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Non-alcoholic fatty liver disease (NAFLD) is the most prevalent liver disorder globally, characterized by fat accumulation in liver cells, which can progress to inflammation, fibrosis, and cirrhosis. The disease predominantly affects individuals with obesity and high body mass index (BMI). It is a globally prevalent condition, with variations in incidence across different regions. The pathophysiology of NAFLD involves insulin resistance, metabolic disturbances, and genetic and gut microbial factors. Current treatments primarily focus on lifestyle modifications and a limited range of pharmacological options. Bempedoic acid (BA), a novel cholesterol-lowering agent, targets adenosine triphosphate (ATP)-citrate lyase to reduce low-density lipoprotein (LDL) cholesterol and has shown potential in managing NAFLD by decreasing liver fat accumulation and improving lipid profiles. BA's unique mechanism offers a promising add-on therapy, particularly for the patient's intolerant to statins. Despite its potential, comprehensive clinical and preclinical studies are needed to further elucidate its efficacy and safety compared to other NAFLD treatments. Future research should focus on comparing BA with existing and emerging therapies to optimize its role in NAFLD management and enhance patient outcomes.

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Background Patients with subclinical hypothyroidism (SCH) have a high serum concentration of thyroid-stimulating hormone (TSH), whereas their serum-free thyroxine concentrations are normal. Lipid metabolism is regulated in large part by thyroid hormones. It could be connected to a changed lipid profile. This study aimed to evaluate the relationship between SCH and alterations in the lipid profile. Methodology Data from 99 patients with SCH and 109 euthyroid cases were collected from King Abdulaziz Medical City, Jeddah, Saudi Arabia, from 2016 to 2022. Patients older than 18 years were included in the study. The groups were matched in terms of gender, age, and body mass index. SCH was defined as a TSH value of 4.5 to 10 mIU/L, and normal T4 as 5 to 18 µg/dL. Control cases had a normal TSH ranging from 0.45 to 4.5 mIU/L. The total serum cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride (TG) levels in both groups were examined and the results were recorded. Results In comparison to the control group, SCH patients had greater median glycated hemoglobin (HbA1C) (p = 0.001) and lower median vitamin D levels (p = 0.004) before therapy. Before therapy, SCH patients also showed considerably lower HDL levels and significantly higher LDL and TG levels (p < 0.001). Conclusions There is a substantial correlation between SCH and reduced HDL and vitamin D levels. It was linked to increased TG, LDL, and HbA1c levels. Only vitamin D and LDL were pathologically high. Treatment with levothyroxine raised total and LDL cholesterol levels. Future research should look into the affordability of treating SCH.

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Background: Familial hypercholesterolemia (FH) is an autosomal dominant disorder characterized by increased LDL-cholesterol levels. About 85% of FH cases are caused by LDLR mutations encoding the low-density lipoprotein receptor (LDLR). LDLR is synthesized in the endoplasmic reticulum (ER) where it undergoes post-translational modifications and then transported through Golgi apparatus to the plasma membrane. Over 2900 LDLR variants have been reported in FH patients with limited information on the pathogenicity and functionality of many of them. This study aims to elucidate the cellular trafficking and functional implications of LDLR missense variants identified in suspected FH patients using biochemical and functional methods. Methods: We used HeLa, HEK293T, and LDLR-deficient-CHO-ldlA7 cells to evaluate the subcellular localization and LDL internalization of ten LDLR missense variants (p.C167F, p.D178N, p.C243Y, p.E277K, p.G314R, p.H327Y, p.D477N, p.D622G, p.R744Q, and p.R814Q) reported in multiethnic suspected FH patients. We also analyzed the functional impact of three variants (p.D445E, p.D482H, and p.C677F), two of which previously shown to be retained in the ER. Results: We show that p.D622G, p.D482H, and p.C667F are largely retained in the ER whereas p.R744Q is partially retained. The other variants were predominantly localized to the plasma membrane. LDL internalization assays in CHO-ldlA7 cells indicate that p.D482H, p.C243Y, p.D622G, and p.C667F have quantitatively lost their ability to internalize Dil-LDL with the others (p.C167F, p.D178N, p.G314R, p.H327Y, p.D445E, p.D477N, p.R744Q and p.R814Q) showing significant losses except for p.E277K which retained full activity. However, the LDL internalization assay is only to able evaluate the impact of the variants on LDL internalization and not the exact functional defects such as failure to bind LDL. The data represented illustrate the hypomorphism nature of variants causing FH which may explain some of the variable expressivity of FH. Conclusion: Our combinatorial approach of in silico, cellular, and functional analysis is a powerful strategy to determine pathogenicity and FH disease mechanisms which may provide opportunitites for novel therapeutic strategies.

