scholarly journals Bilirubin ameliorates murine atherosclerosis through inhibiting cholesterol synthesis and reshaping the immune system

2022 ◽  
Vol 20 (1) ◽  
Author(s):  
Guanmei Wen ◽  
Leyi Yao ◽  
Yali Hao ◽  
Jinheng Wang ◽  
Jinbao Liu

AbstractAtherosclerosis is a chronic inflammatory disease caused mainly by lipid accumulation and excessive inflammatory immune response. Although the lipid-lowering and cardioprotective properties of bilirubin, as well as the negative relationship between bilirubin and atherosclerosis, were well documented, it is not yet clear whether bilirubin can attenuate atherosclerosis in vivo. In this study, we investigated the role of bilirubin in improving atherosclerosis. We found that mildly elevated bilirubin significantly reduced the risk factors of atherosclerosis, such as plasma glucose, total cholesterol, and low-density lipoprotein cholesterol, and the formation of atherosclerotic plaques, liver total cholesterol, and cholesterol ester concentration in apolipoprotein E-deficient (ApoE−/−) mice fed a western-type (high fat) diet. It was further found that bilirubin could promote the degradation of 3-Hydroxy-3-Methylglutaryl-CoA Reductase (HMGCR), a rate-limiting enzyme for endogenous cholesterol synthesis. Using mass cytometry-based high dimensional single cell analysis, we observed a decrease of natural killer cells and an increase of dendritic cells and myeloid-derived suppressor cells, which all are closely associated with atherosclerosis risk factors and contribute to the improvement of atherosclerosis, in ApoE−/− mice treated with bilirubin. By in-depth analysis, modulation of multiple spleen or peripheral blood T cell clusters exhibiting either positive or negative correlations with total cholesterol or low-density lipoprotein cholesterol was detected after bilirubin treatment. In this study, we demonstrate that bilirubin serves as a negative regulator of atherosclerosis and reduces atherosclerosis by inhibiting cholesterol synthesis and modulating the immune system.

1997 ◽  
Vol 3 (2) ◽  
pp. 104-109
Author(s):  
M. Catalano ◽  
E. Perilli ◽  
G. Carzaniga ◽  
G. Scandale ◽  
M. Carotta

The aim of the study was to provide a detailed apolipoproteic profile in stage II peripheral vascular disease (PVD) patients and to ascertain whether lower ankle/ arm pressure index (API) values were associated with a worse profile. Apolipoproteins of 83 stage II PVD patients (average age 64.7 ± 9.3 years) were selected and compared with those of a group of 44 normal control subjects, similar in terms of age, sex, and smoking and eating habits. Neither PVD patients nor controls had ever received lipid-lowering agents or defined dietary treatment. A diagnosis of PVD was confirmed by an API of <0.85. Arteriopathic patients were also split into two groups, depending on their API values, similar in terms of age, sex and smoking habits: API values of one group (n = 38) were ≥0.6, those of the other group (n = 45) were <0.6. The following biohumoral parameters were considered: fasting glycemia, total cholesterol, triglycerides (TGs); high-density lipoprotein cholesterol (HDL-C); low density lipoprotein cholesterol (LDL-C), very low density lipoprotein cholesterol (VLDL-C), total cholesterol (TC)/HDL-C (TC/ HDL-C), Apoproteins (Apos) AI, AII, B, CII, CIII, and E; and lipoprotein a [Lp(a)]. HDL-C and Apo AI were lower ( p < 0.01), while TC/ HDL-C ratios, Apo B, and Apo CII were higher ( p < 0.01) in PVD patients compared with controls. The comparison between the two PVD groups with different API values showed higher blood TG and VLDL-C values for the patients with lower API values (p < 0.05), indicating a relationship between hypertriglyceridemia and greater arterial damage. Key Words: Peripheral arterial occlusive disease-Triglyceride-Lipoprotein a.


Author(s):  
Ching-Yun Hu ◽  
Chia-Lin Lee ◽  
Wayne H.-H. Sheu ◽  
Jun-Sing Wang ◽  
I-Te Lee ◽  
...  

