Correction of Familial LCAT Deficiency by AAV-hLCAT Prevents Renal Injury and Atherosclerosis in Hamsters

Objective: Familial lecithin:cholesterol acyltransferase (LCAT) deficiency is a rare human disease characterized by very low HDL (high-density lipoprotein) and elevated free cholesterol, in which renal injury has been confirmed in, but whether familial LCAT deficiency patients were at higher risk of atherosclerosis-related cardiovascular disease was highly controversial. Using CRISPR/Cas9 gene-editing technology, we established LCAT knockout (LCAT −/− ) hamster model showing both diet-induced and spontaneous atherosclerosis, indicating that this animal model provides a platform for the therapeutic study of renal disease and atherosclerosis caused by LCAT deficiency. Approach and Results: To explore an efficient therapy for familial LCAT deficiency and then investigate whether correction of LCAT deficiency will exert a beneficial role in atherosclerosis-related cardiovascular disease, herein we established a liver-specific adeno-associated virus 8 expressing human LCAT (AAV-hLCAT) to determine the efficacy of gene therapy for dyslipidemia, renal injury, and atherosclerosis-related cardiovascular disease in LCAT −/− hamsters. Single administration of AAV-hLCAT via intrajugular vein could completely restore LCAT expression in LCAT −/− animals in a dose-dependent manner and rapidly normalize plasma HDL levels within 2 weeks. In addition, upon high-fat diet intervention for 4 weeks, AAV-hLCAT administered LCAT −/− hamsters exhibited improved atherogenic lipoprotein profiles, lower urine protein/creatinine ratio, a significant increase in red blood cells and hemoglobin, thus eventually protecting against atherosclerotic development. Conclusions: Single administration of AAV-hLCAT effectively corrects LCAT deficiency for a long-term in LCAT −/− hamsters and completely rescue multiple abnormalities, including renal injury, anemia, and atherosclerosis, suggesting that AAV8-mediated hLCAT expression in liver will be a promising therapeutic approach for familial LCAT deficiency.

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Association of Metabolic Factors with Essential Hypertension

TAJ Journal of Teachers Association ◽

10.3329/taj.v24i1.37444 ◽

2011 ◽

Vol 24 (1) ◽

pp. 21-25

Author(s):

N Rahman Khandaker ◽

Akhtaruzzaman ◽

K Rahat Mahfuz ◽

AR Khandakar ◽

MMR Khan ◽

...

Keyword(s):

Cardiovascular Disease ◽

Metabolic Syndrome ◽

Waist Circumference ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

Metabolic Factors ◽

College Hospital ◽

High Waist Circumference ◽

Increased Risk ◽

Low Hdl

Background-Metabolic syndrome is a risk factor for cardiovascular disease, so it should call attention. South Asian person has preponderance to it. Objectives-The proper findings of metabolic syndrome are a key to prevent cardiovascular disease. Hypertension is a component of metabolic syndrome with which patients are at increased risk for cardiovascular disease. Methods-This study was carried out in cardiology outdoor of Shaheed Suhrawardy medical college hospital, Dhaka. A total of 322 patients were enrolled from January 2008 to December 2010. Metabolic syndrome was defined as three of the followings: (a) Abnormal fasting serum level of glucose (≥110 mg/dl or 6.1 mmol/L), ( b) abdominal obesity (waist circumference >102 cm in men and >88 cm in women), (c) Triglycerides (≥150 mg/dl), (d) High density lipoprotein cholesterol (<40 mg/dl in men and <50 mg/dl in woman), (e) Hypertension, which was common in all patients. Results- Among hypertensive’s patients 31.8% had hyperglycemia, 37.9% had high waist circumference, 69.8% had low HDL cholesterol and 54.3% high triglycerides. As per definition of NCEP-ATP-III, metabolic syndrome had been detected in 17% of male, 37% of female and 27% of the total population. Conclusion- Metabolic factors are a common association in hypertensive cases. These patients are at increased risk of coronary and cerebro-vascular disease and require more vigorous prevention. Furthermore in all hypertensive patients metabolic screening is recommended. TAJ 2011; 24(1): 21-25

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LCAT, HDL Cholesterol and Ischemic Cardiovascular Disease: A Mendelian Randomization Study of HDL Cholesterol in 54,500 Individuals

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2011-1846 ◽

2012 ◽

Vol 97 (2) ◽

pp. E248-E256 ◽

Cited By ~ 161

Author(s):

Christiane L. Haase ◽

Anne Tybjærg-Hansen ◽

Abbas Ali Qayyum ◽

Jesper Schou ◽

Børge G. Nordestgaard ◽

...