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Background: Pseudoxanthoma elasticum (PXE) is a rare, inherited disease characterised by specific skin lesions, progressive loss of vision and early onset atherosclerosis. Atherosclerosis in PXE leads to an increased rate of vascular occlusion and severe intermittent claudication. Although genetically determined, the individual course of PXE is highly variable. Up to now, there is no sufficient parameter to identify individuals at risk of rapid disease progression. This present study focused the lipid profile of patients with PXE and its possible influence on the clinical severity of peripheral artery disease (PAD). Patients and methods: 112 patients with PXE were retrospectively screened. Patients without a complete lipid profile consisting of total cholesterol (TC), triglycerides (TGC), high-density lipoprotein (HDL), low-density lipoprotein (LDL) and Lipoprotein(a) (Lp[a]) where excluded as well as patients with already initiated lipid-lowering therapy. 52 patients met the inclusion criteria. An age-adjusted ordinal regression model was applied to determine the association of each lipid fraction with the severity of PAD assessed as Fontaine classification. Results: The lipid profile of patients with PXE was unremarkable (TGC: 135.8±105.8 mg/dl; TC: 172.5±44.4 mg/dl; HDL: 63.0±18.2 mg/dl; Lp[a]: 64.7±93.5 nmol/l). Ordinal regression showed a significant association of Lp(a) with the severity of PAD with an odds ratio of 1.01 (1.00-1.02; p = 0.004), whereas the other fractions of the lipid profile had no significant influence. Conclusions: This study provides the largest evaluation of blood lipids up to now and the first characterization of Lp(a) levels in patients with PXE. We were able to provide first evidence of a correlation between elevated levels of Lp(a) and the severity of PAD. The present results suggest that determination of Lp(a) in early stages of PXE could help to identify patients at risk of rapid disease progression and with the need of intensified walking exercise training.

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(1) Background: Schizophrenia is a chronic and progressive neuropsychiatric illness. Apart from positive and negative symptoms, 98% of the population diagnosed with schizophrenia have impaired cognitive functioning, which significantly influences the quality of life. The correlation between lipids and cognitive functioning has been well established. Our study aimed to investigate correlations between cognitive functions, the severity of schizophrenia symptoms, and lipid profiles. (2) Methods: Fifty-two women diagnosed with schizophrenia participated in this study. Cognitive functioning was measured using the Wisconsin Card Sorting Test (WCST). The Positive and Negative Symptom Scale (PANSS) was used. The serum lipid profile, including low-density lipoproteins (LDLs), high-density lipoproteins (HDLs), and triglycerides was measured. (3) Results: Better cognitive functions were associated with normal HDL levels, while low HDL levels correlated with worse WSCT scores. Only the PANSS negative subscale showed a correlation with HDL levels. Correlations with chronicity of schizophrenia and the patient's age with poorer cognitive functions, but not with symptom severity, were detected. Early/late age at onset did not influence WSCT scores. (4) Conclusions: Our results suggest high HDL levels might be a protective factor against cognitive impairment. The influences of age and illness duration also play a vital role in cognitive performance.

