Determination of selected oxysterol levels, oxidative stress, and macrophage activation indicators in children and adolescents with familial hypercholesterolemia
Erhan CanbayEbru CandaHavva YazıcıGulcin Kayan KasıkcıBurak DurmazÖznur ÇopurBegüm TahhanDilek DüzgünZeynep Elçim KoruEbru SezerDerya AydınErtürk LeventSema Kalkan UçarMahmut ÇökerEser Yıldırım Sözmen
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Elevated levels of cholesterol in the bloodstream, also referred to as hypercholesterolemia, pose a significant risk for the onset of cardiovascular and cerebrovascular diseases. Oxysterols, cholesterol-derived oxidized compounds that form enzymatically or non-enzymatically, contribute to the development of atherosclerosis and coronary artery disease. This study aimed to examine the critical oxysterol levels in children and adolescents with hypercholesterolemia and explore the correlation between these levels, oxidative stress, and atherosclerosis progression. The study included 20 patients with familial hypercholesterolemia (FH) and 20 healthy individuals aged between 6 and 18 years. Participants were categorized into children (6–9 years) and adolescents (10–18 years). Pediatric and adolescent patients were selected from among subjects with LDL-C ≥ 130 mg/dL and diagnosed with heterozygous familial hypercholesterolemia (HeFH) based on the presence of mutations in the LDL receptor (LDL-R) gene. Patients with HeFH who were receiving regular atorvastatin therapy were included in the study. There were no notable differences in catalase and paraoxonase (PON1) activities among the groups. However, the patient group displayed substantially higher levels of malondialdehyde (MDA) (P = 0.0108) and superoxide dismutase (SOD) activity (P = 0.0103). Compared to the healthy control group, serum chitotriosidase (CHITO) activity (P = 0.037) and chitinase 3-like protein 1 (YKL-40) levels (P = 0.0027) were significantly elevated in the patient group. Furthermore, the carotid intima-media thickness (CIMT) measurements of the patient group were significantly greater than those of the healthy group (**P < 0.0001****). The patient group exhibited significantly elevated levels of 5,6-α-epoxycholesterol, Cholestane-3β,5α,6β-triol (C-triol), and 7-ketocholesterol (7-KC), whereas 27-hydroxycholesterol (27-OHC) was significantly more abundant in the healthy group. On the other hand, while 27-OHC/Total cholesterol (Total-C) levels were significantly higher in healthy individuals, the C-Triol/Total-C ratio was significantly higher in patients. No significant differences were found between the groups in terms of 7-KC/Total-C and 5,6-α-epoxycholesterol/Total-C levels. This study highlights the key roles of oxysterols, oxidative stress, and macrophage activation in the development of atherosclerosis in pediatric and adolescent patients with FH. Elevated C-Triol levels in FH patients, alongside increased CIMT, point to early vascular changes despite atorvastatin therapy. In contrast, higher 27-OHC levels in healthy controls suggest differential oxysterol regulation due to cholesterol-lowering treatments in FH patients. C-Triol and 27-OHC/Total-C ratios showed potential as biomarkers to distinguish patients with FH. These findings emphasize the need for therapies targeting oxidative stress and macrophage activation in addition to cholesterol-lowering interventions.Keywords:
Lipidology
Oxysterol
Clinical nutrition
Some factors related to diet are known to be involved in the progression of atherosclerosis in humans.The relationship between plasma fatty acid (FA) levels and the severity of coronary artery disease (CAD), evaluated by Gensini score (GS), was investigated in CAD Tunisian patients compared to controls. Lipid profiles were analyzed, GS was calculated in CAD and non-CAD patients and compared to controls.CAD patients showed an alteration of conventional lipid parameters. In fact, a significant increase of plasmatic triglycerides (TG) level, atherogenic lipid ratios (TC/HDL-C,TG/HDL-C, LDL-C/HDL-C); and ApoB/ApoA1 was observed in the CAD group comparatively to controls (p < 0.001). Gensini score was showed to be a good indicator to evaluate cholesterol metabolism disorders associated with HDL-C since a negative association was found between HDL-C levels and GS for the two groups of patients. In addition, in the relation with FA and classes of FA, a negative association was found as expected, between Gensini score and total MUFA, PUFA n-3, total PUFA, GLA, DGLA and DHA. Furthermore, a positive association with stearic and erucic acid was found. Suggests that, GS is also a good indicator to evaluate FA metabolic disorders. Higher elongation index and modifications of desaturation index (D5D, D6D and D9D) were observed in patients compared to controls, supporting FA metabolism modifications.In conclusion, although that Tunisian population appears to follow the Mediterranean diet, variations of plasmatic FA levels and desaturase activities in CAD patients highlights an alteration of FA metabolism and suggests an important implication of certain FA in the development of atherosclerosis.
