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1.
Genome-wide meta-analysis of phytosterols reveals five novel loci and a detrimental effect on coronary atherosclerosis.
Scholz, M, Horn, K, Pott, J, Gross, A, Kleber, ME, Delgado, GE, Mishra, PP, Kirsten, H, Gieger, C, Müller-Nurasyid, M, et al
Nature communications. 2022;(1):143
Abstract
Phytosterol serum concentrations are under tight genetic control. The relationship between phytosterols and coronary artery disease (CAD) is controversially discussed. We perform a genome-wide meta-analysis of 32 phytosterol traits reflecting resorption, cholesterol synthesis and esterification in six studies with up to 9758 subjects and detect ten independent genome-wide significant SNPs at seven genomic loci. We confirm previously established associations at ABCG5/8 and ABO and demonstrate an extended locus heterogeneity at ABCG5/8 with different functional mechanisms. New loci comprise HMGCR, NPC1L1, PNLIPRP2, SCARB1 and APOE. Based on these results, we perform Mendelian Randomization analyses (MR) revealing a risk-increasing causal relationship of sitosterol serum concentrations and CAD, which is partly mediated by cholesterol. Here we report that phytosterols are polygenic traits. MR add evidence of both, direct and indirect causal effects of sitosterol on CAD.
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2.
Necrotic debris and STING exert therapeutically relevant effects on tumor cholesterol homeostasis.
Katakam, S, Anand, S, Martin, P, Riggi, N, Stamenkovic, I
Life science alliance. 2022;(3)
Abstract
Malignant tumors commonly display necrosis, which invariably triggers an inflammatory response that supports tumor growth. However, the effect on tumor cells of necrotic debris, or damage-associated molecular patterns (DAMPs) released by dying cells is unknown. Here, we addressed the effect of DAMPs on primary Ewing sarcoma (EwS) cells and cell lines grown in 3D (spheroids) and 2D culture. We show that DAMPs promote the growth of EwS spheroids but not 2D cultures and that the underlying mechanism implicates an increase in cholesterol load in spheroids. In contrast, stimulation of the nucleic acid sensor signaling platform STING by its ligand cyclic GMP-AMP decreases the tumor cell cholesterol load and reduces their tumor initiating ability. Overexpression of STING or stimulation with cyclic GMP-AMP opposes the growth stimulatory effect of DAMPs and synergizes with the cholesterol synthesis inhibitor simvastatin to inhibit tumor growth. Our observations show that modulation of cholesterol homeostasis is a major effect of necrotic cell debris and STING and suggest that combining STING agonists with statins may help control tumor growth.
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Dysbetalipoproteinemia: Differentiating Multifactorial Remnant Cholesterol Disease From Genetic ApoE Deficiency.
Paquette, M, Bernard, S, Paré, G, Baass, A
The Journal of clinical endocrinology and metabolism. 2022;(2):538-548
Abstract
CONTEXT Dysbetalipoproteinemia (DBL) is characterized by the accumulation of remnant lipoprotein particles and associated with an increased risk of cardiovascular and peripheral vascular disease (PVD). DBL is thought to be mainly caused by the presence of an E2/E2 genotype of the apolipoprotein E (APOE) gene, in addition to environmental factors. However, there exists considerable phenotypic variability among DBL patients. OBJECTIVE The objectives were to verify the proportion of DBL subjects, diagnosed using the gold standard Fredrickson criteria, who did not carry E2/E2 and to compare the clinical characteristics of DBL patients with and without E2/E2. METHODS A total of 12 432 patients with lipoprotein ultracentrifugation as well as APOE genotype or apoE phenotype data were included in this retrospective study. RESULTS Among the 12 432 patients, 4% (n = 524) were positive for Fredrickson criteria (F+), and only 38% (n = 197) of the F+ individuals were E2/E2. The F+ E2/E2 group had significantly higher remnant cholesterol concentration (3.44 vs 1.89 mmol/L) and had higher frequency of DBL-related xanthomas (24% vs 2%) and floating beta (95% vs 11%) than the F+ non-E2/E2 group (P < 0.0001). The F+ E2/E2 group had an independent higher risk of PVD (OR 11.12 [95% CI 1.87-66.05]; P = 0.008) events compared with the F+ non-E2/E2 group. CONCLUSION In the largest cohort of DBL worldwide, we demonstrated that the presence of E2/E2 was associated with a more severe DBL phenotype. We suggest that 2 DBL phenotypes should be distinguished: the multifactorial remnant cholesterol disease and the genetic apoE deficiency disease.
