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1.  Caloric Restriction, Aerobic Exercise Training, and Soluble Lectin-like Oxidized LDL Receptor-1 Levels in Overweight and Obese Postmenopausal Women 
Elevated circulating levels of soluble lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) have been observed in obese persons and are reduced by weight loss. However, it is not known if combining caloric restriction (CR) with exercise training is better in reducing sLOX-1 levels than CR alone.
We examined whether the addition of aerobic exercise to a weight loss intervention differentially affects sLOX-1 levels in 61 abdominally obese postmenopausal women randomly assigned to a CR only (n=22), CR + moderate-intensity exercise (n=22), or CR + vigorous-intensity exercise (n=17) intervention for 20 weeks. The caloric deficit was ~2,800 kcal/week for all groups.
The intervention groups were similar at baseline with respect to body weight, body composition, lipids, and blood pressure. However, plasma sLOX-1 levels were higher in the CR only group (99.90 ± 8.23 pg/ml) compared to both the CR + moderate-intensity exercise (69.39 ± 8.23 pg/ml, p=0.01) and CR + vigorous-intensity exercise (72.83 ± 9.36 pg/ml, p=0.03) groups. All three interventions significantly reduced body weight (~14%), body fat, and waist and hip circumferences to a similar degree. These changes were accompanied by a 23% reduction in sLOX-1 levels overall (−19.00 ± 30.08 pg/ml, p<0.0001), which did not differ among intervention groups (p=0.13). Changes in body weight, body fat, and VO2 max were not correlated with changes in sLOX-1 levels. In multiple regression analyses in all women combined, baseline sLOX-1 levels (β = − 0.70 ± 0.06, p<0.0001), age (β = 0.92 ± 0.43, p=0.03) and baseline BMI (β = 1.88 ± 0.66, p=0.006) were independent predictors of the change in sLOX-1 with weight loss.
Weight loss interventions of equal energy deficit have similar effects on sLOX-1 levels in overweight and obese postmenopausal women, with the addition of aerobic exercise having no added benefit when performed in conjunction with CR.
PMCID: PMC3023845  PMID: 20856256
obesity; weight loss; caloric restriction; aerobic exercise; soluble receptor
2.  Variation in the Lectin-like Oxidized LDL Receptor 1 (LOX-1) Gene Is Associated With Plasma Soluble LOX-1 Levels 
Experimental physiology  2008;93(9):1085-1090.
The lectin-like ox-LDL receptor 1 (LOX-1) expressed on vascular cells plays a major role in atherogenesis by internalizing and degrading oxidized LDL. LOX-1 can be cleaved from the cell surface and released as soluble LOX-1 (sLOX-1), and elevated sLOX-1 levels may be indicative of atherosclerotic plaque instability. We examined associations between the LOX-1 3′UTR-C/T and G501C polymorphisms and plasma sLOX-1 levels in 97 healthy older men and women. The frequencies for the 3′UTR-T and 501C alleles were 46% and 10%, respectively. Plasma sLOX-1 levels were significantly higher in the 3′UTR CC genotype group compared to both the CT (p=0.02) and TT (p=0.002) genotype groups. Plasma sLOX-1 were also significantly higher in the 501GC genotype group compared to the GG genotype group (p=0.004). In univariate analyses, sLOX-1 levels were significantly associated with both the 3′UTR-C/T and G501 C polymorphisms. These associations remained significant after adjusting for age, gender, race, and BMI. In conclusion, variation in the LOX-1 gene is associated with plasma sLOX-1 levels in older men and women.
PMCID: PMC2652129  PMID: 18469066
receptor; cardiovascular; gene expression
3.  Pregnancy Followed by Delivery May Affect Circulating Soluble Lectin-Like Oxidized Low-Density Lipoprotein Receptor-1 Levels in Women of Reproductive Age 
Mediators of Inflammation  2012;2012:837375.
Background/Objective. It is known that menopause or lack of endogenous estrogen is a risk factor for endothelial dysfunction and CAD. Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is involved inmultiple phases of vascular dysfunction.The purpose of the current study was to determine the association between soluble LOX-1 (sLOX-1) and pregnancy followed by delivery in women of reproductive age. Materials/Methods. Sixty-eight subjects with pregnancy followed by delivery (group 1) and 57 subjects with nongravidity (group 2) were included in this study. Levels of sLOX-1 were measured in serum by EL SA. Results. Plasma levels of sLOX-1 were significantly lower in Group 1 than Group 2 in women of reproductive age (0.52 ± 0.18 ng/mL and 0.78 ± 0.13, resp., P < 0.001). There were strong correlations between sLOX-1 levels and the number of gravida (r = −0.645, P < 0.001). The levels of sLOX-1 highly correlated with the number of parous (r = −0.683, P < 0.001). Conclusion. Our study demonstrated that serum sLOX-1 levels were associated with pregnancy followed by delivery that might predict endothelial dysfunction. We conclude that pregnancy followed by delivery may delay the beginning and progress of arteriosclerosis and its clinical manifestations in women of reproductive age.
PMCID: PMC3350984  PMID: 22619487
4.  Soluble Lectin-Like Oxidized Low Density Lipoprotein Receptor-1 as a Biochemical Marker for Atherosclerosis-Related Diseases 
Disease markers  2013;35(5):413-418.
Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), the main oxidized low-density lipoprotein (OxLDL) in endothelial cells, is upregulated in atherosclerotic lesions and is involved in several cellular processes that regulate the pathogenesis of atherosclerosis. The LOX-1 expressed on the cell surface can be proteolytically cleaved and released in a soluble form (sLOX-1) in the circulation under pathological conditions. Serum levels of sLOX-1, in fact, are elevated at the early stages of acute coronary syndrome and are associated with coronary plaque vulnerability and with the presence of multiple complex coronary lesions. Moreover, in subjects with stable CAD, levels of serum sLOX-1 are associated with the presence of lesions in the proximal and mid-segments of the left anterior descending artery that are the most prone to rupture; in subjects undergoing percutaneous coronary intervention, baseline preprocedural serum sLOX-1 levels are associated with the incidence of periprocedural myocardial infarction. Altogether, these findings suggest that circulating levels of sLOX-1 might be a diagnostic and prognostic marker for atherosclerotic-related events.
PMCID: PMC3809739  PMID: 24198442
5.  Procoagulant activity of circulating microparticles is associated with the presence of moderate calcified plaque burden detected by multislice computed tomography 
Circulating microparticles (MPs) have been reported to be associated with coronary artery disease (CAD). In this study, we explored the relationship between MPs procoagulant activity and characteristics of atherosclerotic plaque detected by 64-slice computed tomography angiography (CTA).
