Cholesterol Exposure Research Articles

Association between remnant cholesterol and the trajectory of arterial stiffness progression

Objective: To explore the impact of baseline remnant cholesterol levels at a single time point and cumulative remnant cholesterol exposure on the progression trajectories of arterial stiffness. Methods: This prospective cohort study included 2 401 eligible participants from the Beijing Health Management Cohort who consecutively attended health examinations in 2010-2011, 2012-2013, and 2014-2015. The remnant cholesterol value measured in 2014-2015 served as the baseline remnant cholesterol level at a single time point. The cumulative exposure indices were calculated based on remnant cholesterol values from three health examinations from 2010 to 2015, including cumulative exposure, cumulative exposure burden, and duration of high remnant cholesterol exposure. Arterial stiffness was assessed by brachial-ankle pulse wave velocity (baPWV). The follow-up continued until December 31, 2019, with annual check-ups. During the follow-up period, a group-based trajectory model was employed to construct the progression trajectories of baPWV. The associations between the baseline remnant cholesterol level, cumulative exposure indices of remnant cholesterol and baPWV trajectories were examined using ordinal logistic regression models, adjusting for traditional cardiovascular risk factors and low-density lipoprotein cholesterol (LDL-C) levels. Results: The age of the 2 401 participants was 61 (54, 69) years, with 1 801 (75.01%) being male. The group-based trajectory model indicated that the best-fit model categorized the participants into three subgroups: low-rising group (1 036 individuals, 43.15%), moderate-rising group (1 137 individuals, 47.36%), and high-rising group (228 individuals, 9.50%). After adjusting for traditional cardiovascular risk factors, baseline remnant cholesterol levels at a single point (OR=1.170, 95%CI: 1.074-1.274), cumulative remnant cholesterol exposure (OR=1.194, 95%CI: 1.096-1.303), cumulative remnant cholesterol exposure burden (OR=1.270, 95%CI: 1.071-1.507), and high-remnant cholesterol exposure duration (6 years: OR=1.351, 95%CI: 1.077-1.695) were significantly associated with the risk of developing a poor baPWV progression trajectory. These results remained significant after adjusting for cumulative average LDL-C levels. The association between baseline remnant cholesterol levels and baPWV progression became insignificant after adjusting for cumulative remnant cholesterol levels (OR=1.053, 95%CI: 0.923-1.197), while the association between cumulative remnant cholesterol exposure and baPWV progression remained significant after adjusting for baseline remnant cholesterol levels (OR=1.145, 95%CI: 1.008-1.305). Conclusions: Higher levels of baseline remnant cholesterol and cumulative remnant cholesterol are independent risk factors for the progression of arterial stiffness. These associations remain significant even after adjusting for traditional cardiovascular risk factors and LDL-C levels. Furthermore, the effect of cumulative remnant cholesterol levels on the progression of arterial stiffness was stronger than the effect of baseline remnant cholesterol levels.

Association of cumulative non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio with the risk of cardiometabolic disease.

One measurement of non-high-density lipoprotein cholesterol to high-density lipoprotein cholesterol ratio (NHHR) is considered to be associated with insulin resistance and cardiovascular disease (CVD) risk. This study aimed to exploring the association between cumulative non-high-density lipoprotein cholesterol/high-density lipoprotein cholesterol (Cum NHHR) exposure levels and the risk of cardiometabolic disease (CMD). This prospective cohort study included 43,735 participants, who participated in three consecutive health examinations in 2006, 2008, 2010 and had no history of CMD or cancer. The participants were divided into quartiles bases on their cum NHHR. Multivariate Cox proportional hazards model was used to assess the association between cum NHHR and the risk of CMD. Additionally, the direct method of standardized ratios was employed to calculate the absolute risk of CMD attributable to cum NHHR. Over a median follow-up period of 10.92 years (IQR: 10.22-11.26 years), 7,388 participants were newly diagnosed with CMD. In the multivariate-adjusted model, participants in quartiles Q2, Q3 and Q4 showed a progressively increased relative risk of CMD compared to those in Q1, The fully adjusted hazard ratios (95% confidence intervals) for the risk of CMD in the Q2, Q3, and Q4 groups were 1.11 (1.04-1.20), 1.23 (1.14-1.32), and 1.29 (1.20-1.38), respectively, compared with the Q1 group. This association remained significant even after further adjustment for single measurements of NHHR. Moreover, cum NHHR was positively correlated with the absolute risk of CMD, cardiovascular diseases (CVD), and type 2 diabetes (T2DM). Higher cum NHHR is significantly associated with an increased risk of CMD, independent of single-point NHHR level. Additionally, there are significant different strengths of correlations between cum NHHR and different diseases.