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Abstract Background Reference data for plasma lipids and blood pressure are not available for Asian Indian adolescents. This study aimed to develop representative age- and sex- specific percentile reference data for serum lipids [total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), non-HDL cholesterol] and blood pressure for urban Asian Indian adolescents aged 14–18 years. The sample consisted of 680 boys and 521 girls aged 14–18 years from the cross-sectional population survey, E pidemiological S tudy of A dolescents and Y oung Adults (ESAY) for whom the data for serum lipid levels and blood pressure were recorded. Smoothed age- and sex- specific 5 th , 10 th , 25 th , 50 th , 75 th , 85 th , 90 th and 95 th percentiles where derived using LMS regression. Results Percentile-based reference data for serum lipids and blood pressure are presented for adolescent Asian Indian boys and girls for the first time. Asian Indian adolescents had lower levels of serum TC, LDL-C and HDL-C and higher TG than their counterparts in the USA. Interesting trends in TC and HDL-C levels where observed, which might reflect changes in dietary pattern and physical activity in this age group in India. Conclusion These reference data could be used to identify adolescents with an elevated risk of developing dyslipidemia, hypertension and cardiovascular disorders, to plan and implement preventive policies, and to study temporal trends.
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Apolipoprotein B (apoB) contains ligand-binding domain for the binding of LDL to LDL-R site, which enables the removal of LDL from circulation. Our recent data showed that selenium (Se) is involved in the lipid metabolism. The present study was aimed to understand the effect of Se deficiency (0.02 ppm) and selenium supplementation (1 ppm) on apoB expression in liver during hypercholesterolemia in male Sprague Dawley rats. Animals were fed with control and high cholesterol diet (2%) for 1 and 2 months. ApoB levels by ELISA and protein expression by western blot was done. Hepatic LDL receptor (LDL-R) activity (in vivo) and mRNA expression by RT-PCR was monitored.In selenium deficiency and on high cholesterol diet (HCD) feeding apoB levels increased and LDL-R expression decreased significantly after 2 months. On 1 ppm selenium supplementation apoB expression significantly decreased and LDL-R expression increased after 2 months. But after one month of treatment there was no significant change observed in apoB and LDL-R expression.So the present study demonstrates that Se deficiency leads to up regulation of apoB expression during experimental hypercholesterolemia. Selenium supplementation upto 1 ppm leads to downregulation of apoB expression. Further, this study will highlight the nutritional value of Se supplementation in lipid metabolism.