In 127 consecutive patients with CAD but without acute coronary syndrome and who underwent 64-slice CTA, MPs procoagulant activity in plasma (by a thrombin generation test), soluble form of lectin-like oxidized low-density lipoprotein receptor-1 (sLOX-1) and N(epsilon)-(carboxymethyl) lysine (CML) circulating levels (by ELISA) were measured. A quantitative volumetric analysis of the lumen and plaque burden of the vessel wall (soft and calcific components), for the three major coronary vessels, was performed. The patients were classified in three groups according to the presence of calcium volume: non-calcified plaque (NCP) group (calcium volume (%) = 0), moderate calcified plaque (MCP) group (0 < calcium volume (%) < 1), and calcified plaque (CP) group (calcium volume (%) ≥ 1).
MPs procoagulant activity and CML levels were higher in MCP group than in CP or NCP group (P = 0.009 and P = 0.027, respectively). MPs procoagulant activity was positively associated with CML (r = 0.317, P < 0.0001) and sLOX-1 levels (r = 0.216, P = 0.0025).
MPs procoagulant activity was higher in the MCP patient group and correlated positively with sLOX-1 and CML levels, suggesting that it may characterize a state of blood vulnerability that may locally precipitate plaque instability and increase the risk of subsequent major cardiovascular events.
PMCID: PMC3981978  PMID: 24748876
Computed tomography; Microparticles; Low density lipoprotein; Lysine; Coronary artery disease
6.  Cutaneous microvascular dysfunction correlates with serum LDL and sLOX-1 receptor concentrations 
Microvascular research  2012;85:112-117.
The human cutaneous circulation is an accessible and representative regional circulation for investigating mechanisms of microvascular dysfunction, a systemic disease process occurring early in the pathogenesis of atherosclerosis. Elevated concentrations of low-density lipoproteins ([LDL]) are highly atherogenic and independently associated with the severity of coronary atherosclerosis through their actions on the lectin-like oxidized LDL receptors (LOX-1). We hypothesized that cutaneous microvascular dysfunction, as measured by a decrement in endothelial nitric oxide- (NO-) dependent vasodilation during local heating, would be correlated with serum [LDL], oxidized [LDL], and soluble LOX-1 receptors [sLOX-1]. Intradermal microdialysis fibers were placed in the skin of 53 otherwise healthy men and women (aged 52±8 years) whose serum [LDL] ranged from 72 to 233 mg/dL. Skin blood flow was measured by laser Doppler flowmetry over a local forearm skin site as it was heated (42 °C) to induce sustained local vasodilation. After flux plateaued, L-NAME was infused to block endothelial NO synthase in order to determine the NO-dependent portion of the vasodilatory response. Data were normalized to maximal cutaneous vascular conductance (CVC). NO-dependent vasodilation was reduced as a linear function of [LDL] (R2=0.303, p<0.001), oxidized [LDL] (R2=0.214, p<0.001), and [sLOX-1] (R2=0.259, p=0.026) but was unrelated to high-density lipoprotein (HDL) concentration (R2=0.003, p=0.68). Hypercholesterolemia-induced microvascular dysfunction is related to various LDL markers and involves a reduction in NO-dependent vasodilation that appears to be a progressive process measurable in the skin microcirculation.
PMCID: PMC3757520  PMID: 23137925
7.  Pyridine and pyrimidine analogs of acetaminophen as inhibitors of lipid peroxidation and cyclooxygenase and lipoxygenase catalysis† 
Organic & biomolecular chemistry  2009;7(24):5103-5112.
Herein we report an investigation of the efficacy of pyridine and pyrimidine analogs of acetaminophen (ApAP) as peroxyl radical-trapping antioxidants and inhibitors of enzyme-catalyzed lipid peroxidation by cyclooxygenases (COX) and lipoxygenases (LOX). In inhibited autoxidations we find that ApAP, the common analgesic and antipyretic agent, is a very good antioxidant with a rate constant for reaction with peroxyl radicals (kinh = 5 × 105 M−1 s−1) that is higher than many widely-used phenolic antioxidants, such as the ubiquitous butylated hydroxytoluene (BHT). This reactivity is reduced substantially upon incorporation of nitrogen into the phenolic ring, owing to an increase in the O–H bond dissociation enthalpy of pyridinols and pyrimidinols with respect to phenols. Incorporation of nitrogen into the phenolic ring of ApAP was also found to decrease its efficacy as an inhibitor of prostaglandin biosynthesis by ovine COX-1 (oCOX-1). This is explained on the basis of an increase in its oxidation potential and its reduced reactivity as a reducing co-substrate of the peroxidase protoporphyrin. In contrast, the efficacy of ApAP as an inhibitor of lipid hydroperoxide biosynthesis by soybean LOX-1 (sLOX-1) increased upon incorporation of nitrogen into the ring, suggesting a different mechanism of inhibition dependent on the acidity of the phenolic O–H which may involve chelation of the catalytic non-heme iron atom. The greater stability of the 3-pyridinols and 5-pyrimidinols to air oxidation as compared to phenols allowed us to evaluate some electron-rich pyridinols and pyrimidinols as inhibitors of oCOX-1 and sLOX-1. While the pyridinols had the best combination of activities as antioxidants and inhibitors of oCOX-1 and sLOX-1, they were found to be more toxic than ApAP in preliminary assays in human hepatocellular carcinoma (HepG2) cell culture. The pyrimidinols, however, were up to 17-fold more reactive to peroxyl radicals and up to 25-fold better inhibitors of prostaglandin biosynthesis than ApAP, with similar cytotoxicities to HepG2 cells at high levels of exposure.
PMCID: PMC2873786  PMID: 20024105
8.  Sleeve gastrectomy prevents lipoprotein receptor-1 expression in aortas of obese rats 
AIM: To investigate the effects of sleeve gastrectomy on adipose tissue infiltration and lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) expression in rat aortas.
METHODS: Twenty-four rats were randomized into three groups: normal chow (control), high fat diet (HD) and high fat diet with sleeve gastrectomy (SG). After surgery, the HD and SG groups were fed a high fat diet. Animals were sacrificed and plasma high density lipoprotein (HDL) and low density lipoprotein (LDL) levels were determined. LOX-1 protein and LOX-1 mRNA expression was also measured. Aortas were stained with Nile red to visualize adipose tissue.
RESULT: Body weights were higher in the HD group compared to the other groups. HDL levels in control, HD, and SG groups were 32.9 ± 6.2 mg/dL, 43.4 ± 4.0 mg/dL and 37.5 ± 4.3 mg/dL, respectively. LDL levels in control, HD, and SG groups were 31.8 ± 4.5 mg/dL, 53.3 ± 5.1 mg/dL and 40.5 ± 3.7 mg/dL, respectively. LOX-1 protein and LOX-1 mRNA expression was greater in the HD group versus the other groups. Staining for adipose tissue in aortas was greater in the HD group in comparison to the other groups. Thus, a high fat diet elevates LOX-1 protein and mRNA expression in aorta.