Investigation of the Association Between Hyperlipidemia and Ossification of The Posterior Longitudinal Ligament Through Two-Sample Mendelian Randomization Analysis.

A Two-Sample Mendelian Randomization Analysis. This study aimed to investigate the association between genetically predicted hyperlipidemia and ossification of the posterior longitudinal ligament (OPLL) using two-sample Mendelian randomization (MR) analysis. Several observational studies suggested associations between hyperlipidemia and OPLL. Genome-wide association study (GWAS) summary statistics for hyperlipidemia and OPLL were retrieved from the public database. The MR analysis employed the Inverse Variance Weighted (IVW) method, which was supplemented by MR-Egger, weighted median, and weighted mode analyses. Sensitivity analyses, incorporating Cochran's Q test, MR-Egger regression and the MR pleiotropy residual sum and outlier test, additionally assessed the robustness of the findings. The IVW analysis revealed a significant association between total cholesterol levels and OPLL (OR: 1.44,95% CI:1.06-1.96, P=0.02). Similarly, a significant association was observed between LDL cholesterol and OPLL (OR: 1.31,95%CI:1.05-1.63, P=0.02). Supplementary analyses further supported the significant association of total cholesterol levels and LDL cholesterol on OPLL (P <0.05). In sensitivity analyses, LDL cholesterol exposure showed robust results, with no outliers detected by loo or mrpresso, despite MR-Egger hints at pleiotropy. For total cholesterol exposure, MR-Egger suggested no pleiotropy, though heterogeneity and outliers were present. Outlier removal confirmed the initial positive association, underlining study stability. However, no significant associations were found of hyperlipidemia, triglycerides, HDL cholesterol on OPLL. This study suggests a association of total cholesterol levels and LDL cholesterol levels on OPLL. Further research is warranted to validate these findings and explore potential therapeutic implications.

Relationship of cumulative low-density lipoprotein cholesterol with atherosclerosis

Abstract Background The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. Objective The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). Methods This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: &amp;lt;4000 mg･year/dL, 4000-4999 mg･year/dL, 5000-5999 mg･year/dL, and ≥6000 mg･year/dL. Results The odds ratio of the lower quartile of FMD in the cholesterol-year-score &amp;lt;4000 mg･year/dL group was significantly higher than the odds ratios in the other groups (Figure 1A). The odds ratio of the lower quartile of NID in the &amp;lt;4000 mg・year/dL group was significantly higher than the odds ratios in the 5000-5999 mg･year/dL and ≥6000 mg･year/dL groups (Figure 1B). The odds ratio of the prevalence of CCA plaque in the &amp;lt;4000 mg・year/dL group was significantly higher than that in the ≥6000 mg･year/dL group (Figure 1C). Conclusions Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg・year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg･year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg･year/dL.Graphical abstractFigure 1

The association of cumulative low-density lipoprotein cholesterol exposure and carotid intima-media thickness in a young adulthood population

