Low-density Lipoprotein Cholesterol Concentrations Research Articles

From LAL-D to MASLD: Insights into the role of LAL and Kupffer cells in liver inflammation and lipid metabolism

Metabolic dysfunction-associated steatotic liver disease (MASLD) is a prevalent liver pathology worldwide, closely associated with obesity and metabolic disorders. Increasing evidence suggests that macrophages play a crucial role in the development of MASLD. Several human studies have shown an inverse correlation between circulating lysosomal acid lipase (LAL) activity and MASLD. LAL is the sole enzyme known to degrade cholesteryl esters (CE) and triacylglycerols in lysosomes. Consequently, these substrates accumulate when their enzymatic degradation is impaired due to LAL deficiency (LALD). This study aimed to investigate the role of hepatic LAL activity and liver-resident macrophages (i.e., Kupffer cells (KC)) in MASLD. To this end, we analyzed lipid metabolism in hepatocyte-specific (hep)Lal−/− mice and depleted KC with clodronate treatment. When fed a high-fat/high-cholesterol diet (HF/HCD), hepLal−/− mice exhibited CE accumulation and an increased number of macrophages in the liver and significant hepatic inflammation. KC were depleted upon clodronate administration, whereas infiltrating/proliferating CD68-expressing macrophages were less affected. This led to exacerbated hepatic CE accumulation and dyslipidemia, as evidenced by increased LDL-cholesterol concentrations. Along with proteomic analysis of liver tissue, these findings indicate that hepatic LAL-D in HF/HCD-fed mice leads to macrophage infiltration into the liver and that KC depletion further exacerbates hepatic CE concentrations and dyslipidemia.

High intensity statin-ezetimibe combination therapy reduces mortality in patients with ischaemic heart disease and elevated Lipoprotein(a)

Abstract Background Early and prompt reduction of low-density lipoprotein cholesterol concentrations (LDL-C) using combination lipid-lowering therapy (LLT) is recommended to lower cardiovascular risk in patients with ischaemic heart disease (IHD) and elevated LDL-C. Lowering LDL-C is also an important cardiovascular risk mitigation strategy in patients with elevated lipoprotein(a) [Lp(a)]. However, it is unknown if combination LLT reduces mortality in patients with elevated Lp(a). Aim To undertake an observational study to investigate the effect of combination LLT using high intensity statin with ezetimibe on cardiovascular outcomes in patients with and without elevated Lp(a). Methods Serum Lp(a) concentrations were measured in 520 consecutively recruited patients with IHD admitted to hospital, half of whom were admitted for acute myocardial infarction. Patients treated with high intensity statin and ezetimibe within the 1st year from admission to hospital (‘HI statin-ezetimibe group’, n=157) were compared with the rest of patients who had less intensive lipid lowering regimen (‘Others group’, n=363) for cardiovascular outcomes. Results During the 2-year follow-up period, 14.6%, 6.5%, and 53.1% of patients had all-cause mortality, cardiovascular mortality, and major adverse cardiovascular events (MACE) respectively. Median age was 63.5 years and 82.3% were male. Multivariable Cox regression showed that baseline Lp(a) ≥70 nmol/L was associated with increased risk of all-cause mortality (HR 1.97, 95% CI 1.20-3.22, P=0.007). Compared with a less intensive regimen, HI statin-ezetimibe was associated with reduced risk of all-cause mortality (HR 0.44 [0.21-0.89], P=0.023) and MACE (HR 0.71 [0.52-0.95], P=0.027), with no statistically significant effect on cardiovascular mortality (HR 0.43, P=0.142). Notably, the cardiovascular benefits of HI statin-ezetimibe were more pronounced in patients with elevated Lp(a); a greater reduction in risk of MACE was seen for patients with Lp(a) ≥70 nmol/L (HR 0.51, P=0.007) or Lp(a) ≥100 nmol/L (HR 0.36, P=0.009), and in all-cause mortality risk for those with Lp(a) ≥70 nmol/L (HR 0.24, P=0.025). Although LDL-C reduction >50% was associated with reduced risk of all-cause mortality (p=0.027), this could not fully explain the overall cardiovascular benefit of HI statin-ezetimibe use in patients with or without elevated Lp(a). Conclusion Intensification of lipid-lowering therapy with high-intensity statin and ezetimibe improves cardiovascular outcomes in patients at very high cardiovascular risk, particularly those with elevated Lp(a). Larger studies are required to confirm our findings that this cardiovascular benefit is partially independent of LDL-C lowering.