CONCLUSION: Sleeve gastrectomy decreases plasma LDL levels, and downregulates LOX-1 protein and mRNA expression.
PMCID: PMC3181460  PMID: 21990956
Sleeve gastrectomy; Morbid obesity; High fat diet; Aorta; Lipoprotein receptor-1 expression
9.  Bioassay-guided isolation, identification and molecular ligand-target insight of lipoxygenase inhibitors from leaves of Anisomeles malabarica R.Br. 
Pharmacognosy Magazine  2014;10(Suppl 3):S596-S605.
Anisomeles malabarica R. Br. (Lamiaceae) is extensively used in traditional medicine in major parts of India for several medicinal purposes, including their use in rheumatism.
Materials and Methods:
The air-dried leaves of A. malabarica were extracted with ethanol, defatted with n-hexane and then successively partitioned into chloroform and n-butanol fractions. Bioassay-guided fractionation and purification of chloroform fraction from A. malabarica lead to the isolation of lipoxygenase (LOX) inhibitors. The structures of isolated compounds were elucidated by ultraviolet, infrared, 1H nuclear magnetic resonance (NMR), 13C NMR and mass spectrometry spectroscopic techniques and assessed further by in vitro soybean lipoxygenase (sLOX) assay. In addition, the enzyme type inhibition was evaluated through molecular docking technique as a part of computational study.
The bioactive compounds 3, 4 dihydroxy benzoic acid (1) and 4’, 5, 7-trihydroxyflavone (2) were isolated from chloroform fraction of A. malabarica, whose bioactivity was observed to be dose-dependent compared to n-butanol fraction. Among the compounds, 3, 4 dihydroxy benzoic acid showed significant sLOX inhibitory activity with 74.04% ±2.6% followed by 4’, 5, 7-trihydroxyflavone (34.68% ±1.9%). The computational analysis of compounds showed their molecular interaction with important amino acid residues and nonheme iron atom in the catalytic site of LOX by enlightening their potential binding mode at molecular level.
The LOX inhibitory constituents were identified from A. malabarica by means of bioassay-guided fractionation process. The results derived from in vitro and computational experiments confirm the potential of the isolated compounds and provide additional evidence for its traditional use in inflammatory disorders.
PMCID: PMC4189278  PMID: 25298680
3, 4 dihydroxy benzoic acid; Anisomeles malabarica; anti-inflammatory; lipoxygenase; molecular docking
10.  Positive Relationship between Serum Low-Density Lipoprotein Cholesterol Levels and Visceral Fat in a Chinese Nondiabetic Population 
PLoS ONE  2014;9(11):e112715.
It has been reported that obesity and serum low-density lipoprotein cholesterol (LDL-c) are important risk factors of cardiovascular disease (CVD). It is recognized that regionalized adiposity has different cardiovascular risk, visceral versus subcutaneous, is a better predictor of CVD. However, the relationship between regionalized adiposity and LDL-c is unclear. The present study was designed to investigate the relationship between visceral fat accumulation and serum LDL-c levels in a Chinese cohort.
A total of 1 538 subjects (539 men, 999 women; 20–75 years old) with normal glucose tolerance and blood pressure were recruited. All subjects underwent magnetic resonance imaging to quantify visceral fat area (VFA) and subcutaneous fat area. Serum LDL-c levels were detected by direct assay method.
Overweight/obese subjects (body mass index (BMI) ≥25 kg/m2) had significantly higher serum LDL-c levels than the lean subjects (BMI <25 kg/m2) (P<0.01). An increasing trend in serum LDL-c levels was found to accompany the increase in VFA (P for trend <0.01). Within the same BMI category, subjects with abdominal obesity (VFA ≥80 cm2) had significantly higher LDL-c levels than those without abdominal obesity (VFA <80 cm2) (P<0.05). Multiple stepwise regression analysis showed that increased VFA was an independent risk factor for elevated LDL-c levels, not only in the entire study population (Standard β = 0.138; P<0.01), but also when the study population was subdivided into men, premenopausal and postmenopausal women (Standard β = 0.117, 0.145, 0.090 respectively for men, premenopausal women, postmenopausal women; all P<0.01).
VFA was positively correlated with serum LDL-c levels in a nondiabetic Chinese population with normal blood pressure.
PMCID: PMC4232522  PMID: 25398089
11.  Significance of Soluble Lectin-Like Oxidized LDL Receptor-1 Levels in Systemic and Coronary Circulation in Acute Coronary Syndrome 
BioMed Research International  2014;2014:649185.
Background. Soluble lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) level is a novel biomarker for diagnosis of acute coronary syndrome (ACS); however, this level in the coronary circulation has yet to be examined. Methods. Twenty-seven consecutive patients with ACS and 40 patients with effort angina pectoris (EAP) undergoing percutaneous coronary intervention (PCI) had levels of soluble LOX-1 and LOX-1 index measured in paired blood samples from aorta (Ao) and coronary sinus (CS) just prior to the PCI. Results. We found positive correlations between soluble LOX-1 levels in the Ao and CS in both ACS and EAP patients (P < 0.01, for both). The soluble LOX-1 levels in the Ao and CS were higher in ACS than in EAP patients (P < 0.01, for both). The levels of soluble LOX-1 and LOX-1 index of the CS were significantly greater than those of the Ao in both ACS and EAP patients (P < 0.01, for both). Receiver operating characteristic curves for ACS detection demonstrated high sensitivity and specificity for the soluble LOX-1 and LOX-1 index with no differences between the Ao and CS. Conclusions. The present study showed that circulating soluble LOX-1 originates from coronary circulation and soluble LOX-1 and LOX-1 index are useful biomarkers for ACS.
PMCID: PMC4033395  PMID: 24895597
12.  Effect of a weight loss intervention on anthropometric measures and metabolic risk factors in pre- versus postmenopausal women 
Nutrition Journal  2007;6:31.
The present study examines changes in body weight, fat mass, metabolic and hormonal parameters in overweight and obese pre- and postmenopausal women who participated in a weight loss intervention.
Seventy-two subjects were included in the analysis of this single arm study (premenopausal: 22 women, age 43.7 ± 6.4 years, BMI 31.0 ± 2.4 kg/m2; postmenopausal: 50 women, age 58.2 ± 5.1 years, BMI 32.9 ± 3.7 kg/m2). Weight reduction was achieved by the use of a meal replacement and fat-reduced diet. In addition, from week 6 to 24 participants attended a guided exercise program. Body composition was analyzed with the Bod Pod®. Blood pressures were taken at every visit and blood was collected at baseline and closeout of the study to evaluate lipids, insulin, cortisol and leptin levels.
BMI, fat mass, waist circumference, systolic blood pressure, triglycerides, glucose, leptin and cortisol were higher in the postmenopausal women at baseline.