AbstractLow-density lipoprotein cholesterol (LDL-C) is an established risk factor for cardiovascular disease and is usually estimated by the Friedewald formula (FF) calculated from three parameters, namely, total cholesterol (TC), triglyceride (TG), and high-density lipoprotein cholesterol (HDL-C). We aimed to develop a new and simple formula (NF) for LDL-C estimation.This cross-sectional study enrolled two study populations (a testing group, n=16,749, and a validation group, n=4940). Linear regression analysis was used in the testing group to investigate the association between measured LDL-C (mLDL-C) and TC concentration, and was verified in the validation group.The NF yielded an estimated LDL-C (eLDL-C) equal to 0.75×total cholesterol–0.6465 (mmol/L). For the subjects with TC between 2.58 and 7.74 mmol/L, the difference between mLDL-C and eLDL-C using the NF was less than that from the FF (testing group: –0.04 to –0.20 vs. –0.28 to –0.38 mmol/L; validation group: 0.01 to –0.12 vs. –0.23 to –0.30 mmol/L; p<0.001, respectively). The predictability of the NF was not inferior to that of the FF in subjects with different triglyceride and HDL-C concentrations, and was not affected by diabetes diagnosis and statin use. However, the NF performed similar to or worse than the FF at TC concentrations <2.58 mmol/L and >7.74 mmol/L, respectively.In the Chinese population, the accuracy of eLDL-C measurement with the NF was better than that with the FF, especially in subjects with TC levels between 2.58 and 7.74 mmol/L. The NF is simple and may be used for screening as well as for follow-up of patients on lipid lowering agents.


BMC Medicine ◽  
2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Ruurt A. Jukema ◽  
Tarek A. N. Ahmed ◽  
Jean-Claude Tardif

Abstract Background Dyslipidemia and inflammation are closely interrelated contributors in the pathogenesis of atherosclerosis. Disorders of lipid metabolism initiate an inflammatory and immune-mediated response in atherosclerosis, while low-density lipoprotein cholesterol (LDL-C) lowering has possible pleiotropic anti-inflammatory effects that extend beyond lipid lowering. Main text Activation of the immune system/inflammasome destabilizes the plaque, which makes it vulnerable to rupture, resulting in major adverse cardiac events (MACE). The activated immune system potentially accelerates atherosclerosis, and atherosclerosis activates the immune system, creating a vicious circle. LDL-C enhances inflammation, which can be measured through multiple parameters like high-sensitivity C-reactive protein (hsCRP). However, multiple studies have shown that CRP is a marker of residual risk and not, itself, a causal factor. Recently, anti-inflammatory therapy has been shown to decelerate atherosclerosis, resulting in fewer MACE. Nevertheless, an important side effect of anti-inflammatory therapy is the potential for increased infection risk, stressing the importance of only targeting patients with high residual inflammatory risk. Multiple (auto-)inflammatory diseases are potentially related to/influenced by LDL-C through inflammasome activation. Conclusions Research suggests that LDL-C induces inflammation; inflammation is of proven importance in atherosclerotic disease progression; anti-inflammatory therapies yield promise in lowering (cardiovascular) disease risk, especially in selected patients with high (remaining) inflammatory risk; and intriguing new anti-inflammatory developments, for example, in nucleotide-binding leucine-rich repeat-containing pyrine receptor inflammasome targeting, are currently underway, including novel pathway interventions such as immune cell targeting and epigenetic interference. Long-term safety should be carefully monitored for these new strategies and cost-effectiveness carefully evaluated.


2021 ◽  
Vol 8 ◽  
Author(s):  
Jiao Gong ◽  
Yaqiong Chen ◽  
Yusheng Jie ◽  
Mingkai Tan ◽  
Zhaofang Jiang ◽  
...  

