Examining a decade-long trend in exposure to per- and polyfluoroalkyl substances and their correlation with lipid profiles: Insights from a prospective cohort study on the young Taiwanese population.

Per- and polyfluoroalkyl substances (PFAS) are artificial chemicals extensively utilized in everyday products, and numerous cross-sectional epidemiological studies consistently link PFAS exposure with lipid profiles across diverse populations and age groups. In longitudinal studies, the findings also indicate a positive correlation between PFAS and lipid profiles; however, this association remains unexplored in adolescents and young adults. Notably, previous research has predominantly focused on conventional lipid biomarkers, with limited exploration of the relationship between PFAS and diverse lipoprotein subfractions. Furthermore, there is a lack of comprehensive investigation into the temporal trends in PFAS concentrations in Taiwan. To address this research gap, we conducted a prospective study following 592 adolescents and young adults (12-30 years old at enrollment) from the YOung TAiwanese Cohort (YOTA) over a duration of 10 years. During the follow-up period, we measured 11 types of PFAS and various lipid profile biomarkers (low-density lipoprotein cholesterol (LDL-C), small dense LDL-C (sdLDL-C), low-density lipoprotein triglyceride (LDL-TG), high-density lipoprotein cholesterol (HDL-C), HDL3-C, lipoprotein(a), triglyceride). Our results revealed a general decline in PFAS concentrations in the study population. Regarding the correlation between the average levels (averaged across the initial and second tracking periods) of PFAS and lipid profiles (during the second tracking period), we observed positive correlations with total cholesterol and LDL-C for perfluorononanoic acid (PFNA), perfluoroundecanoic acid (PFUdA), perfluorododecanoic acid (PFDoA), N-methylperfluorooctane sulfonamide acetic acid (N-MeFOSAA), and the sum of PFAS (sum of the 11 kinds of PFAS). Additionally, average levels of PFUdA, N-MeFOSAA, and the sum of PFAS exhibited positive associations with sdLDL-C. This study unveiled an overall decrease in PFAS concentrations and underscores a potential link between PFAS exposure and adverse changes in lipid profiles among young populations, emphasizing the need for further exploration into the mechanisms of PFAS on lipid metabolism and atherosclerosis.

The role of small dense LDL-C/large buoyant LDL-C ratio as an independent risk factor in patients with type 2 diabetes mellitus and metabolic syndrome

Dyslipidemia plays a key role in metabolic syndrome (MS), intricately linked to type 2 diabetes mellitus (T2DM). This study aimed to investigate the differences in low-density lipoprotein cholesterol (LDL-C) subfraction levels between T2DM and T2DM with MS, and identify the risk factors associated with the disease. A total of 246 individuals diagnosed with T2DM, including 144 T2DM patients with MS, and 147 healthy subjects were recruited. All participants underwent a comprehensive clinical evaluation. Lipoprotein subfraction analysis was performed using the Lipoprint LDL system. Multivariate logistic regression analysis revealed that several lipid markers, including triglyceride (TG), LDL-C, large buoyant LDL-C (lbLDL-C), small dense LDL-C (sdLDL-C), LDLC2-5, and sdLDL-C/lbLDL-C ratio, were identified as independent risk factors for T2DM. Additionally, TG, sdLDL-C, LDLC-4, LDLC-5, and sdLDL-C/lbLDL-C ratio were found to be independent risk factors for T2DM with MS. Furthermore, the results of the receiver operating characteristic (ROC) curves demonstrated that sdLDL-C, LDLC-4, LDLC-3, and sdLDL-C/lbLDL-C ratio exhibited excellent predictive performance for the risk of T2DM (AUC > 0.9). The sdLDL-C/lbLDL-C ratio emerges as a shared independent risk factor for T2DM and MS complications. Furthermore, sdLDL-C/lbLDL-C ratio, along with LDL-4 and LDL-3, exhibits noteworthy predictive capabilities for T2DM.

Association Between Adequate Serum 25(OH)D Levels and Atherogenic Dyslipidemia in Young Adults.