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Abstract Background The aim of the study was to evaluate the association of immunoglobulin G type of autoantibodies to oxidized low-density lipoprotein (oxLDL-lgG) and oxLDL-lgM with the progression of esophageal squamous cell carcinoma (ESSC). Methods Residents from Feicheng, China aged 40 to 69 years were screened for esophageal lesions in a screening program conducted during the period of January 2008 to December 2006. There were 33 controls with normal esophageal squamous epithelium cells, 37 patients with basal cell hyperplasia, 47 with esophageal squamous cell dysplasia, and 43 with ESCC. All the participants were diagnosed by biopsy and histopathological examination. Adiponectin, oxidized low-density lipoprotein (oxLDL), autoantibodies against oxLDL (oxLDL-ab), OxLDL-lgG, and OxLDL-lgM were determined by enzyme linked immunosorbent assay (ELISA). Total cholesterol, High-density lipoprotein (HDL), triglyceride, serum albumin, and blood pressure were co-estimated. Analysis of covariance for lipid levels was used to control the influence of covariates. Results The level of oxLDL-lgM increased gradually along with esophageal carcinoma progression. The oxLDL-lgM levels in the ESCC group were the highest after possible covariates were controlled. Binary logistic regression showed that oxLDL-lgM had a positive correlation with the development of esophageal carcinoma, while oxLDL and oxLDL-ab had a negative correlation with ESSC. No significant association between the levels of oxLDL-lgG and adiponectin and the different stages of ESSC was observed. Conclusion The present study shows that the decreased oxLDL and oxLDL-ab and the elevated oxLDL-lgM serum levels may relate to the development and progression of ESSC.
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Recent studies showed that dyslipidemia could be a critical factor in the progression of cardiovascular disease in systemic lupus erythematosus (SLE). The aim of the present study was to describe the relationship between serum lipid profile and SLE disease activity in young female adults with SLE.Seventy-one female subjects diagnosed with SLE aged 20~30 years were enrolled. Serum lipid profile including TC, TG, HDL-C, LDL-C, VLDL-C, Apo A, Apo B, and Apo E were evaluated between control and young female SLE patients. Univariate correlation analyses were performed to explore the correlation between serum lipid levels and SLE disease activity.Our results showed that TG and VLDL-C levels were significantly increased in young female SLE as compared to control, with TC, HDL-C, LDL-C, Apo A, and Apo B significantly reduced. Meanwhile, univariate correlation analyses showed negative correlations between SLE disease activity index and HDL-C, LDL-C, Apo A, and Apo B; with positive correlations between SLE disease activity index and TG and VLDL-C.Serum lipid profile was significantly dysregulated in young female SLE patients. Moreover, SLE disease activity was correlated to the serum lipid levels, supporting the notion that the young patients with SLE might also have a higher risk of cardiovascular disease.
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We have previously demonstrated that carrying the apolipoprotein (apo) E epsilon 4 (E4+) genotype disrupts omega-3 fatty acids (n − 3 PUFA) metabolism. Here we hypothesise that the postprandial clearance of n − 3 PUFA from the circulation is faster in E4+ compared to non-carriers (E4−). The objective of the study was to investigate the fasted and postprandial fatty acid (FA) profile of triacylglycerol-rich lipoprotein (TRL) fractions: Sf >400 (predominately chylomicron CM), Sf 60 − 400 (VLDL1), and Sf 20 − 60 (VLDL2) according to APOE genotype. Postprandial TRL fractions were obtained in 11 E4+ (ϵ3/ϵ4) and 12 E4− (ϵ3/ϵ3) male from the SATgenϵ study following high saturated fat diet + 3.45 g/d of docosahexaenoic acid (DHA) for 8-wk. Blood samples were taken at fasting and 5-h after consuming a test-meal representative of the dietary intervention. FA were characterized by gas chromatography. At fasting, there was a 2-fold higher ratio of eicosapentaenoic acid (EPA) to arachidonic acid (P = 0.046) as well as a trend towards higher relative% of EPA (P = 0.063) in the Sf >400 fraction of E4+. Total n − 3 PUFA in the Sf 60 − 400 and Sf 20 − 60 fractions were not APOE genotype dependant. At 5 h, there was a trend towards a time × genotype interaction (P = 0.081) for EPA in the Sf >400 fraction. When sub-groups were form based on the level of EPA at baseline within the Sf >400 fraction, postprandial EPA (%) was significantly reduced only in the high-EPA group. EPA at baseline significantly predicted the postprandial response in EPA only in E4+ subjects (R 2 = 0.816). Despite the DHA supplement contain very low levels of EPA, E4+ subjects with high EPA at fasting potentially have disrupted postprandial n − 3 PUFA metabolism after receiving a high-dose of DHA. Registered at clinicaltrials.gov/show/ NCT01544855 .