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Can non-cholesterol sterols indicate the presence of specific dysregulation of cholesterol metabolism in patients with colorectal cancer?
Vladimirov, S, Gojkovic, T, Zeljkovic, A, Jelic-Ivanovic, Z, Zeljkovic, D, Antonic, T, Trifunovic, B, Spasojevic-Kalimanovska, V
Biochemical pharmacology. 2022;:114595
Abstract
Colorectal cancer (CRC) is a highly prevalent malignancy. Previous studies suggested that cholesterol might play a signficant role in malignant transformation and proliferation. Non-cholesterol sterols (NCS), which are transported by serum lipoproteins alongside cholesterol, are regarded as cholesterol synthesis and absorption markers. Quantification of NCS in serum and HDL fraction (NCSHDL), could provide a better insight into the cholesterol metabolism. The aim of this study was to examine the status of cholesterol synthesis and cholesterol absorption markers in serum and HDL fraction and explore their interrelation in CRC patients. Current study was designed as observational, case-control study. The study included 73 CRC patients and 95 healthy subjects. NCS and NCSHDL concentrations were determined by HPLC-MS/MS. Based on NCS and NCSHDL concentrations, different cholesterol homeostasis indices were calculated. Patients had significantly lower NCS (P<0.001) and NCSHDL concentrations (P<0.001 for desmosterolHDL; P<0.05 for lathosterolHDL, P=0.001 for campesterolHDL, P<0.001 for β-sitosterolHDL). NCSHDL/NCS (P<0.005 for desmosterolHDL/desmosterol; P<0.05 for lathosterolHDL/lathosterol; P<0.001 for both β-sitosterolHDL/β-sitosterol and campesterolHDL/campesterol) and synthesis to absorption ratio (CSI/CAI) (P<0.005) were increased in CRC patients. Additionally, low serum concentrations of desmosterol (P<0.001; OR=0.329; 95%CI (0.199-0.542)) and campesterol (P<0.001; OR=0.540; 95%CI (0.424-0.687)) were independent predictors of CRC presence. Our data suggest that cholesterol homeostasis in CRC is shifted towards increased synthesis. Relative abundance of NCS in HDL particles is increased, suggesting the possible overproduction of cholesterol precursors in peripheral tissues.
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5.
The Bioavailability and Biological Activities of Phytosterols as Modulators of Cholesterol Metabolism.
Li, X, Xin, Y, Mo, Y, Marozik, P, He, T, Guo, H
Molecules (Basel, Switzerland). 2022;(2)
Abstract
Phytosterols are natural sterols widely found in plants that have a variety of physiological functions, and their role in reducing cholesterol absorption has garnered much attention. Although the bioavailability of phytosterols is only 0.5-2%, they can still promote cholesterol balance in the body. A mechanism of phytosterols for lowering cholesterol has now been proposed. They not only reduce the uptake of cholesterol in the intestinal lumen and affect its transport, but also regulate the metabolism of cholesterol in the liver. In addition, phytosterols can significantly reduce the plasma concentration of total cholesterol, triglycerides, and low-density lipoprotein cholesterol (LDL-C), with a dose-response relationship. Ingestion of 3 g of phytosterols per day can reach the platform period, and this dose can reduce LDL-C by about 10.7%. On the other hand, phytosterols can also activate the liver X receptor α-CPY7A1 mediated bile acids excretion pathway and accelerate the transformation and metabolism of cholesterol. This article reviews the research progress of phytosterols as a molecular regulator of cholesterol and the mechanism of action for this pharmacological effect.
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6.
A single dual-targeting fluorescent probe enables exploration of the correlation between the plasma membrane and lysosomes.
Yu, S, Wu, S, Zhang, J, Zhao, X, Liu, X, Yi, X, Li, X
Journal of materials chemistry. B. 2022;(4):582-588
Abstract
The interactions between organelles can maintain normal cell activity. Lysosomes, as waste disposal systems of cells, have many important interactions with the plasma membrane, especially in the repair of cracked plasma membrane. Unfortunately, a way to study the relationship between them synchronously is still lacking. Therefore, in this work, we constructed a dual-targeting probe (Mem-Lyso) to simultaneously visualize the plasma membrane and lysosomes for the first time. Taking advantage of dual-targeting, the probe Mem-Lyso could successfully track and analyze the dynamic changes of the plasma membrane and lysosomes in different bioprocesses. The experimental results demonstrated that, compared to the normal status, there was obvious fusion between the plasma membrane and lysosomes in the apoptosis process. Furthermore, because of the sensitivity to polarity, Mem-Lyso could label the plasma membrane and lysosomes with red and yellow colors in cells, respectively. Moreover, the skeleton and gastrointestinal wall of zebrafish were visualized by dual-color imaging, respectively. More importantly, the dual-targeting property endowed Mem-Lyso with the ability to spatially distinguish the cholesterol (CL) content in the plasma membrane, which provided a potential detection tool for biological research and diagnosis of related diseases.