Keyword(s):

Cardiovascular Disease ◽

Causal Relation ◽

Cholesterol Acyltransferase ◽

Density Lipoprotein ◽

Hdl Cholesterol ◽

General Population Study ◽

Instrumental Variable Analysis ◽

Cholesterol Levels ◽

Increased Risk ◽

Low Hdl

Background: Epidemiologically, high-density lipoprotein (HDL) cholesterol levels associate inversely with risk of ischemic cardiovascular disease. Whether this is a causal relation is unclear. Methods: We studied 10,281 participants in the Copenhagen City Heart Study (CCHS) and 50,523 participants in the Copenhagen General Population Study (CGPS), of which 991 and 1,693 participants, respectively, had developed myocardial infarction (MI) by August 2010. Participants in the CCHS were genotyped for all six variants identified by resequencing lecithin-cholesterol acyltransferase in 380 individuals. One variant, S208T (rs4986970, allele frequency 4%), associated with HDL cholesterol levels in both the CCHS and the CGPS was used to study causality of HDL cholesterol using instrumental variable analysis. Results: Epidemiologically, in the CCHS, a 13% (0.21 mmol/liter) decrease in plasma HDL cholesterol levels was associated with an 18% increase in risk of MI. S208T associated with a 13% (0.21 mmol/liter) decrease in HDL cholesterol levels but not with increased risk of MI or other ischemic end points. The causal odds ratio for MI for a 50% reduction in plasma HDL cholesterol due to S208T genotype in both studies combined was 0.49 (0.11–2.16), whereas the hazard ratio for MI for a 50% reduction in plasma HDL cholesterol in the CCHS was 2.11 (1.70–2.62) (Pcomparison = 0.03). Conclusion: Low plasma HDL cholesterol levels robustly associated with increased risk of MI but genetically decreased HDL cholesterol did not. This may suggest that low HDL cholesterol levels per se do not cause MI.

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Intracellular GSH of Streptococcus thermophilus shows anti-oxidative activity against low-density lipoprotein oxidation in vitro and in a hyperlipidaemic hamster model

Beneficial Microbes ◽

10.3920/bm2017.0065 ◽

2018 ◽

Vol 9 (1) ◽

pp. 143-152 ◽

Cited By ~ 1

Author(s):

S. Kusuhara ◽

M. Ito ◽

T. Sato ◽

W. Yokoi ◽

Y. Yamamoto ◽

...

Keyword(s):

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Streptococcus Thermophilus ◽

Oxidative Modification ◽

Mass Spectrometry Analysis ◽

Oxidative Activity ◽

Ldl Oxidation ◽

Low Density ◽

Dependent Manner ◽

Hamster Model

Streptococcus thermophilus YIT 2001 (ST-1), a lactic acid bacterial strain, was shown to have inhibitory effects on the oxidation of low-density lipoprotein (LDL) and the development of aortic fatty lesions in an animal model, and lower the serum levels of malondialdehyde-modified LDL, an oxidative modification product of LDL, in a clinical trial. This study aimed to identify the intracellular active component of ST-1 associated with anti-oxidative activity against LDL oxidation. High-performance liquid chromatography-electrospray ionisation mass spectrometry analysis after fractionation of the cellular extract by reversed-phase chromatography demonstrated that the active fraction contained reduced glutathione (GSH). GSH showed anti-oxidative activity in a dose-dependent manner, while this activity disappeared following thiol derivatisation. ST-1 had the strongest anti-oxidative activity against LDL oxidation and the highest level of intracellular GSH among five strains of S. thermophilus. In addition, the anti-oxidative activity of ST-1 after thiol derivatisation decreased by about half, which was similar to that of three other strains containing poor or no intracellular GSH or thiol components. Moreover, anti-oxidative activity against LDL oxidation was observed in hyperlipidaemic hamsters fed with high GSH ST-1 cells but not in those given low GSH cells. These findings suggest that intracellular GSH in ST-1 may provide beneficial effects via anti-oxidative activity against LDL oxidation and excess oxidative stress in the blood.

