethnic sample.
Methods
Subjects were genotyped for both the APOC3 -455T>C and INSIG2 rs7566605 polymorphisms, and classified for the presence or absence of MetS (NCEP ATP III and IDF definitions). The total study population included 2675 subjects (≥18 years of age) from six different geographical ancestries.
Results
For the overall study population, the prevalence of MetS was 22.6% (NCEP ATP III definition). Carriers of ≥1 copy of APOC3 -455C were more likely to have MetS (NCEP ATP III definition) than noncarriers (carrier odds ratio 1.73, 95% CI 1.40 to 2.14, adjusting for age and study group). The basis of the association was related not only to a higher proportion of -455C carriers meeting the triglyceride and high-density lipoprotein cholesterol criteria, but also the blood pressure criteria compared with wild-type homozygotes. Plasma apo C-III concentrations were not associated with APOC3 -455T>C genotype. The INSIG2 rs7566605 polymorphism was not associated with MetS or measures of obesity.
Conclusion
Meta-analysis of the sample of multiple geographic ancestries indicated that the functional -455T>C promoter polymorphism in APOC3 was associated with an approximately 2-fold increased risk of MetS, whereas the INSIG2 rs7566605 polymorphism was not associated with MetS.
doi:10.1186/1471-2350-8-80
PMCID: PMC2241585  PMID: 18096054

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