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BACKGROUND: Cardiovascular diseases are one of the prime causes of mortality globally. Therefore, concerted efforts are made to prevent or manage disruptions from normal functioning of the cardiovascular system. Disruption in lipid metabolism is a major contributor to cardiovascular dysfunction. This review examines how lecithin impacts lipid metabolism and cardiovascular health. It emphasizes lecithin's ability to reduce excess low-density lipoproteins (LDL) while specifically promoting the synthesis of high-density lipoprotein (HDL) particles, thus contributing to clearer understanding of its role in cardiovascular well-being. Emphasizing the importance of lecithin cholesterol acyltransferase (LCAT) in the reverse cholesterol transport (RCT) process, the article delves into its contribution in removing surplus cholesterol from cells. This review aims to clarify existing literature on lipid metabolism, providing insights for targeted strategies in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). This review summarizes the potential of lecithin in cardiovascular health and the role of LCAT in cholesterol metabolism modulation, based on articles from 2000 to 2023 sourced from databases like MEDLINE, PubMed and the Scientific Electronic Library Online. MAIN BODY: While studies suggest a positive correlation between increased LCAT activities, reduced LDL particle size and elevated serum levels of triglyceride-rich lipoprotein (TRL) markers in individuals at risk of ASCVD, the review acknowledges existing controversies. The precise nature of LCAT's potential adverse effects remains uncertain, with varying reports in the literature. Notably, gastrointestinal symptoms such as diarrhea and nausea have been sporadically documented. CONCLUSIONS: The review calls for a comprehensive investigation into the complexities of LCAT's impact on cardiovascular health, recognizing the need for a nuanced understanding of its potential drawbacks. Despite indications of potential benefits, conflicting findings warrant further research to clarify LCAT's role in atherosclerosis.

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BACKGROUND: The hypothesized link between low-density lipoprotein (LDL) and oncogenesis has garnered significant interest, yet its explicit impact on lung adenocarcinoma (LUAD) remains to be elucidated. This investigation aims to demystify the function of LDL-related genes (LRGs) within LUAD, endeavoring to shed light on the complex interplay between LDL and carcinogenesis. METHODS: Leveraging single-cell transcriptomics, we examined the role of LRGs within the tumor microenvironment (TME). The expression patterns of LRGs across diverse cellular phenotypes were delineated using an array of computational methodologies, including AUCell, UCell, singscore, ssGSEA, and AddModuleScore. CellChat facilitated the exploration of distinct cellular interactions within LDL_low and LDL_high groups. The findmarker utility, coupled with Pearson correlation analysis, facilitated the identification of pivotal genes correlated with LDL indices. An integrative approach to transcriptomic data analysis was adopted, utilizing a machine learning framework to devise an LDL-associated signature (LAS). This enabled the delineation of genomic disparities, pathway enrichments, immune cell dynamics, and pharmacological sensitivities between LAS stratifications. RESULTS: Enhanced cellular crosstalk was observed in the LDL_high group, with the CoxBoost+Ridge algorithm achieving the apex c-index for LAS formulation. Benchmarking against 144 extant LUAD models underscored the superior prognostic acuity of LAS. Elevated LAS indices were synonymous with adverse outcomes, diminished immune surveillance, and an upsurge in pathways conducive to neoplastic proliferation. Notably, a pronounced susceptibility to paclitaxel and gemcitabine was discerned within the high-LAS cohort, delineating prospective therapeutic corridors. CONCLUSION: This study elucidates the significance of LRGs within the TME and introduces an LAS for prognostication in LUAD patients. Our findings accentuate putative therapeutic targets and elucidate the clinical ramifications of LAS deployment.