Both groups achieved a substantial and comparable weight loss (pre- vs. postmenopausal: 6.7 ± 4.9 vs 6.7 ± 4.4 kg; n.s.). However, in contrast to premenopausal women, weight loss in postmenopausal women was exclusively due to a reduction of fat mass (-5.3 ± 5.1 vs -6.6 ± 4.1 kg; p < 0.01). In premenopausal women 21% of weight loss was attributed to a reduction in lean body mass.
Blood pressure, triglycerides, HDL-cholesterol, and glucose improved significantly only in postmenopausal women whereas total cholesterol and LDL-cholesterol were lowered significantly in both groups.
Both groups showed comparable weight loss and in postmenopausal women weight loss was associated with a pronounced improvement in metabolic risk factors thereby reducing the prevalence of metabolic syndrome.
PMCID: PMC2164948  PMID: 17961235
13.  The Relationship between Endogenous Androgens and Body Fat Distribution in Early and Late Postmenopausal Women 
PLoS ONE  2013;8(3):e58448.
To investigate the relationship between endogenous androgens and body fat distribution in early and late postmenopausal women.
Materials and Methods
We enrolled postmenopausal women consisting of an early group (≤5 years since menopause, n = 105) and a late group (≥10 years since menopause, n = 107). Each group was subdivided into normal weight (BMI <24 kg/m2) group, overweight and obese (BMI ≥24 kg/m2) group. Fasting total testosterone (T), dehydroepiandrosterone-sulfate (DHEA-S) and sex hormone-binding globulin (SHBG) levels were measured. Body fat distribution was evaluated by dual-energy X-ray absorptiometry (DEXA).
Late postmenopausal women had a higher proportion of body fat than early postmenopausal women. The body fat of the overweight and obese women had a greater tendency to accumulate in the abdomen compared with the normal weight women both in early and late postmenopausal groups. The overweight and obese women had a higher free testosterone (FT) than the normal weight women in early postmenopausal women (P<0.05). In late postmenopausal women, the overweight and obese women had higher DHEA-S levels than normal weight women (P<0.05). No direct relationship was observed between the T levels and body fat distribution both in early and late postmenopausal groups (P>0.05).The FT in early postmenopausal women and the DHEA-S levels in late postmenopausal women correlated positively with the trunk/leg fat ratio (T/L) and the proportion of android fat whereas correlated negatively with the proportion of gynoid fat in the partial correlation and multiple linear regression analyses (all P<0.05).
Serum T levels do not correlate directly with body fat distribution, the FT in early postmenopausal women and DHEA-S levels in late postmenopausal women correlate positively with abdominal fat accumulation.
PMCID: PMC3587576  PMID: 23484029
14.  Obesity, coffee consumption and CRP levels in postmenopausal overweight/obese women: Importance of hormone replacement therapy use 
European journal of clinical nutrition  2009;63(12):1419-1424.
Obesity is associated with an inflammatory state that is often characterized by elevated plasma C-reactive protein (CRP) levels. Although coffee is broadly consumed in Western societies, few studies have examined the relationship between obesity, coffee consumption and CRP levels. The objective of the present study was to assess the relationship between obesity, coffee consumption and variation in CRP in postmenopausal, overweight/obese women with or without hormone replacement therapy (HRT) use.
Cross-sectional analyses of 344 healthy sedentary, overweight/obese postmenopausal women (mean age=57.1±6.4 years and mean body mass index [BMI]=36.1±3.9 kg/m2). Plasma CRP levels were measured by a highly sensitive immunoassay that used monoclonal antibodies coated with polystyrene particles. Diet was assessed using the Food Intake and Analysis System semi-quantitative food frequency questionnaire.
Plasma CRP was positively associated with BMI (p<0.001) and negatively associated with coffee consumption (p≤0.05). In women using HRT, plasma CRP was positively associated BMI in women consuming less than one cup of coffee per month (r2=0.15 [p<0.001]), one cup per day (0.14 [p=0.02]) and more than one cup per day (0.12 [p=0.03]). In women who did not use HRT, CRP was associated BMI only in women consuming less than one cup of coffee per day (r2=0.16 [p<0.001]) but not in women consuming one cup per day (0.06 [p=0.10]) or more than one daily cup of coffee (0.03 [p=0.27]).
Among overweight/obese postmenopausal women coffee consumption is negatively associated with CRP. Coffee consumption appears to attenuate the association between BMI and CRP, but only in women not using HRT.
PMCID: PMC2787671  PMID: 19756031
Obesity; Coffee; CRP; Postmenopausal women; Hormone replacement Therapy
15.  Lectin-Like Oxidized LDL Receptor-1 Is an Enhancer of Tumor Angiogenesis in Human Prostate Cancer Cells 
PLoS ONE  2014;9(8):e106219.
Altered expression and function of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) has been associated with several diseases such as endothelial dysfunction, atherosclerosis and obesity. In these pathologies, oxLDL/LOX-1 activates signaling pathways that promote cell proliferation, cell motility and angiogenesis. Recent studies have indicated that olr1 mRNA is over-expressed in stage III and IV of human prostatic adenocarcinomas. However, the function of LOX-1 in prostate cancer angiogenesis remains to be determined. Our aim was to analyze the contribution of oxLDL and LOX-1 to tumor angiogenesis using C4-2 prostate cancer cells. We analyzed the expression of pro-angiogenic molecules and angiogenesis on prostate cancer tumor xenografts, using prostate cancer cell models with overexpression or knockdown of LOX-1 receptor. Our results demonstrate that the activation of LOX-1 using oxLDL increases cell proliferation, and the expression of the pro-angiogenic molecules VEGF, MMP-2, and MMP-9 in a dose-dependent manner. Noticeably, these effects were prevented in the C4-2 prostate cancer model when LOX-1 expression was knocked down. The angiogenic effect of LOX-1 activated with oxLDL was further demonstrated using the aortic ring assay and the xenograft model of tumor growth on chorioallantoic membrane of chicken embryos. Consequently, we propose that LOX-1 activation by oxLDL is an important event that enhances tumor angiogenesis in human prostate cancer cells.
PMCID: PMC4149537  PMID: 25170920
16.  The Oxidized Low-Density Lipoprotein Receptor Mediates Vascular Effects of Inhaled Vehicle Emissions 
Rationale: To determine vascular signaling pathways involved in inhaled air pollution (vehicular engine emission) exposure–induced exacerbation of atherosclerosis that are associated with onset of clinical cardiovascular events.
Objectives: To elucidate the role of oxidized low-density lipoprotein (oxLDL) and its primary receptor on endothelial cells, the lectin-like oxLDL receptor (LOX-1), in regulation of endothelin-1 expression and matrix metalloproteinase activity associated with inhalational exposure to vehicular engine emissions.