Low-density lipoprotein cholesterol (LDL-C) is a well-known risk factor for coronary heart disease but protects against infection and sepsis. We aimed to disclose the exact association between LDL-C and severe 2019 novel coronavirus disease (COVID-19). Baseline data were retrospectively collected for 601 non-severe COVID-19 patients from two centers in Guangzhou and one center in Shenzhen, and patients on admission were medically observed for at least 15 days to determine the final outcome, including the non-severe group (n = 460) and the severe group (severe and critical cases) (n = 141). Among 601 cases, 76 (12.65%) received lipid-lowering therapy; the proportion of patients taking lipid-lowering drugs in the severe group was higher than that in the non-severe group (22.7 vs. 9.6%). We found a U-shaped association between LDL-C level and risk of severe COVID-19 using restricted cubic splines. Using univariate logistic regression analysis, odds ratios for severe COVID-19 for patients with LDL-C ≤1.6 mmol/L (61.9 mg/dL) and above 3.4 mmol/L (131.4 mg/dL) were 2.29 (95% confidence interval 1.12–4.68; p = 0.023) and 2.02 (1.04–3.94; p = 0.039), respectively, compared to those with LDL-C of 2.81–3.40 mmol/L (108.6–131.4 mg/dL); following multifactorial adjustment, odds ratios were 2.61 (1.07–6.37; p = 0.035) and 2.36 (1.09–5.14; p = 0.030). Similar results were yielded using 0.3 and 0.5 mmol/L categories of LDL-C and sensitivity analyses. Both low and high LDL-C levels were significantly associated with higher risk of severe COVID-19. Although our findings do not necessarily imply causality, they suggest that clinicians should pay more attention to lipid-lowering therapy in COVID-19 patients to improve clinical prognosis.


2021 ◽  
Vol 23 (3) ◽  
pp. 411-416
Author(s):  
I. M. Bilai ◽  
M. I. Romanenko ◽  
D. H. Ivanchenko

Statin side effects are not a rare occurrence, in particular dyspeptic disorders, insomnia, headache, skin erythema, rash are often noted. All of this determines scientists to find new effective and low-toxic hypolipidemic agents. Various natural and synthetic xanthine derivatives have been recognized as therapeutically potential compounds and reported to control various diseases. Therefore, the study of new xanthine derivatives and their hypolipidemic effects, which would have a significant therapeutic effect with minimal side effects, is relevant. The aim of the study was to examine the effect of 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkanic acid derivatives on lipidogram parameters in experimental laboratory rats. Materials and methods. The objects of the study were 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkanic acid derivatives. The experiments were performed in white laboratory Wistar rats weighing 180–220 g. Experimental modeling of hyperlipidemia – tween model: intraperitoneal administration of tween-80 at a dose of 200 mg/100 g body weight. The test compounds were administered orally, simultaneously with tween, at a dose of 1/10 of LD50 (previously calculated by Prozorovsky express method) for 6 days. The following indicators of lipidogram were determined: total cholesterol (TC), high-density lipoprotein cholesterol (HDL cholesterol), low-density lipoprotein cholesterol (LDL cholesterol), triglycerides (TG) and atherogenic index of plasma: TC – HDL cholesterol / HDL cholesterol. The experiments were carried out with respect to Bioethical rules and norms. Results. The studies have shown data on the hypolipidemic activity of 7-β-hydroxy-γ-aryloxypropylxanthinyl-8-thioalkane acid derivatives. According to the conditional efficiency index Ʃ, which included the overall percentage of the following indicators – total cholesterol, low-density lipoprotein cholesterol and triglycerides, the leading compounds were 2439 (87.47 %), 6047 (82.30 %). The reference drug atorvastatin had a value of 82.98 %. Conclusions. The major compound was 2439 identified among all compared to the control group. The prospect of further research is a more detailed study on the ability of xanthine derivatives to exhibit hypolipidemic effects and to influence oxidative stress in various hyperlipidemic models.