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BACKGROUND: Understanding the burden of dyslipidemia and its associated factors among adult people living with HIV on dolutegravir (DTG) based anti-retroviral therapy (ART) is critical to provide clinical guidance and risk reduction strategies in our setting. METHODS: We conducted a cross-sectional study on adult people living with HIV on DTG based ART between July and August 2022 at Mengo Hospital, a private not for profit missionary hospital owned by the Church of Uganda. Dyslipidemia was defined as: Total cholesterol (TC) ≥ 5.2 mmol/l, or high-density lipoprotein (HDL) < 1 mmol/l for men and < 1.3 mmol/l for women, or triglycerides (TG) ≥ 1.7 mmol/l, and low-density lipoprotein (LDL) ≥ 3.4 mmol/l. A participant was considered to have dyslipidemia if they had any of the lipid profile parameters in the above ranges. Socio-demographic information, clinical data and behavioral characteristics were collected. Fasting lipid profile and fasting blood glucose levels were also measured. Bivariate and multivariate analyses were done using a generalized linear model regression of the Poisson family with a log link (modified Poisson) using robust standard errors since the prevalence of dyslipidemia was more than 10%. Adjusted prevalence ratios (PR) were reported with their 95% confidence intervals (CI). A p-value of less than 0.05 was considered statistically significant. RESULTS: A total of 341 participants were included. The prevalence of dyslipidemia was 78.0%, (95%CI:73.3-82.1). The highest prevalence was for low HDL (72.1%, 95%CI 67.1-76.7) followed by high TG (20.2%, 95%CI: 16.3-24.9), high TC (12.0%, 95%CI: 9.0-15.9) and high LDL (6.5%, 95%CI: 4.3-9.6). Female sex (aPR:1.55, 95%CI: 1.32-1.84, p < 0.001) and previous use of protease inhibitor (PI) based ART regimen (aPR:1.26, 95%CI: 1.04-1.53, p = 0.018) were significantly associated with dyslipidemia. CONCLUSION: We demonstrate that the prevalence of dyslipidemia is very high as it was present in more than three quarters of the study participants. Female sex and previous use of PI based ART regimen were significantly associated with dyslipidemia. Management of dyslipidemia should be integrated in the HIV treatment package and we recommend further inquiry into the temporal relationship between dyslipidemia and DTG among ART patients, if any.

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Background: Low-density lipoprotein (LDL) and globulin (GLOB) have been found to be predictors for some malignant tumors, but their predictive value in hepatocellular carcinoma (HCC) has hardly been elucidated. This study assessed the prognostic significance of GLOB to LDL ratio (GLR) in HCC patients before ablation. Methods: This study analyzed 312 early-stage HCC patients who were hospitalized and underwent ablative treatment in Beijing You'an Hospital, Capital Medical University, from 1 January 2014 to 1 January 2019. The primary endpoint was the recurrence-free survival (RFS), calculated from treatment initiation to cancer recurrence, whereas the overall survival (OS) was measured from treatment initiation to death or last follow-up. Cox regression analysis was used to assess the GLR independently associated with recurrence and survival. OS and RFS were calculated by Kaplan-Meier analysis and compared between groups using the log rank test. The optimal cut-off value and prognostic role of GLR and other markers were evaluated via the receiver operating characteristic (ROC) curves and the Youden index. Results: Univariate and multivariate analysis found that the tumor number, tumor size, and GLR were independent risk factors of relapse, whereas etiology, tumor number, tumor size, fibrinogen (Fib), and GLR were related to OS. We classified the patients into groups with high and low levels of GLR based on the optimal cut-off value of GLR identified by ROC curve. The cumulative 1-, 3-, and 5-year RFS rates in the low GLR group were 76.4%, 53.8%, and 43.4% respectively, whereas those in the high GLR group were 71%, 31%, and 22%, respectively (P<0.001). In terms of OS, the low GLR group showed a 1-, 3-, and 5-year OS of 99.5%, 92.0%, and 80.2% respectively, and 98%, 73%, and 63% respectively for the high GLR group (P<0.001). Finally, patients were stratified by GLR and tumor size. The outcomes revealed that patients in group A (GLR <16.54 and tumor size ≤30 mm) showed better prognosis than those in group B (GLR ≥16.54 and tumor size ≤30 mm or GLR <16.54 and tumor size >30 mm) and group C (GLR ≥16.54 and tumor size >30 mm) (P<0.001). Conclusions: Preoperative GLR ratio has predictive value for patients with HCC who have undergone complete ablation.

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One of the major risk factors for the progression of cardiovascular diseases is a high blood level of low-density lipoprotein (LDL), so progression of the disease may be prevented by lowering the plasma LDL. Evaluation and monitoring of LDL concentrations are therefore necessary. Friedewald's equation is a calculation method that is currently used routinely to estimate plasma LDL concentrations in hospital laboratories. However, this method cannot be applied to samples with a high concentration of triglyceride (TG). To overcome this limitation, this study aimed to develop direct LDL measurements using in-house generated monoclonal antibodies against human LDL in combination with LDL precipitation using heparin-containing citrate buffer pH 5.04. The method was applied to measure the LDL concentration in 208 randomized samples from Suranaree University of Technology Hospital. The mean values obtained from the developed method and the hospital laboratory were 126.6 ± 43.1 mg/dL and 123.2 ± 42.3 mg/dL, respectively. Linear regression analysis showed a high correlation between these two methods (r = 0.8491, p < 0.0001). High concentrations of TG, total cholesterol, and HDL have no influence on the LDL values obtained by this method. In this study, we offer an alternative technique for the direct measurement of plasma LDL. Further development for more convenient and easy use can now be undertaken.