Methods: Atherosclerotic apolipoprotein E knockout mice were exposed by inhalation to filtered air or mixed whole engine emissions (250 μg particulate matter [PM]/m3 diesel + 50 μg PM/m3 gasoline exhausts) 6 h/d for 7 days. Concurrently, mice were treated with either mouse IgG or neutralizing antibodies to LOX-1 every other day. Vascular and plasma markers of oxidative stress and expression proatherogenic factors were assessed. In a parallel study, healthy human subjects were exposed to either 100 μg PM/m3 diesel whole exhaust or high-efficiency particulate air and charcoal-filtered “clean” air (control subjects) for 2 hours, on separate occasions.
Measurements and Main Results: Mixed emissions exposure increased oxLDL and vascular reactive oxygen species, as well as LOX-1, matrix metalloproteinase-9, and endothelin-1 mRNA expression and also monocyte/macrophage infiltration, each of which was attenuated with LOX-1 antibody treatment. In a parallel study, diesel exhaust exposure in volunteer human subjects induced significant increases in plasma-soluble LOX-1.
Conclusions: These findings demonstrate that acute exposure to vehicular source pollutants results in up-regulation of vascular factors associated with progression of atherosclerosis, endothelin-1, and matrix metalloproteinase-9, mediated through oxLDL–LOX-1 receptor signaling, which may serve as a novel target for future therapy.
PMCID: PMC3172889  PMID: 21493736
atherosclerosis; particulate matter; endothelin-1; matrix metalloproteinase; oxidized low-density lipoprotein
17.  Inhibition of lectin-like oxidized low-density lipoprotein receptor-1 reduces leukocyte adhesion within the intestinal microcirculation in experimental endotoxemia in rats 
Critical Care  2010;14(6):R223.
Lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1), the major endothelial receptor for oxidized low-density lipoprotein, is also involved in leukocyte recruitment. Systemic leukocyte activation in sepsis represents a crucial factor in the impairment of the microcirculation of different tissues, causing multiple organ failure and subsequently death. The aim of our experimental study was to evaluate the effects of LOX-1 inhibition on the endotoxin-induced leukocyte adherence and capillary perfusion within the intestinal microcirculation by using intravital microscopy (IVM).
We used 40 male Lewis rats for the experiments. Ten placebo-treated animals served as a control. Thirty animals received 5 mg/kg lipopolysaccharide (LPS) intravenously. Ten endotoxemic rats remained untreated. In 10 LPS animals, we administered additionally 10 mg/kg LOX-1 antibodies. Ten further LPS animals received a nonspecific immunoglobulin (rat IgG) intravenously. After 2 hours of observation, intestinal microcirculation was evaluated by using IVM; the plasma levels of monocyte chemoattractant protein-1 (MCP-1) and tumor necrosis factor-alpha (TNF-α) were determined; and LOX-1 expression was quantified in intestinal tissue with Western blot and reverse-transcription polymerase chain reaction (PCR).
LOX-1 inhibition significantly reduced LPS-induced leukocyte adhesion in intestinal submucosal venules (P < 0.05). At the protein and mRNA levels, LOX-1 expression was significantly increased in untreated LPS animals (P < 0.05), whereas in animals treated with LOX-1 antibody, expression of LOX-1 was reduced (P < 0.05). MCP-1 plasma level was reduced after LOX-1 antibody administration.
Inhibition of LOX-1 reduced leukocyte activation in experimental endotoxemia. LOX-1 represents a novel target for the modulation of the inflammatory response within the microcirculation in sepsis.
PMCID: PMC3220004  PMID: 21143965
18.  Change in the Body Mass Index Distribution for Women: Analysis of Surveys from 37 Low- and Middle-Income Countries 
PLoS Medicine  2013;10(1):e1001367.
Using cross-sectional surveys, Fahad Razak and colleagues investigate how the BMI (body mass index) distribution is changing for women in low- and middle-income countries.
There are well-documented global increases in mean body mass index (BMI) and prevalence of overweight (BMI≥25.0 kg/m2) and obese (BMI≥30.0 kg/m2). Previous analyses, however, have failed to report whether this weight gain is shared equally across the population. We examined the change in BMI across all segments of the BMI distribution in a wide range of countries, and assessed whether the BMI distribution is changing between cross-sectional surveys conducted at different time points.
Methods and Findings
We used nationally representative surveys of women between 1991–2008, in 37 low- and middle-income countries from the Demographic Health Surveys ([DHS] n = 732,784). There were a total of 96 country-survey cycles, and the number of survey cycles per country varied between two (21/37) and five (1/37). Using multilevel regression models, between countries and within countries over survey cycles, the change in mean BMI was used to predict the standard deviation of BMI, the prevalence of underweight, overweight, and obese. Changes in median BMI were used to predict the 5th and 95th percentile of the BMI distribution. Quantile-quantile plots were used to examine the change in the BMI distribution between surveys conducted at different times within countries. At the population level, increasing mean BMI is related to increasing standard deviation of BMI, with the BMI at the 95th percentile rising at approximately 2.5 times the rate of the 5th percentile. Similarly, there is an approximately 60% excess increase in prevalence of overweight and 40% excess in obese, relative to the decline in prevalence of underweight. Quantile-quantile plots demonstrate a consistent pattern of unequal weight gain across percentiles of the BMI distribution as mean BMI increases, with increased weight gain at high percentiles of the BMI distribution and little change at low percentiles. Major limitations of these results are that repeated population surveys cannot examine weight gain within an individual over time, most of the countries only had data from two surveys and the study sample only contains women in low- and middle-income countries, potentially limiting generalizability of findings.
Mean changes in BMI, or in single parameters such as percent overweight, do not capture the divergence in the degree of weight gain occurring between BMI at low and high percentiles. Population weight gain is occurring disproportionately among groups with already high baseline BMI levels. Studies that characterize population change should examine patterns of change across the entire distribution and not just average trends or single parameters.
Please see later in the article for the Editors' Summary
Editors' Summary
The number of obese people (individuals who have an excessive amount of body fat) is rapidly increasing in many countries. Globally, there were about 200 million obese adults in 1995; by 2010, 475 million adults were obese and another billion were classified as overweight. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30.0 kg/m2. Compared to people with a healthy weight (a BMI between 18.5 and 24.9 kg/m2), obese individuals and overweight individuals (who have a BMI between 25.0 and 29.9 kg/m2) have an increased risk of developing diabetes, heart disease and stroke, and tend to die younger. At the same time in many developing countries substantial numbers of people are underweight (BMI <18.5 kg/m2) or have chronic energy deficiency (BMI <16.0 kg/m2) and are at risk of increased risk of dying due to infectious disease or respiratory problems.
Why Was This Study Done?