1997 ◽  
Vol 92 (5) ◽  
pp. 473-479 ◽  
Author(s):  
Gregory D. Sloop ◽  
David W. Garber

1. Increased blood or plasma viscosity has been observed in almost all conditions associated with accelerated atherosclerosis. Cognizant of the enlarging body of evidence implicating increased viscosity in atherogenesis, we hypothesize that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity correlate with their association with risk of atherosclerosis. 2. Blood viscometry was performed on samples from 28 healthy, non-fasting adult volunteers using a capillary viscometer. Data were correlated with haematocrit, fibrinogen, serum viscosity, total cholesterol, high-density lipoprotein-cholesterol, triglycerides and calculated low-density lipoprotein-cholesterol. 3. Low-density lipoprotein-cholesterol was more strongly correlated with blood viscosity than was total cholesterol (r = 0.4149, P = 0.0281, compared with r = 0.2790, P = 0.1505). High-density lipoprotein-cholesterol levels were inversely associated with blood viscosity (r = −0.4018, P = 0.0341). 4. To confirm these effects, viscometry was performed on erythrocytes, suspended in saline, which had been incubated in plasma of various low-density lipoprotein/high-density lipoprotein ratios. Viscosity correlated directly with low-density lipoprotein/high-density lipoprotein ratio (n = 23, r = 0.8561, P < 0.01). 5. Low-density lipoprotein receptor occupancy data suggests that these effects on viscosity are mediated by erythrocyte aggregation. 6. These results demonstrate that the effects of low-density lipoprotein and high-density lipoprotein on blood viscosity in healthy subjects correlate with their association with risk of atherosclerosis. These effects on viscosity may play a role in atherogenesis by modulating the dwell or residence time of atherogenic particles in the vicinity of the endothelium.


Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Seth S Martin ◽  
Atif N Qasim ◽  
Daniel J Rader ◽  
Muredach P Reilly

Introduction: Accumulating evidence suggests that apolipoprotein B (apoB) is superior to low-density lipoprotein cholesterol (LDL-C) in prediction of cardiovascular events. Yet, an important outstanding question is whether apoB, relative to LDL, is an enhanced marker for subclinical atherosclerosis, particularly in diabetics where LDL levels may underestimate atherogenic lipid burden due to increased proportion of small, dense LDL. Hypothesis: We hypothesized that plasma apoB would be a better predictor than LDL-C of coronary artery calcification (CAC) scores in type 2 diabetics and non-type 2 diabetics. Methods: We performed cross-sectional analyses of asymptomatic Caucasians in (1) The Study of Inherited Risk of Coronary Atherosclerosis (434 men and 383 women; median age 48, non-diabetics) and (2) The Penn Diabetes Heart Study (580 men and 261 women; median age 60, type 2 diabetics). Results: Levels of apoB and LDL-C were correlated in diabetics (r=0.78, p<0.001) and non-diabetics (r=0.77, p<0.001). There was no association between LDL-C and CAC in diabetics. In non-diabetics, an association of LDL-C was lost after adjustment for total cholesterol. In contrast, after controlling for age, gender, statin therapy, and total cholesterol, levels of apoB were positively associated with CAC in diabetics [tobit regression ratio for 30 mg/dl increase in apoB 2.94 (95% CI 1.62 – 5.53), p=0.001) and had a more modest association with CAC in non-diabetics [1.67 (95% CI 1.16 – 2.32), p=0.005]. Conclusions: ApoB, but not LDL-C, predicted CAC scores, a measure of coronary atherosclerotic burden. The strength of this association was greater in diabetics than non-diabetics. Relative to LDL-C, plasma apoB levels may be particularly useful in assessing CVD risk in type 2 diabetes.


Author(s):  
Salim S Virani ◽  
Lechauncy D Woodard ◽  
Supicha Sookanan ◽  
Cassie R Landrum ◽  
Tracy H Urech ◽  
...  