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We previously described the role of low-density lipoprotein (LDL) in aggressiveness in papillary thyroid cancer (PTC). Moreover, the MAPK signaling pathway in the presence of BRAF V600E mutation is associated with more aggressive PTC. Although the link between MAPK cascade and LDL receptor (LDLR) expression has been previously described, it is unknown whether LDL can potentiate the adverse effects of PTC through it. We aimed to investigate whether the presence of LDL might accelerate the oncogenic processes through MAPK pathway in presence or absence of BRAF V600E in two thyroid cell lines: TPC1 and BCPAP (wild-type and BRAF V600E, respectively). LDLR, PI3K-AKT and RAS/RAF/MAPK (MEK)/ERK were analyzed via Western blot; cell proliferation was measured via MTT assay, cell migration was studied through wound-healing assay and LDL uptake was analyzed by fluorometric and confocal analysis. TPC1 demonstrated a time-specific downregulation of the LDLR, while BCPAP resulted in a receptor deregulation after LDL exposition. LDL uptake was increased in BCPAP over-time, as well as cell proliferation (20% higher) in comparison to TPC1. Both cell lines differed in migration pattern with a wound closure of 83.5 ± 9.7% after LDL coculture in TPC1, while a loss in the adhesion capacity was detected in BCPAP. The siRNA knockdown of LDLR in LDL-treated BCPAP cells resulted in a p-ERK expression downregulation and cell proliferation modulation, demonstrating a link between LDLR and MAPK pathway. The modulation of BRAF-V600E using vemurafenib-impaired LDLR expression decreased cellular proliferation. Our results suggest that LDLR regulation is cell line-specific, regulating the RAS/RAF/MAPK (MEK)/ERK pathway in the LDL-signaling cascade and where BRAF V600E can play a critical role. In conclusion, targeting LDLR and this downstream signaling cascade, could be a new therapeutic strategy for PTC with more aggressive behavior, especially in those harboring BRAF V600E.

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Background: Metabolic syndrome is characterized by a cluster-like occurrence of conditions such as hypertension, hyperglycaemia, elevated low-density lipoprotein (LDL) cholesterol or triglycerides (TG) and high visceral fat. Metabolic syndrome is linked to the build-up of plaque within the artery, which leads to disorders of the circulatory, nervous and immune systems. A variety of treatments target the regulation of these conditions; nevertheless, they remain dominant risk factors for the development of type 2 diabetes (T2DM) and cardiovascular disease (CVD), which affect 26.9% of the US population. Management and intervention strategies for improving cholesterol and/or TG are worthwhile, and recent studies on hydrogen treatment are promising, particularly as molecular hydrogen is easily ingested. This study aimed to investigate the lipid-lowering effects and quality of life (QOL) improvement of hydrogen-rich coral calcium (HRCC) in patients with metabolic syndrome. Methods: The patients, all Taiwanese, were randomly assigned to 3 different doses (low, medium, and high) of HRCC capsules. The primary outcome was the adverse effects/symptoms during this 4-week use of HRCC capsules. The secondary outcome was lipid profile changes. Complete blood count, inflammatory biomarkers, and QOL were also measured before and after the course of HRCC. Results: Sixteen patients with metabolic syndrome completed this study (7 males, 9 females; mean age: 62 years; range: 32-80). No obvious adverse effects were recorded. Only changes in blood TG reached significance. The baseline TG value was 193.19 µL (SD = 107.44), which decreased to 151.75 µL (SD = 45.27) after 4 weeks of HRCC (p = 0.04). QOL showed no significant changes. Conclusion: This study is the first human clinical trial evaluating HRCC capsules in patients with metabolic syndrome. Based on the safety and potential TG-lowering effects of short-term HRCC, further long-term investigations of HRCC are warranted. Clinical trial registration: [ClinicalTrials.gov], identifier [NCT05196295].