ObjectiveTo investigate the association between cumulative exposure to low-density lipoprotein cholesterol (LDL-C) and carotid intima-media thickness (IMT) in the young adulthood population.MethodsYoung adult subject (18-45 year old) from the Kailuan Study group who participated in the same period of follow-up and received carotid artery ultrasound were selected as the observation subjects. Among them, 3651 cases met the inclusion criteria, which required that carotid artery color ultrasound examinations be completed from 2010 to 2016, with complete IMT measurements, LDL-C data collected at least twice before carotid ultrasound, and participants’ age to be ≤ 45 years at the time of carotid artery color ultrasound examination. Linear regression was used to analyze the correlation between time-weighted average (TWA) to LDL-C cumulative exposure and IMT the young population. Logistic regression was used to analyze the effects of different TWA groups on IMT thickening. Considering that the use of anti hypertensive drugs and lipid-lowering drugs may affect TWA LDL-C, this study excluded people taking antihypertensive drugs and lipid-lowering drugs, and conducted a repeat analysis of the main results.ResultsThere was a positive correlation between TWA LDL-C and IMT, with IMT increasing by 0.017 mm when TWA LDL-C increased by 1 mmol/L * year. The TWA LDL-C in the highest group was identified as a risk factor for IMT thickening, with odds ratio (OR) values of 1.812(1.027 ~ 3.200) in the T3 group. After excluding patients taking antihypertensive drugs and lipid-lowering drugs, the results still showed that the T3 group with the highest TWA LDL-C was a risk factor for IMT thickening, with an OR value of 1.850(0.988–3.464), P for trend is 0.043.ConclusionThis cohort study revealed that TWA LDL-C is positively correlated with IMT in young adulthood for risk stratification, and control LDL-C levels at an earlier age may reduce the lifetime risk of developing atherosclerotic disease.Trial registrationChiCTR-TNC-11001489.

Prospective associations of maternal cardiometabolic health with children cardiometabolic health at ages 3 to 6 years.

Maternal cardiometabolic health (MCMH) may have critical effects on offspring lifetime CMH, whereas evidence on the relationship between MCMH during pregnancy and children CMH (CCMH) at ages 3∼6 years remains unknown. The study included 1478 mother-child dyads from the Shanghai Maternal-Child Pairs Cohort study. MCMH was examined at a mean of 27.8 (24-36) weeks' gestation based on 8 metrics of 'Life Essential 8' framework involving pre-pregnancy body mass index, total cholesterol, glucose level, blood pressure, physical activity, sleep, diet quality, and nicotine exposure. CCMH was examined at the age of 3 to 6 based on 5 metrics including body mass index, physical activity, sleep health, diet quality, and nicotine exposure. To validate the robustness of main analysis, 499 children were selected to reevaluate CCMH by six metrics (adding blood pressure) for sensitivity analysis. Among 1478 mother-child dyads, the mean (SD) MCMH during pregnancy and CCMH scores were 67.07 (SD 8.82) and 73.80 (SD 10.75), respectively. After adjusting important confounders, each 10 points increase in (more favorable) MCMH score was significantly associated with a higher CCMH score (β: 0.85, [95% confidence interval (CI): 0.22, 1.47]). Subgroup analysis showed similar results in girls but not in boys. For cardiometabolic risks factors in children, the risk of overweight/obesity and hypertension in children decreased with increased MCMH score (overweight/obesity, Relative Risks [RRs]: 0.98, 95%CI: [0.96, 0.99]); hypertension, RRs: 0.66, 95%CI: [0.47, 0.92]). Sensitivity analysis showed similar result. Better MCMH in pregnancy was associated with better CCMH at ages 3∼6 years.

The Role of Fatty Acid Synthase in the Vascular Smooth Muscle Cell to Foam Cell Transition.