The global obesity epidemic is usually described in terms of increases in the average BMI or in the prevalence of obesity (the proportion of the population whose BMI is above 30.0 kg/m2). Such descriptions assume that the BMIs of fat and thin people are increasing at the same rate and that the shape of the population's BMI distribution curve remains constant. However, as average BMI and the prevalence of obesity can increase it is unclear how the prevalence of underweight changes. This is potentially important for the health of the population because underweight individuals, like obese individuals, tend to die younger than healthy weight individuals, particularly in low-income countries. In this study, the researchers use repeated cross-sectional survey data collected from low- and middle-income countries in the Demographic and Health Surveys (DHS) to examine changes in BMI in women across the BMI distribution between 1991 and 2008. Repeated cross-sectional surveys collect data from a population at multiple time points from different individuals drawn from the same population, DHS are a data collection and surveillance project that help developing countries track health and population trends.
What Did the Researchers Do and Find?
The researchers used statistical models to analyze data from DHS surveys of more than 730,000 women living in 37 low- and middle-income countries (two to five surveys per country). Increasing average BMI was associated with an increase in the standard deviation of BMI (a measure of the dispersion of BMI in the population) both across and within countries over time. With increasing average BMI, the BMI at both the 5th and 95th percentile increased; 90% of the BMIs in a population lie between these percentiles so these BMI values indicate the spread of the BMI distribution. However, the BMI at the 95th percentile increased about 2.5 times faster than the BMI at the 5th percentile. Moreover, with increasing average BMI, the prevalence of overweight and obesity increased faster than the decline in the prevalence of underweight. Finally, quantile-quantile plots for each country (a graphical method that compares two distributions) revealed a consistent pattern of unequal weight gain across the BMI distribution as average BMI increased, with pronounced weight gains at the obese end of the distribution and little change at the underweight end.
What Do These Findings Mean?
These findings show that increases in average BMI are associated with an increased spread of BMI across and within populations. Consequently, changes in average BMI or single measurements such as the prevalence of overweight do not capture the divergence in the degree of weight gain occurring between that part of the population that has a low BMI and that part that has a high BMI. In other words, at least for the low- and middle-income countries included in this study, population weight gain is occurring disproportionately among groups with high baseline BMI levels. The researchers suggest, therefore, that the characterization of the BMI of populations over time should examine the patterns of change across the whole BMI distribution. Moreover, rather than a single broad population strategy for weight control, optimum health outcomes, they suggest, might be achieved by a strategy that includes targeted interventions to reduce weight in high BMI segments of the population and to increase weight in low BMI segments.
Additional Information
Please access these Web sites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on obesity (in several languages); Malri's story describes the health risks faced by an obese child
The UK National Health Service Choices website also provides detailed information about obesity and a link to a personal story about losing weight
The International Obesity Taskforce provides information about the global obesity epidemic
The US Department of Agriculture's website provides a personal healthy eating plan; the Weight-control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
MedlinePlus has links to further information about obesity (in English and Spanish)
PMCID: PMC3545870  PMID: 23335861
19.  Electronegative Low-Density Lipoprotein Increases C-Reactive Protein Expression in Vascular Endothelial Cells through the LOX-1 Receptor 
PLoS ONE  2013;8(8):e70533.
Increased plasma C-reactive protein (CRP) levels are associated with the occurrence and severity of acute coronary syndrome. We investigated whether CRP can be generated in vascular endothelial cells (ECs) after exposure to the most electronegative subfraction of low-density lipoprotein (LDL), L5, which is atherogenic to ECs. Because L5 and CRP are both ligands for the lectin-like oxidized LDL receptor-1 (LOX-1), we also examined the role of LOX-1.
Methods and Results
Plasma LDL samples isolated from asymptomatic hypercholesterolemic (LDL cholesterol [LDL-C] levels, 154.6±20 mg/dL; n = 7) patients and normocholesterolemic (LDL-C levels, 86.1±21 mg/dL; P<0.001; n = 7) control individuals were chromatographically resolved into 5 subfractions, L1-L5. The L5 percentage (L5%) and the plasma L5 concentration ([L5]  =  L5% × LDL-C) in the patient and control groups were 8.1±2% vs. 2.3±1% (P<0.001) and 12.6±4 mg/dL vs. 1.9±1 mg/dL (P<0.001), respectively. In hypercholesterolemic patients treated with atorvastatin for 6 months (10 mg/day), [L5] decreased from 12.6±4 mg/dL to 4.5±1.1 mg/dL (P = 0.011; n = 5), whereas both [L5] and L5% returned to baseline levels in 2 noncompliant patients 3 months after discontinuation. In cultured human aortic ECs (HAECs), L5 upregulated CRP expression in a dose- and time-dependent manner up to 2.5-fold (P<0.01), whereas the least electronegative subfraction, L1, had no effect. DiI-labeled L1, internalized through the LDL receptor, became visible inside HAECs within 30 seconds. In contrast, DiI-labeled L5, internalized through LOX-1, became apparent after 5 minutes. L5-induced CRP expression manifested at 30 minutes and was attenuated by neutralizing LOX-1. After 30 minutes, L5 but not L1 induced reactive oxygen species (ROS) production. Both L5-induced ROS and CRP production were attenuated by ROS inhibitor N-acetyl cysteine.
Our results suggest that CRP, L5, and LOX-1 form a cyclic mechanism in atherogenesis and that reducing plasma L5 levels with atorvastatin disrupts the vascular toxicity of L5.
PMCID: PMC3738565  PMID: 23950953
20.  Overweight and Effect of Hormone Replacement Therapy on Lipid Profiles in Postmenopausal Women 
Many experimental and observational studies have suggested that hormone replacement therapy (HRT) in postmenopausal women is cardioprotective. However, the results of randomized controlled trials have been discouraging. We attempted to evaluate the influence of overweight, a frequent risk factor for coronary artery disease, on the lipid-modifying effects of HRT.
A total of 345 postmenopausal women were divided into 2 groups according to body mass index (BMI): the control group; BMI<25 Kg/m2 (n=248) and the overweight group; BMI≥25 Kg/m2 (n=97). All women received either 0.625 mg conjugated equine estrogen (CEE)(n=139), CEE plus 5 mg medroxyprogesterone acetate (MPA)(n=97) or CEE plus 10 mg MPA (n=109). Lipid profiles were measured before and 12 months after HRT.
In both the control and overweight groups, HRT reduced low density lipoprotein cholesterol (LDL-C) (p=0.000 and p=0.000 respectively) and lipoprotein (a) [Lp(a)] levels (p=0.000 and p=0.000 respectively) and raised high density lipoprotein cholesterol (HDL-C) levels (p=0.000 and p=0.002 respectively). However, the elevation of the HDL-C level was higher in the control group than in overweight group (17.5% vs. 10.4%, p=0.015), and this was significant after adjusting for changes in body weights (p=0.016). There were no differences in the reduction of LDL-C (p=0.20) and Lp(a) (p=0.09) levels between the two groups.