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Obesity and cardiovascular disease risk factors in Tehran adults: a population-based study

Eastern Mediterranean Health Journal ◽

10.26719/2004.10.6.887 ◽

2004 ◽

Vol 10 (6) ◽

pp. 887-897 ◽

Cited By ~ 3

Author(s):

F. Fazizi

Keyword(s):

Risk Factors ◽

Cardiovascular Disease ◽

Disease Risk ◽

Cardiovascular Disease Risk ◽

Density Lipoprotein ◽

Population Based ◽

Lipoprotein Cholesterol ◽

Cardiovascular Disease Risk Factors ◽

Obese Women ◽

Low Hdl

The relationship between obesity and cardiovascular disease risk factors was assessed in 3622 males and 5025 females aged 20-70 years. Body mass index, waist circumference, waist-to-height and waist-to-hip ratios were calculated. Obese men had a higher risk of hypertension, high total cholesterol [TC], high triglycerides [TG], high low-density lipoprotein cholesterol [LDL-C] and low high-density lipoprotein cholesterol [HDL-C] levels than non-obese men. Centrally obese men were more susceptible to high TG, hypertension and high TC. Obese women had a higher chance of being hypertensive and having high total TC, high TG, high LDL-C and low HDL-C levels than non-obese females. Centrally obese women had higher odds for high TG and low HDL-C. There is a need for education about lifestyle change in the country

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Associations between cardiovascular disease, cancer, and very low high-density lipoprotein cholesterol in the REasons for Geographical and Racial Differences in Stroke (REGARDS) study

Cardiovascular Research ◽

10.1093/cvr/cvy198 ◽

2018 ◽

Vol 115 (1) ◽

pp. 204-212 ◽

Cited By ~ 18

Author(s):

Peter Penson ◽

D Leann Long ◽

George Howard ◽

Virginia J Howard ◽

Steven R Jones ◽

...

Keyword(s):

Cardiovascular Disease ◽

High Density Lipoprotein ◽

Multiple Imputation ◽

Racial Differences ◽

Density Lipoprotein ◽

Complete Case ◽

All Cause Mortality ◽

Low Hdl ◽

Regards Study ◽

Reduced Risk

AbstractAimsRelatively little is known about the health outcomes associated with very low plasma concentrations of high-density lipoprotein cholesterol (HDL-C) mainly because of the small numbers of individuals with such extreme values included in clinical trials. We, therefore, investigated the association between low and very low HDL-C concentration at baseline and incident all-cause-mortality, death from malignant disease (i.e. cancer), and with fatal or non-fatal incident coronary heart disease (CHD) in individuals from the Reasons for Geographical And Racial Differences in Stroke (REGARDS) study.Methods and resultsAnalysis was based on 21 751 participants from the REGARDS study who were free of CHD, other cardiovascular disease, and cancer at baseline and were categorized by baseline HDL-C into <30 mg/dL (very low), 30–<40 mg/dL (low), and ≥40 mg/dL (reference). A series of incremental Cox proportional hazards models were employed to assess the association between the HDL-C categories and outcomes. Statistical analysis was performed using both complete case methods and multiple imputations with chained equations. After adjustment for age, race, and sex, the hazard ratios (HRs) comparing the lowest and highest HDL-C categories were 1.48 [95% confidence interval (CI) 1.28–1.73] for all-cause mortality, 1.35 (95% CI 1.03–1.77) for cancer-specific mortality and 1.39 (95% CI 0.99–1.96) for incident CHD. These associations became non-significant in models adjusting for demographics, cardiovascular risk factors, and treatment for dyslipidaemia. We found evidence for an HDL paradox, whereby low HDL (30–<40 mg/dL) was associated with reduced risk of incident CHD in black participants in a fully adjusted complete case model (HR 0.63; 95% CI 0.46–0.88) and after multiple imputation analyses (HR 0.76; 95% CI 0.58–0.98). HDL-C (<30 mg/dL) was significantly associated with poorer outcomes in women for all outcomes, especially with respect to cancer mortality (HR 2.31; 95% CI 1.28–4.16) in a fully adjusted complete case model, replicated using multiple imputation (HR 1.81; 95% CI 1.03–3.20).ConclusionLow HDL-C was associated with reduced risk of incident CHD in black participants suggesting a potential HDL paradox for incident CHD. Very low HDL-C in women was significantly associated with cancer mortality in a fully adjusted complete case model.