Vascular smooth muscle cells (VSMCs), in their contractile and differentiated state, are fundamental for maintaining vascular function. Upon exposure to cholesterol (CHO), VSMCs undergo dedifferentiation, adopting characteristics of foam cells-lipid-laden, macrophage-like cells pivotal in atherosclerotic plaque formation. CHO uptake by VSMCs leads to two primary pathways: ABCA1-mediated efflux or storage in lipid droplets as cholesterol esters (CEs). CE formation, involving the condensation of free CHO and fatty acids, is catalyzed by sterol O-acyltransferase 1 (SOAT1). The necessary fatty acids are synthesized by the lipogenic enzyme fatty acid synthase (FASN), which we found to be upregulated in atherosclerotic human coronary arteries. This observation led us to hypothesize that FASN-mediated fatty acid biosynthesis is crucial in the transformation of VSMCs into foam cells. Our study reveals that CHO treatment upregulates FASN in human aortic SMCs, concurrent with increased expression of CD68 and upregulation of KLF4, markers associated with the foam cell transition. Crucially, downregulation of FASN inhibits the CHO-induced upregulation of CD68 and KLF4 in VSMCs. Additionally, FASN-deficient VSMCs exhibit hindered lipid accumulation and an impaired transition to the foam cell phenotype following CHO exposure, while the addition of the fatty acid palmitate, the main FASN product, exacerbates this transition. FASN-deficient cells also show decreased SOAT1 expression and elevated ABCA1. Notably, similar effects are observed in KLF4-deficient cells. Our findings demonstrate that FASN plays an essential role in the CHO-induced upregulation of KLF4 and the VSMC to foam cell transition and suggest that targeting FASN could be a novel therapeutic strategy to regulate VSMC phenotypic modulation.

Clinical Impact of Lipoprotein (a) and Cumulative Low-Density Lipoprotein Cholesterol Exposure on Coronary Artery Disease in Patients with Heterozygous Familial Hypercholesterolemia.

Elevated lipoprotein (a) (Lp[a]), predominantly determined by genetic variability, causes atherosclerotic cardiovascular disease (ASCVD), particularly in patients with familial hypercholesterolemia (FH). We aimed to elucidate the clinical impact of Lp(a) and cumulative exposure to low-density lipoprotein cholesterol (LDL-C) on CAD in patients with FH. One hundred forty-seven patients clinically diagnosed with heterozygous familial hypercholesterolemia (HeFH) were retrospectively investigated. Patients were divided into 2 groups according to the presence of CAD. Their clinical characteristics and lipid profiles were evaluated. There were no significant differences in untreated LDL-C levels between the 2 groups (p=0.4), whereas the cumulative exposure to LDL-C and Lp(a) concentration were significantly higher in patients with CAD (11956 vs. 8824 mg-year/dL, p＜0.01; 40 vs. 14 mg/dL, p＜0.001, respectively). A receiver operating characteristic (ROC) curve analysis demonstrated that the cutoff values of Lp(a) and cumulative LDL-C exposure to predict CAD in patients with FH were 28 mg/dL (AUC 0.71) and 10600 mg-year/dL (AUC 0.77), respectively. A multivariate analysis revealed that cumulative LDL-C exposure ≥ 10600 mg-year/dL (p＜0.0001) and Lp(a) level ≥ 28 mg/dL (p＜0.001) were independent predictors of CAD. Notably, the risk of CAD remarkably increased to 85.7% with smoking, Lp(a) ≥ 28 mg/dL, and cumulative LDL-C exposure ≥ 10600 mg-year/dL (odds ratio: 46.5, 95%CI: 5.3-411.4, p＜0.001). This study demonstrated an additive effect of Lp(a) and cumulative LDL-C exposure on CAD in patients with HeFH. Interaction with traditional risk factors, particularly smoking and cumulative LDL-C exposure, enormously enhances the cardiovascular risk in this population.

A detection system for serum cholesterol based on the fluorescence color detection of beta-cyclodextrin-capped gold nanoclusters

Cholesterol is one of the major markers for cardiovascular diseases. Herein, a portable cholesterol measurement system based on fluorescence color detection was constructed by combining the high sensitivity of fluorescence analysis with the ease of color sensing to determine low levels of serum cholesterol. Cyclodextrin capping gold nanoclusters with blue-green emission were used as fluorescent probes because cholesterol exposure induced fluorescence enhancement of the probe due to the host–guest inclusion interaction between cholesterol and the cavity of cyclodextrin. The integrated sensing system consisted of modules including a microprocessor, a power supply, an LED light with a constant current source, an RGB color sensor, a display, and a darkroom. All the modules except the display screen were placed in a 3D printing darkroom to avoid interference from ambient light. An RGB color sensor TCS230 was applied to capture the RGB signals of the fluorescent color of the probe solution before and after cholesterol addition. Then the obtained RGB signals were converted into the signals in Hue, Saturation, and Value (HSV) color space with a central control chip STM32F407. The Hue value of the fluorescent color of the solution can discriminate the concentration change of cholesterol. Experimental results demonstrate that the system responds linearly to cholesterol in the concentration range of 20.00 ∼ 150.00 μmol·L-1 with a detection limit of 16.07 μmol·L-1 (3σ, n = 3). The detection of the system has good consistency and accuracy compared with the standard instrument, showing potential for the detection of low levels of serum cholesterol.