AIM: This study aimed to investigate the association between vitamin D deficiency and novel biomarkers of atherogenic dyslipidemia among young adults. METHOD: A total of 976 young adults were recruited between 2011 and 2019. Their serum 25(OH)D levels were measured, and lipid profile markers, including low-density lipoprotein cholesterol (LDL-C), low-density lipoprotein triglyceride (LDL-TG), and small-dense low-density lipoprotein cholesterol (sdLDL-C), were assessed as novel biomarkers of atherogenic dyslipidemia. Multivariable linear regression was used to analyze the association between vitamin D levels and lipid profile markers. Odds ratios were calculated to assess the risk of atherogenic dyslipidemia in individuals with serum 25(OH)D levels below 30 ng/mL compared to those with levels above 30 ng/mL. Structural equation modeling (SEM) was employed to explore potential mediation pathways. RESULTS: The study found a significant association between vitamin D levels and lower levels of LDL-C, LDL-TG, sdLDL-C, non-high-density lipoprotein cholesterol (non-HDL-C), triglycerides, and total cholesterol. Individuals with serum 25(OH)D levels below 30 ng/mL exhibited significantly higher odds ratios for developing atherogenic dyslipidemia in a dose-response pattern compared to those with vitamin D levels above 30 ng/mL. Notably, structural equation modeling (SEM) analysis revealed that vitamin D did not affect atherogenic lipid markers through the mediation of insulin resistance markers or high-sensitivity C-reactive protein. CONCLUSION: This study provides evidence of an association between vitamin D deficiency and atherogenic dyslipidemia in young adults. It further highlights that individuals with serum 25(OH)D levels below 30 ng/mL are at a significantly higher risk of developing atherogenic dyslipidemia in a dose-response manner compared to those with higher vitamin D levels. These findings underscore the potential role of vitamin D in dyslipidemia management and emphasize the importance of maintaining sufficient vitamin D levels for cardiovascular health in young adults.

Novel lipid biomarkers and ratios as risk predictors for premature coronary artery disease: A retrospective analysis of 2952 patients.

This study examined the associations between emerging lipid biomarkers (small dense low-density lipoprotein cholesterol [sdLDL-C), lipoprotein(a) [Lp(a)], and free fatty acids [FFA]), two ratios (sdLDL-C/LDL-C and the triglyceride-glucose [TyG) index), and the Gensini score (GS) in patients with premature coronary artery disease (PCAD) in relation to the extent of coronary stenosis. The authors evaluated a cohort of 2952 individuals undergoing coronary angiography (CAG), encompassing those with PCAD (n = 1749), late-onset coronary artery disease (LCAD; n = 328), and non-coronary artery disease (non-CAD; n = 575). Noteworthy differences were observed in the levels of the novel lipid biomarkers and ratio indexes among the PCAD, LCAD, and non-CAD groups (p < .05). Multiple logistic regression analyses pinpointed Lp(a) (OR = 2.62, 95% CI 1.22-5.63, p = .014) and the TyG index (OR = 2.53, 95% CI 1.08-5.93, p = .033) as independent risk factors for PCAD. Furthermore, these biomarkers and ratio indexes discerned substantial distinctions among PCAD patients with varying GS (p < .05). Consequently, these markers can proficiently anticipate the gravity of coronary artery stenosis (GS > 40) in PCAD patients, as evidenced by the ROC analysis. In conclusion, sdLDL-C, Lp(a), FFA, and the sdLDL-C/LDL-C and TyG indexes have considerable potential as risk and diagnostic markers for coronary artery stenosis in individuals afflicted with PCAD.

CYP2C19 metabolizer phenotypes may affect the efficacy of statins on lowering small dense low-density lipoprotein cholesterol of patients with coronary artery disease.

Background: Dyslipidemia is a major cause of arteriosclerotic cardiovascular disease (ASCVD), and low-density lipoprotein cholesterol (LDL-C) is the profile to be reduced to prevent disease progression. Small dense low-density lipoprotein cholesterol (sdLDL-C) has been proven to be a more effective biomarker than LDL-C for ASCVD primary and secondary prevention. CYP2C19 is an important drug metabolism gene. This study aimed to investigate the relationship between sdLDL-C and coronary artery disease (CAD) risk factors and explore the influence of CYP2C19 metabolizer phenotypes on the sdLDL-C lowering efficacy of statins. Methods: This study recruited 182 patients with CAD and 200 non-CAD controls. Baseline laboratory indices of fasting blood were detected, including blood lipids, glucose, and creatinine. In addition, LDL-C subfractions were separated and quantified. Gene polymorphisms of SLCO1B1 and CYP2C19 were detected in patients with CAD. The LDL-C subfractions levels of patients with CAD were followed up after statin drug treatment. Results: Total cholesterol, LDL-C, LDLC-2, LDLC-3, LDLC-4, LDLC-5, LDLC-6, LDLC-7, and sdLDL-C levels of patients with CAD were significantly higher than those in non-CAD controls. Meanwhile, sdLDL-C (AUC = 0.838) and LDLC-4 (AUC = 0.835) performed outstandingly in distinguishing patients with CAD from controls. Based on CYP2C19 metabolizer phenotypes, 113 patients with CAD were divided into the extensive metabolizer (EM, n = 49), intermediate metabolizer (IM, n = 52), and poor metabolizer (PM, n = 12) groups. The patients with IM and PM metabolizer phenotypes had better sdLDL-C lowering efficacy after taking statin drugs than patients with EM phenotype (P = 0.0268, FDR = 0.0536). The SLCO1B1 genotype had no significant impact on the efficacy of statins (P = 0.1611, FDR = 0.1611). Conclusion: sdLDL-C and LDLC-4 outperformed other blood lipids such as LDL-C for CAD risk screening. CYP2C19 metabolizer phenotypes had the potential to predict the efficacy of statins in lowering sdLDL-C.