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Prognostic effect of high-density lipoprotein cholesterol level in patients with atherosclerotic cardiovascular disease under statin treatment

Scientific Reports ◽

10.1038/s41598-020-78828-8 ◽

2020 ◽

Vol 10 (1) ◽

Author(s):

Yi-Heng Li ◽

◽

Wei-Kung Tseng ◽

Wei-Hsian Yin ◽

Fang-Ju Lin ◽

...

Keyword(s):

Cardiovascular Disease ◽

High Density Lipoprotein ◽

Protective Effect ◽

High Density Lipoprotein Cholesterol ◽

Density Lipoprotein ◽

Statin Treatment ◽

Lipoprotein Cholesterol ◽

Atherosclerotic Cardiovascular Disease ◽

Increased Risk ◽

Low Hdl

AbstractIn patients with atherosclerotic cardiovascular disease (ASCVD) under statin treatment, the influence of on-treatment level of high-density lipoprotein cholesterol (HDL-C) on cardiovascular (CV) events is controversial. Statin-treated patients were selected from the Taiwanese Secondary Prevention for patients with AtheRosCLErotic disease (T-SPARCLE) Registry, a multicenter, observational study of adult patients with ASCVD in Taiwan. Low HDL-C was defined as < 40 mg/dL for men and < 50 mg/dL for women. The primary outcome was a composite CV events including CV death, myocardial infarction (MI), stroke or cardiac arrest with resuscitation. A total of 3731 patients (mean age 65.6 years, 75.6% men) were included. Patients with on-treatment low HDL-C (44%, mean HDL-C 34.9 ± 6.8 mg/dL) were younger and with more diabetes and higher body weight. The mean follow-up time was 2.7 years. We used restricted cubic spline curves to examine the potential non-linear association between HDL-C and adverse outcomes. Decreased HDL-C levels were associated with a significantly increased risk of CV events in women (< 49 mg/dL in women) but not in men (< 42 mg/dL in men). However, the protective effect of elevated HDL-C levels was more prominent in men than in women. In ASCVD patients with statin therapy, low on-treatment HDL-C was common in Taiwan and associated with an increased risk of CV events in women. Higher HDL-C levels provided more protective effect in men than in women.

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Spontaneous Atherosclerosis in Aged LCAT-Deficient Hamsters With Enhanced Oxidative Stress—Brief Report

Arteriosclerosis Thrombosis and Vascular Biology ◽

10.1161/atvbaha.120.315265 ◽

2020 ◽

Vol 40 (12) ◽

pp. 2829-2836

Author(s):

Mengmeng Guo ◽

Zongyu Liu ◽

Yitong Xu ◽

Ping Ma ◽

Wei Huang ◽

...

Keyword(s):