Association of cumulative low-density lipoprotein cholesterol exposure with vascular function

The relationship between cumulative low-density lipoprotein cholesterol (LDL-C) exposure and progression of atherosclerosis remains uncertain. The aim of this study was to determine the relationship between cumulative LDL-C level and flow-mediated vasodilation (FMD), nitroglycerine-induced vasodilation (NID) and the presence of plaque in the common carotid artery (CCA). This was a cross-sectional study. We measured FMD in 8208 subjects, NID in 1822 subjects, and CCA plaque in 591 subjects who were not taking lipid-lowering drugs. The subjects were divided into four groups based on cumulative LDL-C exposure: <4000 mg·year/dL, 4000-4999 mg·year/dL, 5000-5999 mg·year/dL, and ≥6000 mg·year/dL. The odds ratio of the lower quartile of FMD in the cholesterol-year-score <4000 mg·year/dL group was significantly higher than the odds ratios in the other groups. The odds ratio of the lower quartile of NID in the <4000 mg·year/dL group was significantly higher than the odds ratios in the 5000-5999 mg·year/dL and ≥6000 mg·year/dL groups. The odds ratio of the prevalence of CCA plaque in the <4000 mg·year/dL group was significantly higher than that in the ≥6000 mg·year/dL group. Endothelial dysfunction occurred from cumulative LDL-C exposure of 4000 mg·year/dL, vascular smooth muscle dysfunction occurred from cumulative LDL-C exposure of 5000 mg·year/dL, and prevalence of CCA plaque occurred from cumulative LDL-C exposure of 6000 mg·year/dL. CLINICAL TRIAL REGISTRY INFORMATION: http://www.umin.ac.jp (UMIN000012950, UMIN000012951, and UMIN000012952, UMIN000003409).

Assessment of Role of Job Components and Individual Parameters on the Raised Blood Pressure in a Noisy Industry

The present study aimed to determine the role of job components and individual parameters on the raised blood pressure among male workers of textile industry who were exposed to continuous high noise level. Information of all eligible subjects including demographic and individual characteristics, medical history and job characteristics were obtained by direct interview and referring to the medical records. All blood pressure measurements were done using mercury sphygmomanometer in the morning before work. The 8-hours equivalent A-weighted sound pressure level, the level of blood cholesterol and triglyceride, and noise annoyance was determined for each worker. As the result of weighted regression in path analysis (direct effect), only the work shift did not have a significant effect on blood pressure among the studied variables. It can be seen that variables including the level of triglyceride, cholesterol, and noise exposure have the most direct effects on blood pressure. The results of total effects showed that variables, including using the hearing protection device, age, work experience and visibility of sound source, did not have a significant effect on blood pressure. The results of this study indicate that occupational noise exposure alone and combined with other job components and individual parameters is associated with raised blood pressure. However, noise exposure was probably a stronger stressor for increased blood pressure.

Adverse effect of oxidized cholesterol exposure on colitis is mediated by modulation of gut microbiota