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7.
Increased serum cholesterol and long-chain fatty acid levels are associated with the efficacy of nivolumab in patients with non-small cell lung cancer.
Karayama, M, Inui, N, Inoue, Y, Yoshimura, K, Mori, K, Hozumi, H, Suzuki, Y, Furuhashi, K, Fujisawa, T, Enomoto, N, et al
Cancer immunology, immunotherapy : CII. 2022;(1):203-217
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Abstract
BACKGROUND Lipids have immunomodulatory functions and the potential to affect cancer immunity. METHODS The associations of pretreatment serum cholesterol and long-chain fatty acids with the objective response rate (ORR), progression-free survival (PFS), and overall survival (OS) were evaluated in 148 patients with non-small cell lung cancer who received nivolumab. RESULTS When each lipid was separately evaluated, increased low-density lipoprotein (LDL)-cholesterol (P < 0.001), high-density lipoprotein (HDL)-cholesterol (P = 0.014), total cholesterol (P = 0.007), lauric acid (P = 0.015), myristic acid (P = 0.022), myristoleic acid (P = 0.035), stearic acid (P = 0.028), linoleic acid (P = 0.005), arachidic acid (P = 0.027), eicosadienoic acid (P = 0.017), dihomo-γ-linolenic acid (P = 0.036), and behenic acid levels (P = 0.032) were associated with longer PFS independent of programmed death ligand 1 (PD-L1) expression. Meanwhile, increased LDL-cholesterol (P < 0.001), HDL-cholesterol (P = 0.009), total cholesterol (P = 0.036), linoleic acid (P = 0.014), and lignoceric acid levels (P = 0.028) were associated with longer OS independent of PD-L1 expression. When multiple lipids were evaluated simultaneously, LDL-cholesterol (P = 0.003), HDL-cholesterol (P = 0.036), and lauric acid (P = 0.036) were independently predictive of PFS, and LDL-cholesterol (P = 0.008) and HDL-cholesterol (P = 0.031) were predictive of OS. ORR was not associated with any serum lipid. CONCLUSIONS Based on the association of prolonged survival in patients with increased serum cholesterol and long-chain fatty acid levels, serum lipid levels may be useful for predicting the efficacy of immune checkpoint inhibitor therapy.
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Predicting psoriasis using routine laboratory tests with random forest.
Zhou, J, Li, Y, Guo, X
PloS one. 2021;(10):e0258768
Abstract
Psoriasis is a chronic inflammatory skin disease that affects approximately 125 million people worldwide. It has significant impacts on both physical and emotional health-related quality of life comparable to other major illnesses. Accurately prediction of psoriasis using biomarkers from routine laboratory tests has important practical values. Our goal is to derive a powerful predictive model for psoriasis disease based on only routine hospital tests. We collected a data set including 466 psoriasis patients and 520 healthy controls with 81 variables from only laboratory routine tests, such as age, total cholesterol, HDL cholesterol, blood pressure, albumin, and platelet distribution width. In this study, Boruta feature selection method was applied to select the most relevant features, with which a Random Forest model was constructed. The model was tested with 30 repetitions of 10-fold cross-validation. Our classification model yielded an average accuracy of 86.9%. 26 notable features were selected by Boruta, among which 15 features are confirmed from previous studies, and the rest are worth further investigations. The experimental results demonstrate that the machine learning approach has good potential in predictive modeling for the psoriasis disease given the information only from routine hospital tests.
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Dose-dependent reductions in plasma ceramides after anthocyanin supplementation are associated with improvements in plasma lipids and cholesterol efflux capacity in dyslipidemia: A randomized controlled trial.