MassARRAY multigene screening combined with LDL-C and sdLDL-C detection for more favorable outcomes in type 2 diabetes mellitus therapy.

BACKGROUND: To determine the clinical value of multigene polymorphisms, LDL-C and sdLDL-C on T2DM therapy. METHODS: In total, 352 T2DM patients before and after treatment and 48 healthy individuals were enrolled in this study. LDL-C and sdLDL-C were detected in 352 T2DM patients and 48 healthy individuals by Quantimetrix Lipoprint System. The 11 gene polymorphisms-HTR3B (rs2276307, A > G), APOE (rs7412, c.526C > T), APOE (rs429358, c.388 T > C), CYP2C9*3 (rs1057910, c.1075A > C), KIF6 (rs20455, c.2155 T > C), HMGCR (rs17238540, T > G), HMGCR (rs17244841, A > T), ABCB1 (rs2032582, A > C/T), HTR7 (rs1935349, C > T), SLCO1B1 (rs4149056, c.521 T > C), and CETP (rs708272, G > A)-were screened in these 352 T2DM patients by the Agena Bioscience MassARRAY system before therapy. RESULTS: Genetic polymorphisms associated with T2DM and statin effects in pretreatment patients were detected, then results showed that all 11 genes had heterozygous mutation, and 7 genes had homozygous mutation in 352 T2DM patients, more specifically reflected that these gene polymorphisms were common in Chinese T2DM patients. LDL-C and sdLDL-C were detected before and after treatment, sdLDL mainly existed in T2DM patients, and T2DM patients had higher mean levels of sdLDL-C than healthy people. After pharmacotherapy, the coincidence rates of decreases in LDL-C and sdLDL-C levels were 88.35% (311/352) and 84.09% (296/352), consistent with patients in remission. CONCLUSIONS: Gene polymorphisms related to pharmacotherapy were common in Chinese T2DM patients. And the expression of LDL-C and sdLDL-C was consistent with the T2DM disease course. Combined multigene screening before therapy and LDL-C and sdLDL-C detection before and after therapy could better assist T2DM treatment.

Transiently Elevated TC and sdLDL-C Levels and Falsely Low LDL-C Levels in Patients with Extrahepatic Cholangiocarcinoma.

PURPOSE: Most patients diagnosed with extrahepatic cholangiocarcinoma (ECCA) exhibit cholestasis caused by obstruction of the bile duct. Cholestasis is associated with lipid disorders, but studies focused on the changing lipid parameters in patients with ECCA are lacking. Here, we observed lipid profiles in patients with ECCA and investigated whether the removal of biliary obstruction could correct dyslipidemia. PATIENTS AND METHODS: We consecutively included patients admitted to the hepatobiliary surgery department at the Affiliated Hospital of Xuzhou Medical University. The patients were divided into an ECCA group or a non-ECCA group based on the disease assessment. Patients with histological confirmation of ECCA were included in the ECCA group. Blood samples were collected on admission as well as five days after treatment. An automatic biochemistry analyzer was used to test liver function and serum lipid levels. Serum lipoprotein electrophoresis was performed using barbitone sodium buffer and Sudan black B. RESULTS: A total of 180 patients met inclusion criteria and were enrolled for this study. Of these, 76 patients were diagnosed with ECCA; all other patients were enrolled in the non-ECCA group. Total cholesterol (TC) and small and dense low-density lipoprotein cholesterol (sdLDL-C) levels were significantly elevated in the ECCA group. LDL-C levels were found to be slightly lower in the ECCA group. In the ECCA group, serum samples were detained in sample wells and lipoproteins failed to be separated. TC and sdLDL-C levels significantly decreased after cholestasis relief in the ECCA group. Lipoprotein electrophoresis revealed that patients with ECCA showed normal lipoprotein patterns after treatment. CONCLUSION: Patients with ECCA exhibited transiently elevated TC and sdLDL-C levels and falsely low LDL-C results. TC, sdLDL-C, and LDL-C levels could be restored to normal levels after biliary obstruction removal and cholestasis relief.