Both cholesterol and oxidized cholesterol (OXC) are present in human diets. The incidence of inflammatory bowel diseases (IBDs) is increasing in the world. The present study was to investigate the mechanism by which OXC promotes colitis using C57BL/6 mice as a model. Results shown that more severe colitis was developed in OXC-treated mice with the administration of dextran sulfate sodium (DSS) in water. Direct effects of short-term OXC exposure on gut barrier or inflammation were not observed in healthy mice. However, OXC exposure could cause gut microbiota dysbiosis with a decrease in the relative abundance of short-train fatty acids (SCFAs)-producing bacteria (Lachnospiraceae_NK4A136_group and Blautia) and an increase in the abundance of some potential harmful bacteria (Bacteroides). OXC-induced symptoms of colitis were eliminated when mice were administered with antibiotic cocktails, indicating the promoting effect of OXC on DSS-induced colitis was mediated by its effect on gut microbiota. Moreover, bacteria-depleted mice colonized with gut microbiome from OXC-DSS-exposed mice exhibited a severe colitis, further proving the gut dysbiosis caused by OXC exposure was the culprit in exacerbating the colitis. It was concluded that dietary OXC exposure increased the susceptibility of colitis in mice by causing gut microbiota dysbiosis.

Abstract 262: A Novel Humanized ACE2 Mouse Model For Evaluating COVID-19 Infection In Cardiovascular Disease

The COVID-19 pandemic has resulted in over 6.7 million deaths worldwide. Patients with cardiovascular disease are at increased risk for severe illness and mortality with COVID-19. Increased systemic inflammation driven by macrophages, a key cellular source of inflammatory cytokine IL-1β, may play a role in the mechanism of SARS-CoV-2 pathogenesis. We seek to understand the mechanisms whereby inflammation associated with vascular disease may drive severity of COVID-19. Under culture conditions that mimic atherosclerotic plaque cholesterol exposure, we found that macrophage IL-1β signaling may promote expression of ACE2, the established receptor for SARS-CoV-2, through NF-κB-mediated transcription. We generated a novel, “humanized” ACE2 mouse strain ( hACE2 ) by using CRISPR-Cas9 technology to insert the human ACE2 cDNA sequence into the native mouse ACE2 locus under regulation of the native promoter. Using lung tissue, presence of hACE2 mRNA was verified by RT-qPCR and protein expression was verified by immunofluorescence staining. Overall, SARS-CoV-2 intranasal inoculation of hACE2 mice revealed milder infection when compared to the K18 promoter driven hACE2 ( K18-hACE2 ) overexpression strain, which exhibits severe infection with high morality. hACE2 mice had 100% survival after infection with stable body weight despite detectable viral burden in the lung fields. Histological analysis of the lungs revealed inflammatory infiltrate and pulmonary consolidation with alveolar hemorrhage that were comparable to the K18-hACE2 mice, and immunohistochemistry confirmed detection of viral nucleocapsid in the lung consolidations. Infected hACE2 mice also demonstrated a unique plasma cytokine signature relative to K18-hACE2 mice, including elevated levels of IL-1β, IL-1α, and VEGF-A, but decreased IL-6 and TNF-α. In summary, we have established a novel model of COVID-19 that survives infection and may facilitate comparative studies involving experimental vascular disease. The ability to model COVID-19 in the context of experimental atherosclerosis may help to define new mechanisms driving severity of SARS-CoV-2 infection.

Time to run: Late rather than early exercise training in mice remodels the gut microbiome and reduces atherosclerosis development.

The metabolic and inflammatory processes that are implicated in the development of cardiovascular diseases are under control of the biological clock. While skeletal muscle function exhibits circadian rhythms, it is unclear to what extent the beneficial health effects of exercise are restricted to unique time windows. We aimed to study whether the timing of exercise training differentially modulates the development of atherosclerosis and elucidate underlying mechanisms. We endurance-trained atherosclerosis-prone female APOE*3-Leiden.CETP mice fed a Western-type diet, a well-established human-like model for cardiometabolic diseases, for 1 h five times a week for 4 weeks either in their early or in their late active phase on a treadmill. We monitored metabolic parameters, the development of atherosclerotic lesions in the aortic root and assessed the composition of the gut microbiota. Late, but not early, exercise training reduced fat mass by 19% and the size of early-stage atherosclerotic lesions by as much as 29% compared to sedentary animals. No correlation between cholesterol exposure and lesion size was evident, as no differences in plasma lipid levels were observed, but circulating levels of the pro-inflammatory markers ICAM-1 and VCAM-1 were reduced with late exercise. Strikingly, we observed a time-of-day-dependent effect of exercise training on the composition of the gut microbiota as only late training increased the abundance of gut bacteria producing short-chain fatty acids with proposed anti-inflammatory properties. Together, these findings indicate that timing is a critical factor to the beneficial anti-atherosclerotic effects of exercise with a great potential to further optimize training recommendations for patients.