Sex differences in management of LDL-cholesterol in patients with chronic coronary syndrome

Abstract Background Effective management of low-density lipoprotein cholesterol (LDL-C) is crucial for preventing recurrent cardiovascular (CV) events in patients with chronic coronary syndrome (CCS). Sex may impact the LDL-C management, by gender bias and/or sex-specific responses to pharmacological interventions. Purpose We examined sex-specific LDL-C management in CCS patients, assessing target achievement rates and their implications for CV outcomes. Methods In the international CLARIFY registry, we included 22,134 CCS patients with baseline LDL-C measurements. LDL-C levels were monitored annually over the 5-year follow-up period. Target LDL-C was set at 100 mg/dL, in line with prevailing recommendations at that time. Sex-specific differences in LDL-C were adjusted for age, geographical region and indication for lipid lowering drugs (stroke, MI, PAD). The primary endpoint was the incidence of MACE, defined as CV death or MI during the 5-year follow-up, evaluated using multivariable analysis adjusted for known predictors of recurrent CV events in CCS patients. Results Of 22,134 patients, 21.6% were women. Upon inclusion (6.5 ± 6.3 years after CCS diagnosis), women were more likely than men to have LDL-C levels above the recommended threshold (45.6% vs. 37.4%; aOR 1.47, 95%CI 1.38-1.58, p<0.001) and less likely to receive statin treatment (82.7% vs. 85.4%, p<0.001). Although women and men had comparable numbers of LDL-C measurements during follow-up, the discrepancies endured over the 5-year observation period, with women consistently showing lower likelihoods of achieving LDL-C targets at 1, 2, 3, 4, and 5 years post-inclusion (p<0.001 for all time points). Overall, women were less likely than men to have all available LDL-C concentrations within the target range (37.8% vs. 44.6%; aOR 0.70, 95% CI 0.64-0.76, p<0.001) and more likely to never reach the target LDL-C goal during follow-up (22.6% vs. 17.5%; aOR 1.43, 95% CI 1.32-1.55, p<0.001). Failing to achieve at least one LDL-C concentration below 100 mg/dL was associated with an increased risk of subsequent MACE (adjusted HR 1.57, 95%CI 1.38-1.77, p<0.001), with similar associations observed in both men (aHR 1.66, 95% CI 1.44-1.91, p<0.001) and women (aHR 1.31, 95% CI 1.01-1.70, p=0.05). Conclusion In patients with CCS, women consistently showed lower likelihood of reaching LDL-C targets throughout follow-up compared to men, even after adjusting for age, geographical region and other statin indications. Notably, women were more likely to have no LDL-C concentration within recommended range during follow-up, which is particularly concerning given its association with an increased risk of CV events. A contributing factor to this sex disparity in LDL-C control is women's lower likelihood of receiving lipid-lowering drugs than men. These results highlight the need for tailored interventions to address sex-related disparities in LDL-C management and improve cardiovascular outcomes in CCS patients.

Clinical outcomes according to residual cholesterol and inflammatory risk in patients undergoing PCI

Abstract Background Elevated concentrations of low-density lipoprotein cholesterol (LDL-c) and low grade vascular inflammation, commonly quantified using high-sensitivity C-reactive protein (hsCRP), have been demonstrated to be causal in the development of atherosclerotic disease. Whilst recent large-scale trials have investigated the relative impact of LDL-c and inflammation on cardiovascular outcomes, there is a scarcity of data in real-world patients undergoing percutaneous coronary intervention (PCI). Purpose To investigate the relative drivers of residual risk in patients with established statin treatment undergoing PCI in a contemporary large-scale cohort. Methods From January 2012 to February 2020 patients undergoing PCI at a tertiary center were included for current analysis. Patients were categorized into 4 subgroups according to different combinations of LDL-c and hsCRP concentrations at baseline: no residual cholesterol or inflammatory risk (LDL-c <70 mg/dL + hsCRP <2 mg/L), residual cholesterol risk (LDL-c ≥70 mg/dL + hsCRP <2 mg/L), residual inflammatory risk (LDL-c <70 mg/dL + hsCRP ≥2 mg/L), and combined residual cholesterol and inflammatory risk (LDL-c ≥70 mg/dL + hsCRP ≥2 mg/L). Individuals who presented with acute myocardial infarction, neoplastic disease and hsCRP concentrations >10 mg/l were excluded. The outcome of interest was major adverse cardiac events (MACE - composite of all-cause mortality, myocardial infarction, or stroke). A univariable cox regression model was calculated. Results Overall, 10,845 patients were included. In total, 3,210 patients displayed neither cholesterol nor inflammatory risk and 3,059 individuals had elevated cholesterol risk only. In 1,839 patients an inflammatory risk was noted, whilst 2,737 patients presented with combined cholesterol and inflammatory risk. Kaplan-Meier curves for 1-year follow-up are displayed in Figure 1. Patients with residual inflammatory risk had the highest event rate of the composite endpoint (5.2%), followed by patients with combined residual risk (3.5%), individuals with residual cholesterol risk (2.3%) and persons with neither cholesterol nor inflammatory risk (2.4%; p<0.0001 for log rank test across all groups). An association with MACE was solely documented for patients with residual inflammatory risk (HR: 2.09, 95% CI: 1.52 - 2.88; p<.001), and also borderline significant for combined cholesterol and inflammatory risk (HR: 1.41, 95% CI: 1.03 - 1.95; p=0.034), whilst this was not the case for patients with elevated cholesterol risk only (see Figure 2). Conclusion In a contemporary real-world cohort of statin treated patients undergoing PCI, inflammation irrespective of LDL-c concentrations was the driver for adverse cardiovascular outcomes. This data might be helpful to further define target populations for both intensified lipid-lowering as well as anti-inflammatory treatment approaches.