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To study the effects of supplementation of a marine omega-3 poly-unsaturated fatty acids (n3-PUFA) formulation (Omega3Q10) in older adults with hypertension and/or hypercholesterolemia. A total of 97 people were enrolled to receive 12-week supplementation of either Omega3Q10 (n = 48) or soybean oil (n = 49). Total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and hypertension-related symptoms were determined before and after the supplementation. There were no baseline differences between the two groups. Omega3Q10 supplementation significantly reduced diastolic blood pressure (DBP) (from 81.6 ± 5.3 mmHg to 79.3 ± 5.2 mmHg, P < 0.05). Blood concentrations of TC and LDL-C decreased significantly and blood HDL-C level increased significantly after 12 weeks of Omega3Q10 (5.5 ± 0.7 vs. 5.3 ± 0.5, P < 0.05; 3.7 ± 0.8 vs. 3.3 ± 0.6, P < 0.05; 1.2 ± 0.6 vs. 1.3 ± 0.5, P < 0.05, respectively) and soybean oil supplementation (5.7 ± 0.8 vs. 5.6 ± 0.7, P < 0.05; 3.6 ± 0.7 vs. 3.4 ± 0.8, P < 0.05; 1.0 ± 0.8 vs. 1.2 ± 0.7, P < 0.05, respectively) but no group differences were found. A significantly greater proportion of the people in the Omega3Q10 group became free from headache and palpitations & chest tightness symptoms after the 12-week supplementation compared to that of the soybean oil group (95.5% vs. 71.4%, P < 0.01; 95.8 vs. 75.5%, P < 0.01, respectively). 12-week supplementation of Fish oil-based PUFA appear to be more effective in improving DBP and hypertension-related symptoms than soybean oil in old adults with hypertension and hypercholesterolemia although both supplementation improved TC, LDL-C and HDL-C concentrations.
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Previous animal model studies have highlighted a role for cholesterol and its oxidized derivatives (oxysterols) in uterine contractile activity, however, a lipotoxic state associated with hypercholesterolemia may contribute to labor dystocia. Therefore, we investigated if maternal mid-pregnancy cholesterol and oxysterol concentrations were associated with labor duration in a human pregnancy cohort.We conducted a secondary analysis of serum samples and birth outcome data from healthy pregnant women (N = 25) with mid-pregnancy fasting serum samples collected at 22-28 weeks of gestation. Serum was analyzed for total-C, HDL-C, and LDL-C by direct automated enzymatic assay and oxysterol profile including 7α-hydroxycholesterol (7αOHC), 7β-hydroxycholesterol (7βOHC), 24-hydroxycholesterol (24OHC), 25-hydroxycholesterol (25OHC), 27-hydroxycholesterol (27OHC), and 7-ketocholesterol (7KC) by liquid chromatography-selected ion monitoring-stable isotope dilution-atmospheric pressure chemical ionization-mass spectroscopy. Associations between maternal second trimester lipids and labor duration (minutes) were assessed using multivariable linear regression adjusting for maternal nulliparity and age.An increase in labor duration was observed for every 1-unit increment in serum 24OHC (0.96 min [0.36,1.56], p < 0.01), 25OHC (7.02 min [1.92,12.24], p = 0.01), 27OHC (0.54 min [0.06, 1.08], p < 0.05), 7KC (8.04 min [2.7,13.5], p < 0.01), and total oxysterols (0.42 min [0.18,0.06], p < 0.01]. No significant associations between labor duration and serum total-C, LDL-C, or HDL-C were observed.In this cohort, mid-pregnancy concentrations of maternal oxysterols (24OHC, 25OHC, 27OHC, and 7KC) were positively associated with labor duration. Given the small population and use of self-reported labor duration, subsequent studies are required for confirmation.
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