The Berberis vulgaris L. extract berberine exerts its anti-oxidant effects to ameliorate cholesterol overloading-induced cell apoptosis in the primary mice hepatocytes: an in vitro study.

Cholesterol overloading stress damages normal cellular functions in hepatocytes and induces metabolic disorders to facilitate the development of multiple diseases, including cardiovascular diseases, which seriously degrades the life quality of human beings. Recent data suggest that the Berberis vulgaris L. extract berberine is capable of regulating cholesterol homeostasis, which is deemed as potential therapeutic drug for the treatment of cholesterol overloading-associated diseases, but its detailed functions and molecular mechanisms are still largely unknown. In the present study, we evidenced that berberine suppressed cell apoptosis in high-cholesterol-diet mice liver and cholesterol-overloaded mice hepatocytes. Also, cholesterol overloading promoted reactive oxygen species (ROS) generation to trigger oxidative damages in hepatocytes, which were reversed by co-treating cells with both berberine and the ROS scavenger N-acetylcysteine (NAC). Moreover, the underlying mechanisms were uncovered, and we validated that berberine downregulated Keap1, and upregulated Nrf2 to activate the anti-oxidant Nrf2/HO-1 signaling pathway in cholesterol overloading-treated hepatocytes, and both Keap1 upregulation and Nrf2 downregulation abrogated the suppressing effects of berberine on cell apoptosis in the hepatocytes with cholesterol exposure. Taken together, we concluded that berberine activated the anti-oxidant Keap1/Nrf2/HO-1 pathway to eliminate cholesterol overloading-induced oxidative stress and apoptotic cell death in mice hepatocytes, and those evidences hinted that berberine might be used as putative therapeutic drug for the treatment of cholesterol overloading-associated cardiovascular diseases.

Modeling maternal cholesterol exposure reveals a reduction of neural progenitor proliferation using human cerebral organoids

Abstract Maternal obesity raises the risk of high-cholesterol exposure for their offspring. Studies in cohorts and animal models report that maternal obesity could increase the risk of neurodevelopmental disorders in offspring including intellectual disabilities and autism spectrum disorders (ASDs). However, whether exposure to high cholesterol is responsible for brain developmental defects, as well as its underlying mechanism, is still unclear. Here, we constructed a cholesterol exposure model utilizing human pluripotent stem cell (hPSC)-derived cerebral organoids by exogenously adding cholesterol into the culture system. We observed enlargement of endosomes, decreased neural progenitor proliferation, and premature neural differentiation in brain organoids with the treatment of cholesterol. Moreover, in comparison with published transcriptome data, we found that our single-cell sequencing results showed a high correlation with ASD, indicating that high cholesterol during maternal might mediate the increased risk of ASD in the offspring. Our results reveal a reduction of neural progenitor proliferation in a cholesterol exposure model, which might be a promising indicator for prenatal diagnosis and offer a dynamic human model for maternal environment exposure.

Surface cholesterol-enriched domains specifically promote invasion of breast cancer cell lines by controlling invadopodia and extracellular matrix degradation

Tumor cells exhibit altered cholesterol content. However, cholesterol structural subcellular distribution and implication in cancer cell invasion are poorly understood mainly due to difficulties to investigate cholesterol both quantitatively and qualitatively and to compare isogenic cell models. Here, using the MCF10A cell line series (non-tumorigenic MCF10A, pre-malignant MCF10AT and malignant MCF10CAIa cells) as a model of breast cancer progression and the highly invasive MDA-MB-231 cell line which exhibits the common TP53 mutation, we investigated if cholesterol contributes to cancer cell invasion, whether the effects are specific to cancer cells and the underlying mechanism. We found that partial membrane cholesterol depletion specifically and reversibly decreased invasion of the malignant cell lines. Those cells exhibited dorsal surface cholesterol-enriched submicrometric domains and narrow ER-plasma membrane and ER-intracellular organelles contact sites. Dorsal cholesterol-enriched domains can be endocytosed and reach the cell ventral face where they were involved in invadopodia formation and extracellular matrix degradation. In contrast, non-malignant cells showed low cell invasion, low surface cholesterol exposure and cholesterol-dependent focal adhesions. The differential cholesterol distribution and role in breast cancer cell invasion provide new clues for the understanding of the molecular events underlying cellular mechanisms in breast cancer.