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PCOS (polycystic ovary syndrome) is a common endocrine disorder that affects 8-13% of women of reproductive age. Increased body weight and insulin resistance may be associated with chronic inflammation, which increases the risk of cardiovascular complications. CRP (C-reactive protein) tests may be use to assess persistent inflammation. Elevated CRP levels may be associated with insulin resistance and type 2 diabetes. Determination of hsCRP, highly sensitive C-reactive protein, can be used to assess cardiovascular risk in women with PCOS. In this study, 120 women between the ages of 18 and 42 were divided into two groups: patients with polycystic ovary syndrome (n = 80) and regular menstruating women in whom PCOS was excluded (n = 40). Lipid and carbohydrate metabolism parameters and hsCRP levels were assessed, followed by receiver operating characteristic (ROC) analysis for hsCRP, where metabolic syndrome was the dependent variable. For hsCRP, the cutoff point was 1.44 (mg/dL). Sensitivity for the cutoff point was 0.913 and specificity was 0.691. The area under the curve (AUC) was 0.851 (p < 0.000). The closer the AUC value is to unity, the better the predictive ability of the studied variable. There was also a statistically significant correlation between hsCRP levels and the presence of metabolic syndrome.

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INTRODUCTION: Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia, dysregulation of high-density lipoprotein (HDL), and low-density lipoprotein (LDL). Furthermore, SARS-Co-2 infection is associated with noteworthy changes in lipid profile, which is suggested as a possible biomarker to support the diagnosis and management of Covid-19. METHODS: This paper adopts the literature review method to obtain information about how Covid-19 affects high-risk group patients and may cause severe and critical effects due to the development of acute lung injury and acute respiratory distress syndrome. A narrative and comprehensive review is presented. RESULTS: Reducing HDL in Covid-19 is connected to the disease severity and poor clinical outcomes, suggesting that high HDL serum levels could benefit Covid-19. SARS-CoV-2 binds HDL, and this complex is attached to the co-localized receptors, facilitating viral entry. Therefore, SARS-CoV-2 infection may induce the development of dysfunctional HDL through different mechanisms, including induction of inflammatory and oxidative stress with activation of inflammatory signaling pathways. In turn, the induction of dysfunctional HDL induces the activation of inflammatory signaling pathways and oxidative stress, increasing Covid-19 severity. CONCLUSIONS: Covid-19 is linked with the development of cardio-metabolic disorders, including dyslipidemia in general and dysregulation of high-density lipoprotein and low-density lipoprotein. Therefore, the present study aimed to overview the causal relationship between dysfunctional high-density lipoprotein and Covid-19.

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Cholesterol homeostasis disorder and hypertriglyceridemia, as common metabolic conditions, have rarely been reported to affect the immune responses to the hepatitis B vaccine. Our study found that higher high-density lipoprotein (HDL) level showed a significant relationship with positive anti-HBs results (cOR = 1.479, 95% CI: 1.150, 1.901, p = 0.002; aOR = 1.304, 95% CI: 1.006, 1.691, p = 0.045), especially in individuals aged 18- to 40-year-old, female, smoking more than 100 cigarettes in life, and drinking more than 12 times every year. Lower low-density lipoprotein (LDL) level was associated with a negative anti-HBs result among participants aged 18- to 40-year-old, and participants who were obese. Higher level of HDL and lower level of LDL may be protective factors of better immune effect of hepatitis B vaccine. More research should be conducted to investigate the influence of the cholesterol level on the immune responses to the hepatitis B vaccine, and more in-depth research should be performed to uncover the mechanism.