Cholesterol Acyltransferase ◽

Density Lipoprotein ◽

Standard Laboratory ◽

Wild Type ◽

Male And Female ◽

Atherosclerotic Lesions ◽

Low Hdl ◽

Lcat Deficiency ◽

Underlying Mechanisms ◽

Standard Laboratory Diet

Objective: LCAT (lecithin cholesterol acyltransferase) deficiency results in severe low HDL (high-density lipoprotein). Although whether LCAT is pro- or antiatherosclerosis was in debate in mouse studies, our previous study clearly shows that LCAT deficiency (LCAT −/− ) in hamster accelerates atherosclerotic development on high-fat diet. However, unlike in hypercholesterolemia and hypertriglyceridemia, whether LCAT deficiency could lead to spontaneous atherosclerosis has not been studied yet in animal models. We, therefore, sought to investigate the atherosclerosis in LCAT −/− hamsters on standard laboratory diet and explore the potential underlying mechanisms. Approach and Results: Young (<8 months) and aged (>16 months) male and female wild-type and LCAT −/− hamsters on standard laboratory diet were used. Compared with age- and sex-matched wild-type hamsters, LCAT −/− hamsters showed a complete loss of plasma HDL and an increase in triglyceride by 2- to 8-fold at different stages of age. In aged LCAT −/− hamsters, the lesion areas at the aortic roots were ≈40×10 4 μm 3 in males and 18×10 4 μm 3 in females, respectively, which were consistent with the en face plaques observed in male (1.2%) and (1.5%) female groups, respectively. The results of plasma malondialdehyde measurement showed that malondialdehyde concentrations were markedly elevated to 54.4 μmol/L in males and 30 μmol/L in females, which are significantly associated with the atherosclerotic lesions. Conclusions: Our study demonstrates the development of spontaneous atherosclerotic lesions in aged male and female LCAT −/− hamsters with higher plasma oxidative lipid levels independent of plasma total cholesterol levels, further confirming the antiatherosclerotic role of LCAT.

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IgM anti-phosphorylcholine antibodies associate with senescent and IL-17+ T cells in SLE patients with a pro-inflammatory lipid profile

Rheumatology ◽

10.1093/rheumatology/kez264 ◽

2019 ◽

Vol 59 (2) ◽

pp. 407-417 ◽

Cited By ~ 4

Author(s):

Patricia López ◽

Javier Rodríguez-Carrio ◽

Aleida Martínez-Zapico ◽

Ángel I Pérez-Álvarez ◽

Lorena Benavente ◽

...

Keyword(s):

Cardiovascular Disease ◽

T Cell ◽

Lipid Profile ◽

Low Density Lipoprotein ◽

Density Lipoprotein ◽

Serum Levels ◽

T Cell Subsets ◽

Glucocorticoid Treatment ◽

Low Hdl ◽

High Triglyceride

Abstract Objective The aim was to evaluate whether T cell subsets and the lipid profile could be linked to the cardioprotective effect of IgM anti-phosphorylcholine (PC) antibodies in SLE. Methods Anti-PC antibodies were quantified by ELISA in 197 patients and 99 controls and analysed in relationship to clinical features, treatments and serum lipids. Carotid atheromatosis was evaluated by ultrasonography; Th1, Th17, Treg and CD4+CD28null cells by flow cytometry; and cytokine serum levels by immunoassays, in a subgroup of 120 SLE patients and 33 controls. Results IgM anti-PC serum levels were reduced in SLE patients compared with controls (P < 0.001) and were associated with age (β= −0.252; P = 0.002), high-density lipoprotein (HDL; β = 0.271; P = 0.001), low-density lipoprotein (LDL; β= −0.192; P = 0.017) and glucocorticoid treatment (β= −0.201; P = 0.012), whereas the IgG-to-IgM anti-PC ratio was increased (P = 0.007) and associated with age (β = 0.194; P = 0.028) and SLEDAI (β = 0.250; P = 0.005). Also, patients with clinical or subclinical cardiovascular disease exhibited reduced IgM anti-PC levels compared with their cardiovascular disease-free counterparts, regardless of glucocorticoid usage (P = 0.001). CD4+CD28null and Th17 cells were increased in SLE patients compared with controls (P < 0.01) and correlated inversely with IgM anti-PC levels. These associations were observed in patients displaying high triglyceride or low HDL levels, even after adjusting for clinical parameters and treatments (CD4+CD28null: β = −0.455, P = 0.001; Th17: β= −0.280, P = 0.035), but not in those with a normal lipid profile. High triglyceride and low HDL profiles were related to low IgM anti-PC and Treg levels, respectively, whereas both lipid profiles were associated with inflammatory markers and cytokines. Conclusion The present study provides evidence for an association of IgM anti-PC antibodies with pro-atherogenic T cell subsets in SLE, with a high triglyceride/low HDL lipid profile playing a facilitating major role.

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Free cholesterol transfer to high-density lipoprotein (HDL) upon triglyceride lipolysis underlies the U-shape relationship between HDL-cholesterol and cardiovascular disease

European Journal of Preventive Cardiology ◽

10.1177/2047487319894114 ◽

2019 ◽

Vol 27 (15) ◽

pp. 1606-1616 ◽

Cited By ~ 3

Author(s):

Ma Feng ◽

Maryam Darabi ◽

Emilie Tubeuf ◽

Aurélie Canicio ◽

Marie Lhomme ◽

...