Sex-specific guideline target value attainment and prognostic value of low-density lipoprotein cholesterol in tertiary care

Abstract Background Factors contributing to guideline-target-level-attainment of low-density lipoprotein cholesterol (LDL-C) in countries with high healthcare expenditure are incompletely understood. Purpose the primary aim of this study was to test two hypotheses: 1) LDL-C control may be inferior in women versus men; 2) within the secondary prevention group, presence of a previous acute atherothrombotic event (acute myocardial infarction and stroke) may result in superior LDL-C control. Methods LDL-C levels and guideline target level attainment were determined in 4090 consecutive patients referred for myocardial perfusion single photon emission tomography (MPI-SPECT) between 2010 and 2016. Findings were validated in an independent cohort (n=1228) of consecutively enrolled patients in an outpatient cardiac rehabilitation program, between 2016 and 2023. Results About one third of patients (33%) were women, median age was 68 years, 1439 patients had a history of atherothrombosis, 759 patients a history of atherosclerosis without atherothrombosis, and 1892 were in primary prevention. LDL-C levels were higher and guideline target level attainment worse in women than in men in all three strata: age-adjusted difference in atherothrombosis 0.19 mmol/L (95%CI 0.03,0.35 mmol), guideline-target-value-attainment 39.5 % versus 49.4%, p<0.01; in atherosclerosis 0.33 mmol/L (95%CI 0.10-0.57), guideline-target-value-attainment 27.3 % versus 42.2 %, p<0.01; and in primary prevention 0.24 mmol/L (95% CI 0.13-0.38). This was confirmed in the validation cohort. LDL-C levels were higher and guideline-target-value-attainment worse in women versus men: age-adjusted difference age-adjusted difference 0.17 mmol/L (95%CI 0.02-0.33) guideline-target-value-attainment 43.8% versus 49.5%, After multivariate adjustment, female sex remained an independent predictor for higher LDL-C levels. LDL-C concentrations with atherothrombosis was 1.93 mmol/L (IQR 1.48-2.47) versus 2.07 mmol/L (IQR 1.40-2.72, p=0.003) with atherosclerosis and guideline target value attainment 47.5% vs 38.6%, p<0.001, respectively. Conclusion Concerning age-adjusted sex-inequalities with higher LDL-C levels and lower guideline-target-value-attainment in women were found in both primary and secondary prevention. Within secondary prevention, a previous atherothrombotic event was associated with lower LDL-C levels and higher guideline-target-value-attainment.

Deletion of the asialyloglycoprotein receptor-1 (ASGR1) causes atheroprotective effects in vitro and in vivo

Abstract Introduction The asialoglycoprotein receptor 1 (ASGR1) is a hepatic receptor that clears desialylated glycoproteins from the circulation. A loss-of-function mutation in ASGR1 was reported to associate with a 34% reduction in coronary artery disease (CAD) risk, suggesting a role for ASGR1 in CAD. Aim To determine the role of ASGR1 in atherosclerosis and whether deletion of ASGR1 elicits atheroprotective effects. Methods Western blotting, mass spectrometry and flow cytometry assessed ASGR1 expression in cultured macrophages or immune cells collected from the blood and aortas of wildtype mice. Bone marrow-derived macrophages (BMDMs) from wildtype and Asgr1-/- mice were subjected to cholesterol efflux and oxidised low-density lipoprotein (oxLDL) uptake in vitro functionalassays. ELISA and qPCR measured changes in lipid regulators in BMDMs. Asgr1-/- mice were crossed with atherosclerosis-prone apolipoprotein (Apo)e-/- mice (Apoe-/-Asgr1-/-). Stable plaque area was assessed histologically in the aortic sinuses of mice fed a high-cholesterol diet for 8 weeks (n=16/group). Using the tandem stenosis surgical model, unstable plaque was assessed in carotid arteries (n=10/group). Human ASGR1 was measured by ELISA in peripheral blood mononuclear cells (PBMCs) isolated from patient samples (n=18). Results Western blotting and mass spectrometry discovered ASGR1 is expressed in macrophages. Immunofluorescence identified the presence of ASGR1 in aortic sinus plaque. Flow cytometry revealed ASGR1 is expressed in both inflammatory and patrolling monocytes, neutrophils, macrophages and dendritic cells of blood and aortas. Asgr1-/- BMDMs elicited greater cholesterol efflux (+39%, P<0.05) and decreased oxLDL uptake (-15%, P<0.05), compared to wildtype BMDMs. Moreover, Asgr1-/- BMDMs had significantly higher LDL receptor protein levels (+2-fold), and Lxra (+2-fold) and Pparg (+1.5-fold) mRNA levels than wildtype BMDMs, P<0.001. Plasma from Asgr1-/- mice had lower total (-25%, P<0.05) and LDL (-36%, P<0.05) cholesterol concentrations than wildtype mice. Apoe-/-Asgr1-/- mice developed less stable plaque in aortic sinuses (-37%, P<0.001) than Apoe-/- controls, as well as smaller unstable plaques in carotid arteries (-49%, P<0.05). Finally, in a human population, ASGR1 protein levels were higher in PBMCs from patients with coronary plaque (+61%, P<0.05), than those without plaque, determined from coronary angiograms. Conclusion ASGR1 is expressed on monocytes, macrophages and in plaques, and human PBMC ASGR1 associates with coronary plaque. Deletion of ASGR1 causes atheroprotective functions in macrophages in vitro and reduced plaque burden in vivo. Our findings demonstrate ASGR1 is important in atherosclerosis with implications for ASGR1 as a therapeutic target.