Background: Although current cholesterol performance measures define good quality as low density lipoprotein cholesterol (LDL-C) levels < 100mg/dl in cardiovascular disease (CVD) patients, they provide a snap shot at one time point and do not inform whether an appropriate action was taken to manage elevated LDL-C levels. We assessed frequency and predictors of this appropriate response (AR). Methods: We used administrative data to assess 22,902 CVD patients receiving care in a Veterans Affairs network of 7 hospitals and affiliated clinics. We determined the proportion of CVD patients at LDL-C goal <100 mg/dl, and the proportion of patients with uncontrolled LDL-C levels (>100 mg/dl) who had an AR [defined as the initiation or dosage increase of a lipid lowering medication (LLM), addition of a new LLM, receipt of maximum dosage or >1 LLM, or LDL-C reading <100 mg/dl] at 45 days follow-up. Logistic regression was performed to evaluate facility, provider and patient characteristics associated with AR. Results: LDL-C levels were at goal in 16,350 (71.4%) patients. An additional 2,110 (9.2%) had an AR at 45 days of follow-up. Controlling for clustering between facilities and patient's illness severity, history of diabetes (OR 1.18, 95% CI 1.03-1.35), hypertension (OR 1.21, 95% CI 1.02-1.44), patients showing good medication adherence (medication possession ratio > 0.8) [OR 2.29, 95% CI 1.99-2.64] were associated with AR. Older CVD patients (age >75 years) were less likely to receive AR (OR 0.60, 95% CI 0.52-0.70). Teaching vs. non-teaching facility (p=0.40), physician vs. non-physician provider (p=0.14), specialist vs. non-specialist primary care provider (p=0.12), and patient's race (p=0.12) were not predictors of AR. Conclusion: Among patients with CVD and LDL-C above guideline recommended levels, only one-third receive AR. Diabetic and hypertensive CVD patients are more likely to receive AR, whereas older Veterans with CVD receive AR less often likely reflecting providers' belief of lack of efficacy from treatment intensification in older CVD patients. Our findings are important for quality improvement and policy making initiatives as they provide more actionable information compared with isolated LDL-C goal attainment as a quality indicator.


Circulation ◽  
2020 ◽  
Vol 141 (Suppl_1) ◽  
Author(s):  
Hiroaki Ikezaki ◽  
Elise Lim ◽  
Ching-Ti Liu ◽  
L Adrienne Cupples ◽  
Bela F Asztalos ◽  
...  

Introduction: Elevated plasma low-density lipoprotein cholesterol (LDL-C), small-dense LDL-C (sdLDL-C), LDL-triglyceride (LDL-TG), triglycerides (TG), remnant-lipoprotein cholesterol (RLP-C), triglyceride-rich lipoprotein-C (TRL-C), very low-density lipoprotein cholesterol (VLDL-C), and lipoprotein(a) [Lp(a)] levels have been associated with increased atherosclerotic cardiovascular disease (ASCVD) risk. However, these parameters have not been included in risk factors for ASCVD in the pooled cohort equation (PCE). Hypothesis: We assessed the hypothesis that these atherogenic lipoprotein parameters add significant information for ASCVD risk prediction in the Framingham Offspring Study. Methods: We evaluated 3,147 subjects without ASCVD at baseline (mean age 58 years) from participants of Framingham Offspring Study cycle 6, 677 (21.5%) of whom developed inclusive ASCVD over 16 years. Biomarkers of risk were assessed in frozen plasma samples. Total cholesterol, TG, HDL-C, direct LDL-C, sdLDL-C, LDL-TG, Lp(a), RLP-C, and TRL-C were measured by standardized automated analysis. Calculated LDL-C, large buoyant low-density lipoprotein cholesterol (lbLDL-C), VLDL-C, and non-HDL-C values were calculated. Data were analyzed using Cox proportional regression analysis and net reclassification improvement (NRI) analysis to identify parameters significantly associated with the incidence of ASCVD after controlling for standard ASCVD risk factor and applying the PCE model. Results: All specialized lipoprotein parameters were significant ASCVD risk factors on univariate analysis, but only direct LDL-C, sdLDL-C, and Lp(a) were significant on multivariate analysis with standard risk factors in the model. Together these parameters significantly improved the model c statistic (0.716 vs 0.732, P < 0.05) and net risk reclassification (mean NRI 0.104, P < 0.01) for ASCVD risk. Using the ASCVD risk pooled cohort equation, sdLDL-C, TG, LDL-TG, LDL-C, RLP-C, and TRL-C individually added significant information, but no other parameter added significant information with sdLDL-C (hazard ratio 1.30 for 75th vs 25th percentile, P < 0.0001) in the model. Conclusions: In multivariate analysis, sdLDL-C, direct LDL-C, and Lp(a) contributed significantly to ASCVD risk, but only sdLDL-C added significant risk information to the PCE model, indicating that sdLDL-C may be the most atherogenic lipoprotein particle.


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