Coronary Artery Disease Risk of Familial Hypercholesterolemia Genetic Variants Independent of Clinically Observed Longitudinal Cholesterol Exposure.

Familial hypercholesterolemia (FH) genetic variants confer risk for coronary artery disease independent of LDL-C (low-density lipoprotein cholesterol) when considering a single measurement. In real clinical settings, longitudinal LDL-C data are often available through the electronic health record. It is unknown whether genetic testing for FH variants provides additional risk-stratifying information once longitudinal LDL-C is considered. We used the extensive electronic health record data available through the Million Veteran Program to conduct a nested case-control study. The primary outcome was coronary artery disease, derived from electronic health record codes for acute myocardial infarction and coronary revascularization. Incidence density sampling was used to match case/control exposure windows, defined by the date of the first LDL-C measurement to the date of the first coronary artery disease code of the index case. Adjustments for the first, maximum, or mean LDL-C were analyzed. FH variants in LDLR, APOB, and PCSK9 (Proprotein convertase subtilisin/kexin type 9) were assessed by custom genotype array. In a cohort of 23 091 predominantly prevalent cases at enrollment and 230 910 matched controls, FH variant carriers had an increased risk for coronary artery disease (odds ratio [OR], 1.53 [95% CI, 1.24-1.89]). Adjusting for mean LDL-C led to the greatest attenuation of the risk estimate, but significant risk remained (odds ratio, 1.33 [95% CI, 1.08-1.64]). The degree of attenuation was not affected by the number and the spread of LDL-C measures available. The risk associated with carrying an FH variant cannot be fully captured by the LDL-C data available in the electronic health record, even when considering multiple LDL-C measurements spanning more than a decade.

Gestational hypercholesterolemia programs hepatic steatosis in a sex-specific manner in ApoE-deficient mice

Maternal hypercholesterolemia (MHC), a pathological condition characterized by an exaggerated rise in maternal serum cholesterol during pregnancy, may influence offspring hepatic lipid metabolism and increase the risk of nonalcoholic fatty liver disease (NAFLD). As NAFLD is characterized by a sexual dimorphic response, we assessed whether early-life exposure to excessive cholesterol influences the development of NAFLD in offspring and whether this occurs in a sex-specific manner. Female apoE−/− mice were randomly assigned to a control (CON) or a high cholesterol (CH; 0.15%) diet prior to breeding. At parturition, a cross-fostering approach was used to establish three groups: (1) normal cholesterol exposure throughout gestation and lactation (CON-CON); (2) excessive cholesterol exposure throughout gestation and lactation (CH-CH); and (3) excessive cholesterol exposure in the gestation period only (CH-CON). Adult male offspring (PND 84) exposed to excessive cholesterol during gestation only (CH-CON) demonstrated hepatic triglyceride (TG) accumulation and reduced lipogenic gene expression. However, male mice with a prolonged cholesterol exposure throughout gestation and lactation (CH-CH) had a similar, but not exacerbated hepatic response. Further, with the exception of higher serum TG in adult CH-CH females, evidence for a programming effect in female offspring was largely absent in comparison with males. These results indicate a sexual dimorphic response with respect to the effect of MHC on later life hepatic steatosis and highlight the gestation period as the most influential malprogramming window for hepatic lipid dysfunction in males.

Prevention guidelines and EAS/ESC guidelines for the treatment of dyslipidaemias: A look to the future

Prevention guidelines and EAS/ESC guidelines for the treatment of dyslipidaemias: A look to the future