Temporal trends in lipid management among Korean patients following acute myocardial infarction from 2011 to 2020

Abstract Background/Purpose Real-world data trends on dyslipidaemia prevalence and lipid management for patients following acute myocardial infarction (AMI) are lacking in South Korea, one of the Asia-Pacific nations. Our study aimed to evaluate the 10-year temporal trends of dyslipidaemia prevalence and lipid management in this patient population. Methods The study utilized datasets from two Korean AMI observational cohort (2011–2020) including a total of 26,751 participants (Figure 1A). The primary endpoints were as follows: (1) absolute low-density lipoprotein cholesterol (LDL-C) target of <70 mg/dL; (2) relative LDL-C target of >50% LDL-C reduction from the baseline; (3) absolute or relative LDL-C target (American target); and (4) both absolute and relative LDL-C targets (European target). Results The prevalence of dyslipidaemia increased from 11.1% to 17.1% (Table 1, Figure 1B), while the statin prescription rates increased from 92.9% to 97.0% from 2011 to 2020. High-intensity statin use increased from 12.80% in 2012 to 69.30% in 2020 (Table 1) Interestingly, the yearlong substantial increases in the prescription rates of high-intensity statins were prominent between 2013 (21.9%) and 2014 (37.7%) and between 2018 (52.4%) and 2019 (66.1%), which may have been influenced by major revisions to the international lipid management guidelines and their adoption (Figure 1C). Ezetimibe use increased from 4.50% in 2016 to 22.50% in 2020. The achievement rate of the absolute and relative LDL-C targets increased from 41.4% and 20.8% in 2012 to 62.5% and 39.5% in 2019, respectively (Table 1). The achievement rates of the American (45.7% in 2012 to 68.6% in 2019) and European (16.5% in 2012 to 33.8% in 2019) targets showed similar increasing trends (Table 1, Figure 1D). Conclusions Despite the adoption of lipid management guidelines in clinical practice has improved, some patients some patients are unable to reduce their LDL-C concentrations to their target levels. Our real-world analyses emphasise the need for multidirectional and continued efforts to optimise lipid management and improve the clinical outcomes in these patients.Figure 1

An equation for estimating low-density lipoprotein-triglyceride content and its use for cardiovascular disease risk stratification

BackgroundThe triglyceride (TG) content of low-density lipoprotein (LDL-TG) has been shown to be more predictive of atherosclerotic cardiovascular disease (ASCVD) events than the cholesterol content of LDL (LDL-C). The goal of our study was to develop an equation for estimating LDL-TG (eLDL-TG) based on the standard lipid panel and to compare it to estimated LDL-C as an ASCVD risk biomarker.MethodsUsing least-square regression analysis, the following eLDL-TG equation was developed: eLDL-TG=TG38.5+NonHDL-C5.75+9.75TGNonHDL-C+244HDL-C−2.95. LDL-TG was measured by the β-quantification (BQ) reference method (N = 40,202). LDL-C was calculated by the Sampson-NIH equation. The association of LDL-C and eLDL-TG with ASCVD risk markers was performed in the National Heart and Nutrition Examination Survey (NHANES) (N = 37,053) and with ASCVD events in a primary prevention cohort from the UK Biobank (UKB) (N = 429,367) and the Atherosclerosis Risk in Communities (ARIC) study (N = 14,632).ResultseLDL-TG showed better ASCVD risk stratification of UKB participants than LDL-C (Wilcoxon Chi-Square: 2,099.6 vs. 418.7, respectively). Receiving-operating characteristics analysis revealed that eLDL-TG had a stronger association with ASCVD events than LDL-C (AUC: 0.596 vs. 0.542, respectively) and other conventional lipid markers. Similar findings were found in ARIC. Discordance analysis in UKB showed that the group with low LDL-C/high eLDL-TG had a similar risk as the high LDL-C/high eLDL-TG group. Furthermore, these same two groups with the highest eLDL-TG levels and the highest ASCVD event rate also had higher mean levels of systolic blood pressure, Body Mass Index, hemoglobin A1C, and C-reactive protein than the two lower eLDL-TG groups. Using eLDL-TG > 44.6 mg/dl (80th percentile) as a cut-point leads to a hazard ratio of 1.32 (95% CI, 1.29–1.36) for ASCVD events, which remained significant after adjustment for LDL-C and apoB. Furthemore, using eLDL-TG as a risk-enhancer test leads to reclassification of 50% more high-risk individuals than current lipid-enhancer test rules.ConclusionsLike LDL-C, LDL-TG can also be calculated from the results of the standard lipid panel. Compared to estimated LDL-C, eLDL-TG was a better risk marker for primary prevention and hence could improve initial ASCVD risk stratification.