Zhao, Y, Xu, H, Tian, Z, Wang, X, Xu, L, Li, K, Gao, X, Fan, D, Ma, X, Ling, W, et al
Clinical nutrition (Edinburgh, Scotland). 2021;(4):1871-1878
Abstract
BACKGROUND & AIMS Plasma ceramides have been identified as novel risk factors for metabolic and cardiovascular diseases. We aimed to evaluate the effects of dietary anthocyanins on plasma ceramides and to disentangle whether the alterations in ceramides could be related with those in other cardiometabolic risk factors in the dyslipidemia. METHODS In a randomized double-blinded placebo-controlled trial, 176 eligible dyslipidemia subjects were randomly assigned into four groups receiving placebo, 40, 80, or 320 mg/day anthocyanins, respectively for 12 weeks. RESULTS A total of 169 subjects completed the study. After 12-week intervention, dietary anthocyanins dose-dependently reduced plasma concentrations of all six ceramide species in the dyslipidemia subjects (all Ptrend values < 0.05). Specifically, 320 mg/day anthocyanins effectively lowered plasma N-palmitoylsphingosine (Cer 16:0, mean change: -28.3 ± 41.2 versus 2.9 ± 38.2, nmol/L, P = 0.018) and N-tetracosanoylsphingosine (Cer 24:0, mean change: -157.1 ± 493.9 versus 10.7 ± 439.9, nmol/L, P = 0.002) compared with the placebo. The declines in plasma Cer 16:0 and Cer 24:0 were significantly correlated with the decreases in plasma non-high-density lipoprotein cholesterol (nonHDL-C, Spearman's r = 0.32, P = 0.040 for Cer 16:0; Spearman's r = 0.35, P = 0.026 for Cer 24:0), apolipoprotein B (Spearman's r = 0.33, P = 0.031 for Cer 16:0; Spearman's r = 0.48, P = 0.002 for Cer 24:0), and total cholesterol (Spearman's r = 0.34, P = 0.026 for Cer 16:0; Spearman's r = 0.31, P = 0.042 for Cer 24:0) after 12-week 320 mg/day anthocyanin administration. Besides, we found that anthocyanins at 320 mg/day also markedly enhanced cholesterol efflux capacity in the dyslipidemia, the changes of which were positively associated with the reductions in Cer 16:0 (Spearman's r = 0.42, P = 0.006) independent of HDL-C and apolipoprotein A-I. CONCLUSIONS Reductions in plasma Cer 16:0 and Cer 18:0 after 12-week anthocyanin intervention were dose-dependently associated with improvements in plasma lipids and cholesterol efflux capacity in the dyslipidemia. CLINICAL TRIAL REGISTRATION The study was registered at ClinicalTrials.gov with the identifier No. NCT03415503.
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Elevated Serum Concentrations of Remnant Cholesterol Associate with Increased Carotid Intima-Media Thickness in Children and Adolescents.
Di Costanzo, A, Perla, FM, D'Erasmo, L, Arca, M, Chiesa, C, Pacifico, L
The Journal of pediatrics. 2021;:133-139.e1
Abstract
OBJECTIVE To evaluate the relationship between remnant cholesterol and carotid intima-media thickness (cIMT), a surrogate marker for atherosclerosis, in children and adolescents. STUDY DESIGN Anthropometric, laboratory, liver, and carotid ultrasonographic data were obtained from 767 youths (594, overweight/obese; 173, normal weight). Fasting remnant cholesterol was calculated from the standard lipid profile. cIMT ≥0.56 mm (corresponding to the 90th percentile of values observed in normal-weight children) was chosen to define elevated cIMT. Logistic regression analysis was used to estimate the risk of elevated cIMT according to tertiles of remnant cholesterol levels. RESULTS In the entire cohort, the mean concentration of remnant cholesterol was 17.9 ± 10.3 mg/dL and mean cIMT value was 0.51 ± 0.8 mm. Remnant cholesterol significantly correlated with age, sex, body mass index, waist circumference, blood pressure, lipids, liver enzymes, and insulin resistance. cIMT value increased progressively with rising remnant cholesterol tertiles (Pfor trend < .001). Compared with subjects in the lowest remnant cholesterol tertile, those in the middle and highest remnant cholesterol tertiles had a 2.3- and 2.4-fold increased risk of elevated cIMT, independently of age, sex, pubertal stage, body mass index, and apolipoprotein B (all Padj ≤ .003). When the effects of overweight/obesity on the association between remnant cholesterol and cIMT were determined, normal-weight as well as overweight/obese subjects in the highest remnant cholesterol tertile had a 3.8- and 2.3-fold increased risk to have elevated cIMT compared with the respective study groups in the lowest tertile, after adjustment for conventional risk factors (Padj = .038 and Padj = .003, respectively). CONCLUSIONS In youths, elevated levels of remnant cholesterol might represent a marker of early atherosclerotic damage.