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1.
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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2.
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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3.
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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4.
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.
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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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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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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HPLC with spectrophotometric or mass spectrometric detection for quantifying very-long chain fatty acids in human plasma and its association with cardiac risk factors.
Shrestha, R, Chen, Z, Gao, Z, Chen, Y, Okada, E, Ukawa, S, Nakagawa, T, Nakamura, K, Tamakoshi, A, Chiba, H, et al
Annals of clinical biochemistry. 2021;(5):400-410
Abstract
BACKGROUND We developed and compared two liquid chromatography methods, one with UV/Visible spectrophotometric detection (HPLC) and the other with mass spectrometric detection (LC-MS), for quantifying very-long chain fatty acids (VLCFA) in human plasma. Association of VLCFA with various cardiovascular risk factors were evaluated. METHOD Fasting blood samples were collected from 541 human volunteers (242 men and 299 women; mean age ±SD, 58.9 ± 12.4 years), including 429 and 112 individuals with and without hypertriglyceridemia, respectively. Esterified VLCFA were saponified and derivatized with 2-nitrophenylhydrazine. Separation of VLCFA species was achieved with C4 Mightysil column (HPLC) and Ascentis Express Phenyl-Hexyl column (LC-MS) followed by spectrophotometric and selected-reaction monitoring mode of mass spectrometric detection, respectively. RESULTS The HPLC assay of VLCFA was precise with intra-assay imprecision of 2.5% to 6.9% and inter-assay imprecision of 3.2% to 9.5%. Moreover, there was an excellent correlation (r > 0.96) between HPLC and LC-MS methods. The 95 percentile reference intervals (RI; upper limit) of VLCFA were determined to be 41.3 µmol/L in healthy volunteers. Plasma VLCFA were significantly correlated with triglycerides (Spearman's ρ = 0.306, P < 0.001) and total cholesterol (Spearman's ρ = 0.251, P < 0.001). All species of VLCFA were significantly elevated in hypertriglyceridaemic individuals compared with control. CONCLUSION We established LC-based assays of VLCFA with either spectrophotometry or mass spectrometry as a detection system. Hypertriglyceridaemia is significantly associated with elevated concentration of each species of VLCFA.
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Persistence of Lipoproteins and Cholesterol Alterations after Sepsis: Implication for Atherosclerosis Progression.
Laudanski, K
International journal of molecular sciences. 2021;(19)
Abstract
(1) Background: Sepsis is one of the most common critical care illnesses with increasing survivorship. The quality of life in sepsis survivors is adversely affected by several co-morbidities, including increased incidence of dementia, stroke, cardiac disease and at least temporary deterioration in cognitive dysfunction. One of the potential explanations for their progression is the persistence of lipid profile abnormalities induced during acute sepsis into recovery, resulting in acceleration of atherosclerosis. (2) Methods: This is a targeted review of the abnormalities in the long-term lipid profile abnormalities after sepsis; (3) Results: There is a well-established body of evidence demonstrating acute alteration in lipid profile (HDL-c ↓↓, LDL-C -c ↓↓). In contrast, a limited number of studies demonstrated depression of HDL-c levels with a concomitant increase in LDL-C -c in the wake of sepsis. VLDL-C -c and Lp(a) remained unaltered in few studies as well. Apolipoprotein A1 was altered in survivors suggesting abnormalities in lipoprotein metabolism concomitant to overall lipoprotein abnormalities. However, most of the studies were limited to a four-month follow-up and patient groups were relatively small. Only one study looked at the atherosclerosis progression in sepsis survivors using clinical correlates, demonstrating an acceleration of plaque formation in the aorta, and a large metanalysis suggested an increase in the risk of stroke or acute coronary event between 3% to 9% in sepsis survivors. (4) Conclusions: The limited evidence suggests an emergence and persistence of the proatherogenic lipid profile in sepsis survivors that potentially contributes, along with other factors, to the clinical sequel of atherosclerosis.
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10.
Maternal cholesterol levels during gestation: boon or bane for the offspring?
Jayalekshmi, VS, Ramachandran, S
Molecular and cellular biochemistry. 2021;(1):401-416
Abstract
An increase in cholesterol levels is perceived during pregnancy and is considered as a normal adaptive response to the development of the fetus. In some pregnancies, excessive increase in total cholesterol with high levels of Low-Density Lipoprotein leads to maladaptation by the fetus to cholesterol demands, resulting in a pathological condition termed as maternal hypercholesterolemia (MH). MH is considered clinically irrelevant and therefore cholesterol levels are not routinely checked during pregnancy, as a consequence of which there is scarce information on its global prevalence in pregnant women. Studies have reported that MH during pregnancy can cause atherogenesis in adults emphasizing the concept of in utero programming of fetus. Moreover, Gestational Diabetes Mellitus, obesity and Polycystic Ovary Syndrome are potential risk factors which strengthen combined pathologies in placenta and fetuses of mothers with MH. However, lack of conclusive evidence on cholesterol transport and underlying programming demand substantial research to develop population-based life style strategies for women in their childbearing years. The current review focuses on the mechanisms and outcomes of MH from existing epidemiological as well as experimental data and presents a detailed insight on this novel risk factor of cardiovascular diseases.