The Effects of Bitter Melon (Mormordica charantia) on Lipid Profile: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Research indicates that bitter melon could be useful in the management of dyslipidemia. Still, there is disagreement concerning the findings. This systematic study was undertaken to clarify the impact of consuming bitter melon on lipid profile. The databases Web of Science, Cochrane Library, PubMed, and Scopus were queried from inception until February 9, 2023. The study assessed triglyceride (TG), total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C) levels. The effect sizes were calculated using weighted mean differences (WMDs) and 95% confidence intervals (CIs). Eight randomized controlled trials (RCTs) with a total of 423 participants were included. Bitter melon consumption resulted in a significant decrease in plasma concentrations of TC (WMD; -9.71 mg/dL; CI: -17.69 to -1.74, p = 0.01) and TG (WMD; -10.24 mg/dL; CI: -19.92 to -0.56, p = 0.03), while bitter melon did not significantly lower blood LDL-C (WMD; -8.66 mg/dL; CI: -19.83 to 2.50, p = 0.12) and HDL-C concentrations (WMD; 0.54 mg/dL; CI: -2.38 to 3.45, p = 0.71). Subgroup analysis showed a significant decrease in TC and LDL-C and an increase in HDL-C at a dose of ≤ 2000 mg/day and an intervention period of ≤ 8 weeks. Also, the greatest impact of LDL-C and HDL-C was seen in diabetic and prediabetic people. Bitter melon supplementation positively impacts TC and TG levels. The limitations of this study were short-term trials (less than 3 months).

Performance of Holstein dairy cows fed a diet supplemented with rosemary and ginger essential oils: milk production, milk fatty acid, and ruminal fermentation

Abstract The study determined the impact of Rosmarinus officinalis and/or Zingiberene officinalis essential oil (EO) on milk yield, composition, milk fatty acids profile, blood biochemicals, and rumen fermentation in dairy cows. Twenty-eight Holstein lactating cows were distributed into four groups using a completely randomized block design in a 70-d experiment. The control diet consisted of 13 kg of concentrate and 40 kg of fresh berseem clover per head per day, without supplementation. In the other treatments, the control diet was supplemented with 10 mL of EO per head per day, using either ginger EO (GEO treatment), rosemary (REO treatment) EO or a blend of both at a 1:1 v/v ratio (BEO treatment). Supplementation did not affect intake, milk production, or composition. Omega-n3 and omega-n5 were increased with REO (p < 0.05) compared to the control. Both REO and BEO decreased (p = 0.003) serum globulin and increased (p < 0.005) albumin to globulin ratio, high-density lipoprotein cholesterol, and total lipid. Serum total antioxidant capacity was increased (p ˂ 0.001) with the supplementation, without affecting glucose, total protein, albumin, serum cholesterol, low-density lipoprotein cholesterol, alanine aminotransferase, aspartate aminotransferase, and urea concentrations. In conclusion, supplementing Holstein dairy cows with GEO and/ or REO increased the level of omega-3 and omega-5 fatty acids while reduced saturated fatty acids in milk, without affecting feed intake, milk production or milk composition.

Serum concentrations of lipids, ketones and acylcarnitines during the postprandial and fasting state: the Postprandial Metabolism (PoMet) study in healthy young adults.

To improve the interpretation and utilisation of blood lipids, ketones and acylcarnitine concentrations as biomarkers in clinical assessments, more information is needed on their dynamic alterations in response to dietary intake and fasting. The aim of this intervention study was to characterise the changes in serum lipid, ketone and acylcarnitine concentrations 24 h after a standardised breakfast meal. Thirty-four healthy subjects (eighteen males and sixteen females) aged 20-30 years were served a breakfast meal (∼500 kcal, 36 E% fat, 46 E% carbohydrates, 16 E% protein, 2E% fibre), after which they consumed only water for 24 h. Blood samples were drawn before and at thirteen standardised timepoints after the meal. Metabolite concentrations were plotted as a function of time since the completion of the breakfast meal. Results demonstrated that concentrations of HDL-cholesterol and LDL-cholesterol decreased until ∼2 h (-4 % for both), while TAG concentrations peaked at 3 h (+27 %). Acetoacetate and β-hydroxybutyrate were highest 24 h after the meal (+433 and +633 %, respectively). Acetylcarnitine, butyrylcarnitine, hexanoylcarnitine, octanoylcarnitine, decanoylcarnitine and dodecanoylcarnitine reached the lowest values at 60 min (decreases ranging from -47 to -70 %), before increasing and peaking at 24 h after the meal (increases ranging from +86 to +120 %). Our findings suggest that distinguishing between fasting and non-fasting blood samples falls short of capturing the dynamics in lipid, ketone, carnitine and acylcarnitine concentrations. To enhance the utility of serum acylcarnitine analyses, we strongly recommend accounting for the specific time since the last meal at the time of blood sampling.

Lower activity of cholesteryl ester transfer protein (CETP) and the risk of dementia: a Mendelian randomization analysis

BackgroundElevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia.MethodsDrug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson’s dementia.ResultsMR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4.ConclusionsThese results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

Advanced chelate technology-based trace minerals reduce inflammation and oxidative stress in Eimeria-infected broilers by modulating NF-kB and Nrf2 pathways