HRT had less favorable effects on HDL-C levels in overweight postmenopausal women than in women with normal body weight. This finding may be partially associated with no cardioprotective effect of HRT in postmenopausal patients at a high risk due to multiple risk factors including obesity.
PMCID: PMC3891410  PMID: 15906951
Overweight; Lipids; Lipoproteins; Hormones; Women
21.  LOX-1 Plays an Important Role in Ischemia-Induced Angiogenesis of Limbs 
PLoS ONE  2014;9(12):e114542.
LOX-1, lectin-like oxidized low-density lipoprotein (LDL) receptor-1, is a single transmembrane receptor mainly expressed on endothelial cells. LOX-1 mediates the uptake of oxidized LDL, an early step in atherosclerosis; however, little is known about whether LOX-1 is involved in angiogenesis during tissue ischemia. Therefore, we examined the role of LOX-1 in ischemia-induced angiogenesis in the hindlimbs of LOX-1 knockout (KO) mice. Angiogenesis was evaluated in a surgically induced hindlimb ischemia model using laser Doppler blood flowmetry (LDBF) and histological capillary density (CD) and arteriole density (AD). After right hindlimb ischemia, the ischemic/nonischemic hindlimb blood flow ratio was persistently lower in LOX-1 KO mice than in wild-type (WT) mice. CD and AD were significantly smaller in LOX-1 KO mice than in WT mice on postoperative day 14. Immunohistochemical analysis revealed that the number of macrophages infiltrating ischemic tissues was significantly smaller in LOX-1 KO mice than in WT mice. The number of infiltrated macrophages expressing VEGF was also significantly smaller in LOX-1 KO mice than in WT mice. Western blot analysis and ROS production assay revealed that LOX- KO mice show significant decrease in Nox2 expression, ROS production and HIF-1α expression, the phosphorylation of p38 MAPK and NF-κB p65 subunit as well as expression of redox-sensitive vascular cell adhesion molecule-1 (VCAM-1) and LOX-1 itself in ischemic muscles, which is supposed to be required for macrophage infiltration expressing angiogenic factor VEGF. Reduction of VEGF expression successively suppressed the phosphorylation of Akt and eNOS, which accelerated angiogenesis, in the ischemic leg of LOX-1 KO mice. Our findings indicate that LOX-1 plays an important role in ischemia-induced angiogenesis by 1) Nox2-ROS-NF-κB activation, 2) upregulated expression of adhesion molecules: VCAM-1 and LOX-1 and 3) promoting macrophage infiltration, which expresses angiogenic factor VEGF.
PMCID: PMC4267738  PMID: 25514797
22.  Protective Effects of Let-7a and Let-7b on Oxidized Low-Density Lipoprotein Induced Endothelial Cell Injuries 
PLoS ONE  2014;9(9):e106540.
Lectin-like low-density lipoprotein receptor 1 (LOX-1) is a receptor for oxidized low density lipoprotein (oxLDL) in endothelial cells. The activation of LOX-1 by oxLDL stimulates the apoptosis and dysfunction of endothelial cells, and contributes to atherogenesis. However, the regulatory factors for LOX-1 are still unclear. MicroRNAs are small, endogenous, non-coding RNAs that regulate gene expressions at a post-transcriptional level. The let-7 family is the second microRNA been discovered, which plays important roles in cardiovascular diseases. Let-7a and let-7b were predicted to target LOX-1 3′-UTR and be highly expressed in endothelial cells. The present study demonstrated that LOX-1 was a target of let-7a and let-7b. They inhibited the expression of LOX-1 by targeting the positions of 310-316 in LOX-1 3′-UTR. Over-expression of let-7a and let-7b inhibited the oxLDL-induced endothelial cell apoptosis, NO deficiency, ROS over-production, LOX-1 upregulation and endothelial nitric oxide synthase (eNOS) downregulation. Moreover, we found that oxLDL treatment induced p38MAPK phosphorylation, NF-κB nuclear translocation, IκB degradation and PKB dephosphorylation. Let-7a or let-7b over-expression attenuated these alterations significantly. The present study may provide a new insight into the protective properties of let-7a and let-7b in preventing the endothelial dysfunction associated with cardiovascular disease, such as atherosclerosis.
PMCID: PMC4172475  PMID: 25247304
23.  VCre/VloxP and SCre/SloxP: new site-specific recombination systems for genome engineering 
Nucleic Acids Research  2011;39(8):e49.
We developed two new site-specific recombination systems named VCre/VloxP and SCre/SloxP for genome engineering. Their recognition sites are different from Cre recognition sites because VCre and SCre recombinases share less protein similarity with Cre, even though the basic 13-8-13 structures of their recognition sites are identical. Mutant VloxP and SloxP, which have the same uses as mutant loxP, were also developed. VCre/VloxP and SCre/SloxP in combination with Cre/loxP and Flp/FRT systems can serve as powerful tools for genome engineering, especially when used to genetically modify both alleles of a single gene in mouse and human cells.
PMCID: PMC3082901  PMID: 21288882
24.  Association between Class III Obesity (BMI of 40–59 kg/m2) and Mortality: A Pooled Analysis of 20 Prospective Studies 
PLoS Medicine  2014;11(7):e1001673.
In a pooled analysis of 20 prospective studies, Cari Kitahara and colleagues find that class III obesity (BMI of 40–59) is associated with excess rates of total mortality, particularly due to heart disease, cancer, and diabetes.
Please see later in the article for the Editors' Summary
The prevalence of class III obesity (body mass index [BMI]≥40 kg/m2) has increased dramatically in several countries and currently affects 6% of adults in the US, with uncertain impact on the risks of illness and death. Using data from a large pooled study, we evaluated the risk of death, overall and due to a wide range of causes, and years of life expectancy lost associated with class III obesity.
Methods and Findings
In a pooled analysis of 20 prospective studies from the United States, Sweden, and Australia, we estimated sex- and age-adjusted total and cause-specific mortality rates (deaths per 100,000 persons per year) and multivariable-adjusted hazard ratios for adults, aged 19–83 y at baseline, classified as obese class III (BMI 40.0–59.9 kg/m2) compared with those classified as normal weight (BMI 18.5–24.9 kg/m2). Participants reporting ever smoking cigarettes or a history of chronic disease (heart disease, cancer, stroke, or emphysema) on baseline questionnaires were excluded. Among 9,564 class III obesity participants, mortality rates were 856.0 in men and 663.0 in women during the study period (1976–2009). Among 304,011 normal-weight participants, rates were 346.7 and 280.5 in men and women, respectively. Deaths from heart disease contributed largely to the excess rates in the class III obesity group (rate differences = 238.9 and 132.8 in men and women, respectively), followed by deaths from cancer (rate differences = 36.7 and 62.3 in men and women, respectively) and diabetes (rate differences = 51.2 and 29.2 in men and women, respectively). Within the class III obesity range, multivariable-adjusted hazard ratios for total deaths and deaths due to heart disease, cancer, diabetes, nephritis/nephrotic syndrome/nephrosis, chronic lower respiratory disease, and influenza/pneumonia increased with increasing BMI. Compared with normal-weight BMI, a BMI of 40–44.9, 45–49.9, 50–54.9, and 55–59.9 kg/m2 was associated with an estimated 6.5 (95% CI: 5.7–7.3), 8.9 (95% CI: 7.4–10.4), 9.8 (95% CI: 7.4–12.2), and 13.7 (95% CI: 10.5–16.9) y of life lost. A limitation was that BMI was mainly ascertained by self-report.