Keyword(s):

Cardiovascular Disease ◽

Cardiovascular Risk ◽

High Density Lipoprotein ◽

Lipoprotein Lipase ◽

Free Cholesterol ◽

Density Lipoprotein ◽

High Density ◽

Knock Out ◽

Low Hdl

Background Low concentrations of high-density lipoprotein cholesterol (HDL-C) represent a well-established cardiovascular risk factor. Paradoxically, extremely high HDL-C levels are equally associated with elevated cardiovascular risk, resulting in the U-shape relationship of HDL-C with cardiovascular disease. Mechanisms underlying this association are presently unknown. We hypothesised that the capacity of high-density lipoprotein (HDL) to acquire free cholesterol upon triglyceride-rich lipoprotein (TGRL) lipolysis by lipoprotein lipase underlies the non-linear relationship between HDL-C and cardiovascular risk. Methods To assess our hypothesis, we developed a novel assay to evaluate the capacity of HDL to acquire free cholesterol (as fluorescent TopFluor® cholesterol) from TGRL upon in vitro lipolysis by lipoprotein lipase. Results When the assay was applied to several populations markedly differing in plasma HDL-C levels, transfer of free cholesterol was significantly decreased in low HDL-C patients with acute myocardial infarction (−45%) and type 2 diabetes (–25%), and in subjects with extremely high HDL-C of >2.59 mmol/L (>100 mg/dL) (−20%) versus healthy normolipidaemic controls. When these data were combined and plotted against HDL-C concentrations, an inverse U-shape relationship was observed. Consistent with these findings, animal studies revealed that the capacity of HDL to acquire cholesterol upon lipolysis was reduced in low HDL-C apolipoprotein A-I knock-out mice and was negatively correlated with aortic accumulation of [3H]-cholesterol after oral gavage, attesting this functional characteristic as a negative metric of postprandial atherosclerosis. Conclusions Free cholesterol transfer to HDL upon TGRL lipolysis may underlie the U-shape relationship between HDL-C and cardiovascular disease, linking HDL-C to triglyceride metabolism and atherosclerosis.

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The beneficial effects of pumpkin extract on atherogenic lipid, insulin resistance and oxidative stress status in high-fat diet-induced obese rats

Journal of Complementary and Integrative Medicine ◽

10.1515/jcim-2017-0051 ◽

2017 ◽

Vol 15 (2) ◽

Cited By ~ 6

Author(s):

Atefe Ghahremanloo ◽

Reza Hajipour ◽

Mina Hemmati ◽

Maryam Moossavi ◽

Zabihullah Mohaqiq

Keyword(s):

Oxidative Stress ◽

Cardiovascular Disease ◽

Liver Enzymes ◽

Density Lipoprotein ◽

Lipid Lowering ◽

Alcoholic Extract ◽

Dependent Manner ◽

Oxidative Stress Status ◽

Obese Rats ◽

And Oxidative Stress

Abstract Background Prevention and treatment of obesity is a way to reduce cardiovascular disease, diabetes and depression. Pumpkin as a favorable plant has different properties notably antioxidant, lipid-lowering and anti-diabetic potential. The aim of this study was to assess the anti-obesity effects of pumpkin in diet-induced obese rats. Methods Thirty adult male Wistar rats were randomly divided into five groups (n=6) of healthy control, dietary fatty control rats, and three experimental dietary fatty rats that received hydro-alcoholic extract of pumpkin once daily at doses 100 and 200 and 400 mg/kg, respectively. At the end of 6 weeks, lipid profile, atherogenicity, liver enzymes, and oxidative stress status were measured. Results Pumpkin in a dose-dependent manner dramatically decreased triglycerides and low-density lipoprotein, and liver enzymes while high-density lipoprotein was markedly increased in treated groups. Pumpkin also increased glutathione level in comparison with obese control group. Conclusions Pumpkin ameliorated oxidative stress and dyslipidemia in obese rats, leading to decrease cardiovascular disease risk in obesity.

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