This study investigated the effects of substituting inorganic trace minerals (ITM) with advanced chelate technology-based TM (ACTM) in broiler chicken feed on productive performance, metabolic profile, humoral immunity, antioxidant status, and modulation of NF-kB and Nrf2 signaling pathways in mixed Eimeria species exposure. The study involved 480 newly hatched male broiler chickens, which were divided into 5 treatment groups, each with 6 replicate cages and 16 chickens per replicate. The experimental treatments included an uninfected negative control group fed a basal diet with recommended inorganic TM levels (NC), an infected positive control group fed the same diet (PC), a PC group supplemented with salinomycin (SAL), and two PC groups in which the basal diet was replaced with 50% and 100% ACTM instead of inorganic TM (ACTM50 and ACTM100, respectively). All groups, except for the NC group, were orally challenged with mixed Eimeria species oocysts on day 14. According to the results, the PC group showed lower feed intake, breast yield, low-density lipoprotein-cholesterol concentration, lactobacillus spp. counts, and serum IgG levels, but higher jejunal TGF-β expression versus the NC group. The broilers in the NC, SAL, and ACTM100 groups showed higher body weight gain, carcass yield, and TGF-β expression, but lower serum alkaline phosphatase activity, ileal E. coli count, and jejunal expression levels of IL-1β, IL-6, IFN-γ, Nrf2, and SOD1 compared to the PC group, with the NC group having the highest body weight gain and lowest IL-1β and Nrf2 expression levels. Furthermore, the administration of ACTM100 treatment improved feed efficiency, increased serum iron, zinc, manganese, and copper levels, enhanced total antioxidant capacity and different antioxidant enzyme activities, and reduced malondialdehyde concentration. In conclusion, complete replacement of ITM with ACTM effectively protects broilers from Eimeria infection, with similar positive effects to SAL treatment in terms of productive performance and anti-inflammatory responses and better antioxidant responses and mineral availability.

Unveiling the Potential of Silymarin, Spirulina platensis, and Chlorella vulgaris towards Cardiotoxicity via Modulating Antioxidant Activity, Inflammation, and Apoptosis in Rats

This study assessed the possible pharmacological effects of Chlorella vulgaris (Cg), Spirulina platensis (St), and silymarin (Sl) against thioacetamide (TA)-induced cardiotoxicity in rats, with a focus on their antioxidant, cardioprotective, and anti-inflammatory properties. The following is the random grouping of sixty male rats into six groups of ten animals each: the control (negative control), TA-intoxicated group (positive control; 300 mg/kg body weight (BW)), Sl + TA group (100 mg Sl/kg BW + TA), St + TA group (400 mg St/kg BW + TA), Cg + TA (400 mg Cg/kg BW + TA), and St + Cg + TA group (400 St + 400 Cg mg/kg BW + TA) were all administered for 30 days. At the start of the study, groups 2 through 6 were administered TA intraperitoneally at a dosage of 300 mg/kg BW for two consecutive days, with a 24 h gap between each dose, to induce cardiac damage. Blood samples were obtained to measure hematological parameters and perform biochemical assays, including lipid profiles and cardiac enzymes. For histopathology and immunohistochemistry determination, tissue samples were acquired. The current findings showed that TA injection caused hematological alterations and cardiac injury, as evidenced by greater serum levels of troponin I, creatine kinase-MB, and total creatine kinase (p < 0.05), as well as significantly elevated serum malondialdehyde and decreased serum total antioxidant capacity (p < 0.05) concentrations. Moreover, an increase in blood low-density lipoprotein and total cholesterol concentration (p < 0.05) was recorded in the TA group. There were alterations in the heart tissue’s histological structure of the TA group compared to the control ones. These alterations were characterized by vacuolar degeneration of myocytes, loss of cross striation, coagulative necrosis, and fibrosis of interstitial tissue, which was ameliorated by the supplementation of SI, St, and Cg. The TA-intoxicated group showed weak expression of B-cell lymphoma protein 2 (p < 0.05) and strong immunoreactivity of tumor necrosis factor-α and B-cell lymphoma protein 2-associated X (p < 0.05). However, the groups receiving Sl, St, and Cg experienced the opposite. The administration of Sl, St, Cg, and St + Cg along with TA significantly improved and restored (p < 0.05) erythrogram indices, including RBCs, hemoglobin, total leukocytic count, lymphocytes, and monocyte, to the normal control values. The administration of Sl, St, and Cg alleviated the cardiotoxicity caused by TA via reducing oxidative stress, inflammatory markers, and apoptosis in heart tissue. In summary, the current findings suggest that the treatment with Sl, St, and Cg was beneficial in ameliorating and reducing the cardiotoxicity induced by TA in rats.

Familial hypercholesterolaemia with high triglycerides: A diagnostic challenge.

Combined or mixed hyperlipidaemia is characterised by hypercholesterolaemia together with high triglyceride concentrations. It is found in approximately 1 in 100 people in the United Kingdom. Most cases are secondary to an underlying condition such as the metabolic syndrome, diabetes mellitus (especially poorly controlled) or individuals with a high alcohol intake. Mixed hyperlipidaemia is also a feature of some primary hyperlipidaemia conditions such familial combined hyperlipidaemia (FCH) or type III hyperlipidaemia (dysbetalipoproteinaemia). One differential diagnosis for mixed hyperlipidaemia that can easily be overlooked is a patient with an underlying diagnosis of familial hypercholesterolaemia (FH) who also has a hypertriglyceridaemia due to any other cause. Those patients may have very high total and low-density lipoprotein cholesterol concentrations (LDL-C) with a moderately elevated triglyceride concentration. In this article, we report 4 cases of familial hypercholesterolaemia, confirmed by genetic testing, in patients initially presenting with hypertriglyceridaemia in addition to high total cholesterol and LDL-C. This article discusses the diagnostic challenges associated with this presentation and highlights the key role of directly measuring LDL-C to aid diagnosis in these specific situations.