Class III obesity is associated with substantially elevated rates of total mortality, with most of the excess deaths due to heart disease, cancer, and diabetes, and major reductions in life expectancy compared with normal weight.
Please see later in the article for the Editors' Summary
Editors' Summary
The number of obese people (individuals with an excessive amount of body fat) is increasing rapidly in many countries. Worldwide, according to the Global Burden of Disease Study 2013, more than a third of all adults are now overweight or obese. Obesity is defined as having a body mass index (BMI, an indicator of body fat calculated by dividing a person's weight in kilograms by their height in meters squared) of more than 30 kg/m2 (a 183-cm [6-ft] tall man who weighs more than 100 kg [221 lbs] is obese). Compared to people with a healthy weight (a BMI between 18.5 and 24.9 kg/m2), overweight and obese individuals (who have a BMI between 25.0 and 29.9 kg/m2 and a BMI of 30 kg/m2 or more, respectively) have an increased risk of developing diabetes, heart disease, stroke, and some cancers, and tend to die younger. Because people become unhealthily fat by consuming food and drink that contains more energy (kilocalories) than they need for their daily activities, obesity can be prevented or treated by eating less food and by increasing physical activity.
Why Was This Study Done?
Class III obesity (extreme, or morbid, obesity), which is defined as a BMI of more than 40 kg/m2, is emerging as a major public health problem in several high-income countries. In the US, for example, 6% of adults are now morbidly obese. Because extreme obesity used to be relatively uncommon, little is known about the burden of disease, including total and cause-specific mortality (death) rates, among individuals with class III obesity. Before we can prevent and treat class III obesity effectively, we need a better understanding of the health risks associated with this condition. In this pooled analysis of prospective cohort studies, the researchers evaluate the risk of total and cause-specific death and the years of life lost associated with class III obesity. A pooled analysis analyzes the data from several studies as if the data came from one large study; prospective cohort studies record the characteristics of a group of participants at baseline and follow them to see which individuals develop a specific condition.
What Did the Researchers Do and Find?
The researchers included 20 prospective (mainly US) cohort studies from the National Cancer Institute Cohort Consortium (a partnership that studies cancer by undertaking large-scale collaborations) in their pooled analysis. After excluding individuals who had ever smoked and people with a history of chronic disease, the analysis included 9,564 adults who were classified as class III obese based on self-reported height and weight at baseline and 304,011 normal-weight adults. Among the participants with class III obesity, mortality rates (deaths per 100,000 persons per year) during the 30-year study period were 856.0 and 663.0 in men and women, respectively, whereas the mortality rates among normal-weight men and women were 346.7 and 280.5, respectively. Heart disease was the major contributor to the excess death rate among individuals with class III obesity, followed by cancer and diabetes. Statistical analyses of the pooled data indicate that the risk of all-cause death and death due to heart disease, cancer, diabetes, and several other diseases increased with increasing BMI. Finally, compared with having a normal weight, having a BMI between 40 and 59 kg/m2 resulted in an estimated loss of 6.5 to 13.7 years of life.
What Do These Findings Mean?
These findings indicate that class III obesity is associated with a substantially increased rate of death. Notably, this death rate increase is similar to the increase associated with smoking among normal-weight people. The findings also suggest that heart disease, cancer, and diabetes are responsible for most of the excess deaths among people with class III obesity and that having class III obesity results in major reductions in life expectancy. Importantly, the number of years of life lost continues to increase for BMI values above 50 kg/m2, and beyond this point, the loss of life expectancy exceeds that associated with smoking among normal-weight people. The accuracy of these findings is limited by the use of self-reported height and weight measurements to calculate BMI and by the use of BMI as the sole measure of obesity. Moreover, these findings may not be generalizable to all populations. Nevertheless, these findings highlight the need to develop more effective interventions to combat the growing public health problem of class III obesity.
Additional Information
Please access these websites via the online version of this summary at
The US Centers for Disease Control and Prevention provides information on all aspects of overweight and obesity (in English and Spanish)
The World Health Organization provides information on obesity (in several languages); Malri's story describes the health risks faced by an obese child
The UK National Health Service Choices website provides information about obesity, including a personal story about losing weight
The Global Burden of Disease Study website provides the latest details about global obesity trends
The US Department of Agriculture's website provides a personal healthy eating plan; the Weight-Control Information Network is an information service provided for the general public and health professionals by the US National Institute of Diabetes and Digestive and Kidney Diseases (in English and Spanish)
MedlinePlus provides links to other sources of information on obesity (in English and Spanish)
PMCID: PMC4087039  PMID: 25003901
25.  Dyslipidemia-Induced Neuropathy in Mice 
Diabetes  2009;58(10):2376-2385.
Neuropathy is a frequent and severe complication of diabetes. Multiple metabolic defects in type 2 diabetic patients result in oxidative injury of dorsal root ganglia (DRG) neurons. Our previous work focused on hyperglycemia clearly demonstrates induction of mitochondrial oxidative stress and acute injury in DRG neurons; however, this mechanism is not the only factor that produces neuropathy in vivo. Dyslipidemia also correlates with the development of neuropathy, even in pre-diabetic patients. This study was designed to explore the contribution of dyslipidemia in neuropathy.
Mice (n = 10) were fed a control (10% kcal %fat) or high-fat (45% kcal %fat) diet to explore the impact of plasma lipids on the development of neuropathy. We also examined oxidized lipid–mediated injury in cultured DRG neurons from adult rat using oxidized LDLs (oxLDLs).
Mice on a high-fat diet have increased oxLDLs and systemic and nerve oxidative stress. They develop nerve conduction velocity (NCV) and sensory deficits prior to impaired glucose tolerance. In vitro, oxLDLs lead to severe DRG neuron oxidative stress via interaction with the receptor lectin-like oxLDL receptor (LOX)-1 and subsequent NAD(P)H oxidase activity. Oxidative stress resulting from oxLDLs and high glucose is additive.
Multiple metabolic defects in type 2 diabetes directly injure DRG neurons through different mechanisms that all result in oxidative stress. Dyslipidemia leads to high levels of oxLDLs that may injure DRG neurons via LOX-1 and contribute to the development of diabetic neuropathy.
PMCID: PMC2750230  PMID: 19592619

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