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PURPOSE OF REVIEW: Cholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition. RECENT FINDINGS: Genetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

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The simultaneous detection of atherosclerotic cardiovascular disease (ACSVD) biomarkers was recently of great scientific interest. In this work, magnetic beads-based immunosensors for the simultaneous detection of low density lipoprotein (LDL) and malondialdehyde-modified low density lipoprotein (MDA-LDL) were presented. The approach proposed was based on the formation of two types of specific immunoconjugates consisting of monoclonal antibodies: anti-LDL or anti-MDA-LDL, together with redox active molecules: ferrocene and anthraquinone, respectively, coated on magnetic beads (MBs). The decrease in redox agent current in the concentration range: 0.001-1.0 ng/mL for LDL and 0.01-10.0 ng/mL for MDA-LDL, registered by square wave voltammetry (SWV), was observed upon the creation of complex between LDL or MDA-LDL and appropriate immunoconjugates. The detection limits of 0.2 ng/mL for LDL and 0.1 ng/mL for MDA-LDL were estimated. Moreover, the results of selectivity against the possible interferents were good, as human serum albumin (HSA) and high density lipoprotein (HDL), stability and recovery studies demonstrated the potential of platform proposed for early prognosis and diagnosis of ASCVD.

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Prion diseases are fatal and infectious neurodegenerative diseases that occur in humans and animals. They are caused by the misfolding of the cellular prion protein PrPc into the infectious isoform PrPSc. PrPSc accumulates mostly in endolysosomal vesicles of prion-infected cells, eventually causing neurodegeneration. In response to prion infection, elevated cholesterol levels and a reduction in membrane-attached small GTPase Rab7 have been observed in neuronal cells. Here, we investigated the molecular events causing an impaired Rab7 membrane attachment and the potential mechanistic link with elevated cholesterol levels in prion infection. We demonstrate that prion infection is associated with reduced levels of active Rab7 (Rab7.GTP) in persistently prion-infected neuronal cell lines, primary cerebellar granular neurons, and neurons in the brain of mice with terminal prion disease. In primary cerebellar granular neurons, levels of active Rab7 were increased during the very early stages of the prion infection prior to a significant decrease concomitant with PrPSc accumulation. The reduced activation of Rab7 in prion-infected neuronal cell lines is also associated with its reduced ubiquitination status, decreased interaction with its effector RILP, and altered lysosomal positioning. Consequently, the Rab7-mediated trafficking of low-density lipoprotein to lysosomes is delayed. This results in an impaired feedback regulation of cholesterol synthesis leading to an increase in cholesterol levels. Notably, transient overexpression of the constitutively active mutant of Rab7 rescues the delay in the low-density lipoprotein trafficking, hence reducing cholesterol levels and attenuating PrPSc propagation, demonstrating a mechanistic link between the loss of Rab7.GTP and elevated cholesterol levels.

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Hereditary haemorrhagic telangiectasia (HHT) is a vascular dysplasia inherited as an autosomal dominant trait, due to a single heterozygous loss-of-function variant, usually in ACVRL1 (encoding activin receptor-like kinase 1 [ALK1]), ENG (encoding endoglin [CD105]), or SMAD4. In a consecutive single-centre series of 37 positive clinical genetic tests performed in 2021-2023, a skewed distribution pattern was noted, with 30 of 32 variants reported only once, but ACVRL1 c.1231C>T (p.Arg411Trp) identified as the disease-causal gene in five different HHT families. In the same centre's non-overlapping 1992-2020 series where 110/134 (82.1%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was identified in nine further families. In a 14-country, four-continent HHT Mutation Database where 181/250 (72.4%) HHT-causal variants were reported only once, ACVRL1 c.1231C>T (p.Arg411Trp) was reported by 12 different laboratories, the adjacent ACVRL1 c.1232G>A (p.Arg411Gln) by 14, and ACVRL1 c.1120C>T (p.Arg374Trp) by 18. Unlike the majority of HHT-causal ACVRL1 variants, these encode ALK1 protein that reaches the endothelial cell surface but fails to signal. Six variants of this type were present in the three series and were reported 6.8-25.5 (mean 8.9) times more frequently than the other ACVRL1 missense variants (all p-values < 0.0039). Noting lower rates of myocardial infarction reported in HHT, we explore potential mechanisms, including a selective paradigm relevant to ALK1's role in the initiating event of atherosclerosis, where a plausible dominant negative effect of these specific variants can be proposed. In conclusion, there is an ~9-fold excess of kinase-inactive, cell surface-expressed ACVRL1/ALK1 pathogenic missense variants in HHT. The findings support further examination of differential clinical and cellular phenotypes by HHT causal gene molecular subtypes.