Clinical application of centrifugal-membrane hybrid plasmapheresis in the treatment of hyperlipidemia.

This study aimed to clarify the clinical application of centrifugal-membrane hybrid plasmapheresis (CMHP) in the treatment of hyperlipidemia. A retrospective study was conducted on 48 patients who were diagnosed with hyperlipidemia and had received CMHP treatment. Serum total cholesterol (TC), triglycerides (TG), high-density lipoprotein cholesterol (HDL-C), and low-density lipoprotein cholesterol (LDL-C) were monitored, and adverse reactions to the treatment were observed. Forty-eight patients with hyperlipidemia received CMHP over 59 sessions. The average age of the 48 patients with hyperlipidemia, including 32 males (66.67%) and 16 females (33.33%), was 44.23 ± 12.02 years. Twenty-nine outpatients (60.42%) and 19 inpatients (39.58%) were included. Hypertriglyceridemia was diagnosed in 16 cases (33.33%), mixed hyperlipidemia in 31 cases (64.58%), and hypercholesterolemia in one case (2.08%). The pretreatment blood lipid concentrations were significantly different after the 59 CMHP treatments (p < .001). The concentrations of TC, TG, HDL-C, and LDL-C decreased significantly after the treatment, and the median ratios of reduction were 67.06% (range: 58.97%-71.87%), 63.33% (range: 55.20%-74.86%), 45.87% (range: 35.86%-52.95%), and 66.09% (range: 44.37%-73.94%), respectively. Three adverse reactions (5.08%) were recorded. No differences were detected in therapeutic parameters, effects, or adverse reactions between the two blood cell separators, there was no difference in Lipoprotein apheresis efficacy. This preliminary study demonstrated the clinical application of CMHP in patients in the treatment of hyperlipidemia. However, further studies are needed applying CMHP with hyperlipidemia.

The effect of Oleoylethanolamide supplementation on lipid profile, fasting blood sugar and dietary habits in obese people: a randomized double-blind placebo-control trial.

Abnormalities in biochemical parameters and changes in eating habits are considered complications of obesity. Oleoylethanolamide (OEA), an endocannabinoid-like compound, has been shown to have protective effects on many metabolic disorders. Given this evidence, the present study aimed to assess the effects of OEA on lipid profile parameters, fasting blood sugar (FBS), and dietary habits in healthy obese people. In this randomized, double-blind, placebo-controlled clinical trial, which was carried out in 2016 in Tabriz, Iran, 60 obese people were enrolled in the study based on inclusion criteria. The intervention group consumed 125mg of OEA capsules, and the placebo group received the same amount of starch twice for 8 weeks. Blood samples (5 mL) were taken at baseline and the end of the study in a fasting state. Serum concentrations of FBS, triglycerides (TGs), high-density lipoprotein cholesterol (HDL-C), and total cholesterol (TC) were measured by enzymatic methods using commercial kits. The low-density lipoprotein cholesterol (LDL-C) concentration was obtained using the Friede-Wald formula. To assess dietary habits, a food frequency questionnaire (147 items) was used at baseline and the end of the study. A value less than < 0.05 was considered to indicate statistical significance. The TG concentration decreased significantly in the intervention group (mean (SD): 166.29 (70.01) mg/dL to 142.22 (48.05) mg/dL, p = 0.047). Changes in the placebo group were not significant (p > 0.05). After adjusting for baseline values and demographic characteristics, the difference in TG between groups remained significant (p = 0.044). Changes in other biochemical parameters were not significant. There was no significant difference between or within groups in terms of food groups. OEA, as a complementary agent, plays a protective role in TG regulation. However, future studies with longer durations are needed to explore the impact of OEA on regulating dietary habits and to identify the mechanisms related to metabolic abnormalities in obese people. The study was registered in the Iranian Registry of Clinical Trials (IRCT) center as IRCT201607132017N30 with URL. www.IRCT.IR in date 03/10/2016.

Hypercholesterolemia and inflammation-Cooperative cardiovascular risk factors.

Maintaining low concentrations of plasma low-density lipoprotein cholesterol (LDLc) over time decreases the number of LDL particles trapped within the artery wall, slows the progression of atherosclerosis and delays the age at which mature atherosclerotic plaques develop. This substantially reduces the lifetime risk of atherosclerotic cardiovascular disease (ASCVD) events.In this context, plaque development and vulnerability result not only from lipid accumulation but also from inflammation. Changes in the composition of immune cells, including macrophages, dendritic cells, T cells, B cells, mast cells and neutrophils, along with altered cytokine and chemokine release, disrupt the equilibrium between inflammation and anti-inflammatory mechanisms at plaque sites. Considering that it is not a competition between LDLc and inflammation, but instead that they are partners in crime, the present narrative review aims to give an overview of the main inflammatory molecular pathways linked to raised LDLc concentrations and to describe the impact of lipid-lowering approaches on the inflammatory and lipid burden. Although remarkable changes in LDLc are driven by the most recent lipid lowering combinations, the relative reduction in plasma C-reactive protein appears to be independent of the magnitude of LDLc lowering. Identifying clinical biomarkers of inflammation (e.g. interleukin-6) and possible targets for therapy holds promise for monitoring and reducing the ASCVD burden in suitable patients.

Xylanase and phytase supplementation of Moringa oleifera diets: effects on the performance, egg quality and blood profile of laying hens

Context Moringa oleifera leaves present enormous potential as an alternative feedstuff for laying hens. The utilisation of the leaves can be improved by exogenous enzymes owing to the presence of non-starch polysaccharides and phytate. Aims This study evaluated the influence of Moringa oleifera leaf meal (MOL) in diets supplemented with xylanase and phytase on laying hen performance and egg quality at peak production. Methods In total, 288 Dekalb White laying hens (32 weeks old) were distributed in a completely randomised design, following a 2 × 4 factorial arrangement (with or without MOL × 4 enzyme supplementations). Each treatment comprised six repetitions, each containing six hens. The control diet was based on ground corn and soybean meal, and the treatment diets were supplemented with 5% MOL, followed by three enzyme additives (xylanase, phytase and a xylanase + phytase blend). Key results The enzyme supplementation in MOL diets positively influenced egg production (P = 0.012), egg weight (P = 0.021) and egg mass (P = 0.009). The birds offered xylanase-supplemented diets had higher feed intakes (P = 0.015) than did those fed other diets. Moringa oleifera increased the albumen height (P &lt; 0.001) and Haugh unit (P &lt; 0.001), whereas MOL and phytase improved eggshell thickness (P &lt; 0.001) and the candling score (P = 0.049), compared with treatments without phytase supplementation. MOL and enzyme supplementation improved yolk colour intensity (L, A and R parameters) and decreased plasma total cholesterol and LDL cholesterol concentrations. The inclusion of 5% MOL in diets did not impair laying performance. However, when MOL diets were supplemented with exogenous enzymes, there was an increase in egg weight. Conclusions MOL can be included at 5% in layer diets without affecting performance. When used in combination with xylanase and phytase, they improve performance, intensify yolk colour, and improve shell thickness, candling score, as well as serum biochemical profile. Implications These findings suggest that the combination of dietary MOL + xylanase + phytase can improve performance and egg quality in laying hens at peak production.

Association between lipid-lowering agents with intervertebral disc degeneration, sciatica and low back pain: a drug-targeted mendelian randomized study and cross-sectional observation

BackgroundAbnormal lipid metabolism is linked to intervertebral disc degeneration (IVDD), sciatica, and low back pain (LBP), but it remains unclear whether targeted interventions can prevent these issues. This study investigated the causal effects of lipid-lowering drug use on IVDD, sciatica, and LBP development.MethodsSingle-nucleotide polymorphisms (SNPs) linked to total cholesterol (TC), low-density-lipoprotein cholesterol (LDL-C), and non-high-density-lipoprotein cholesterol (non-HDL-C) were obtained from the Global Lipids Genetics Consortium’s genome-wide association study (GWAS). Genes near HMGCR, PCSK9, and NPC1L1 were selected to represent therapeutic inhibition targets. Using Mendelian randomization (MR) focusing on these drug targets, we identified causal effects of PCSK9, HMGCR, and NPC1L1 on the risk of developing IVDD, sciatica, and LBP, with coronary heart disease risk serving as a positive control. Using summary data from Mendelian randomization (SMR) analysis, we evaluated potential therapeutic targets for IVDD, sciatica, and LBP through protein quantitative trait loci (pQTL). The genetic associations with IVDD, sciatica, LBP, and coronary heart disease were derived from FinnGen (discovery) and UK Biobank (replication). Additionally, a cross-sectional observational study was performed using data from the National Health and Nutrition Examination Survey (NHANES) to further investigate the connection between LBP and statin use, with a sample size of 4343 participants. Odds ratios (ORs) and corresponding 95% confidence intervals (CIs) were calculated to assess the outcomes.ResultsThe NHANES-based cross-sectional study indicated that non-statin use was associated with an increased risk of developing LBP (OR = 1.29, 95% CI [1.04, 1.59], P = 0.019). Moreover, Inverse-variance weighting (IVW) analysis revealed that NPC1L1-mediated reductions in TC, LDL-C, and non-HDL-C concentrations were associated with a decreased risk of developing IVDD (P = 9.956E-03; P = 3.516E-02; P = 1.253E-04). Similarly, PCSK9-mediated reductions in LDL-C and TC concentrations were linked to a lower risk of developing sciatica (P = 3.825E-02; P = 2.709E-02). Sensitivity analysis confirmed the stability and reliability of the MR results. MST1 (macrophage stimulating 1) levels was inversely associated with IVDD, sciatica, and LBP risks.ConclusionThe results of cross-sectional study suggested that non-use of statins was positively correlated with LBP. The results of Mendelian randomization study suggest that NPC1L1 could lower the risk of developing IVDD by reducing TC, LDL-C, and non-HDL-C levels. Additionally, PCSK9 may reduce the risk of developing sciatica by lowering LDL-C and TC levels. In contrast, HMGCR appears to have no significant effect on IVDD, sciatica, or LBP development. Nonetheless, further research is needed to verify these preliminary results. MST1 warrants further exploration as a potential therapeutic target. It is necessary to do further research to validate these findings.