Correlation between small and dense low-density lipoprotein cholesterol and cardiovascular events in Beijing community population.

The relationship between small dense low-density lipoprotein cholesterol (sdLDL-C) and different cardiovascular events has been observed in several large community studies, and the results have been controversial. However, there is currently no cross-sectional or longitudinal follow-up study on sdLDL-C in the Chinese hypertension population. We analyzed the association of plasma sdLDL-C levels with major adverse cardiovascular events in 1325 subjects from a longitudinal follow-up community-based population in Beijing, China. During the follow-up period, a total of 191 subjects had MACEs. Cox regression analysis showed that sdLDL-C is a major risk factor for MACEs independent of sex, age, BMI, hypertension, diabetes, smoking, SBP, DBP, FBG, eGFR in the general community population (1.013 (1.001 -1.025, P < .05)), but the correlation disappeared after adjusting for TC and HDL-C in Model 3. Cox analysis showed that hypertension combined with high level of sdLDL-C was still the risk factor for MACEs ((2.079 (1.039-4.148)). Our findings in the Chinese cohort support that sdLDL-C is a risk factor for major adverse cardiovascular events in hypertension subjects.

Association of Small Dense Low-Density Lipoprotein Cholesterol with Stroke Risk, Severity and Prognosis.

AIM: To investigate the association of small dense low-density lipoprotein cholesterol (sdLDL-C) and acute ischemic stroke (AIS) in terms of risk, severity, and outcomes. Prediction models were established to screen high-risk patients and predict prognosis of AIS patients. METHODS: We enrolled in this study 355 AIS patients and 171 non-AIS controls. AIS was subtyped according to TOAST criteria, and the severity and outcomes of AIS were measured. Blood glucose and lipid profiles including total cholesterol, triglyceride, and lipoproteins were measured in all patients using automatic measure. Lipoprotein subfractions were detected by the Lipoprint LDL system. RESULTS: As compared with the non-AIS control group, the AIS group had higher sdLDL-C levels. Pearson correlation analysis revealed that the sdLDL-C level and risk of AIS, especially non-cardioembolic stroke, were positively correlated. The area under the curve of sdLDL-C for AIS risk was 0.665, better than that of other lipids. Additionally, the sdLDL-C level was significantly correlated with AIS severity and bad outcomes. A logistic regression model for assessing the probability of AIS occurrence and a prognostic prediction model were established based on sdLDL-C and other variables. CONCLUSIONS: Elevated levels of sdLDL-C were associated with a higher prevalence of AIS, especially in non-cardioembolic stroke subtypes. After adjustment for other risk factors, sdLDL-C was found to be an independent risk factor for AIS. Also, sdLDL-C level was strongly associated with AIS severity and poor functional outcomes. Logistic regression models for AIS risk and prognosis prediction were established to help clinicians provide better prevention for high-risk subjects and monitor their prognosis.

Association Between Fat-soluble Vitamins and Lipid Profile in the Overweight Population.

BACKGROUND & AIMS: It is well-known that the coronary artery stenosis is related to lipid profile. This is a descriptive cross-sectional study to investigate the relationship between the serum fat-soluble vitamins (A, E and D), circulating proprotein convertase subtilisin/kexin type 9 (PCSK9), and lipid profile in the study population. METHODS: A total of 120 overweight subjects were participated in this study. The circulating PCSK9 and vitamin D were measured by ELISA technique. The serum vitamin A and vitamin E amounts were simultaneously measured by the HPLC method. The Serum Small Dense LDLCholesterol (sdLDL-C) values were evaluated using heparin-Mg2+ precipitation technique. The lipid profile was measured by routine laboratory techniques. RESULTS: The serum vitamin E values correlated significantly to vitamin A (r= 0.47, P= 0.0001), VLDL-C (r= 0.30, P= 0.002), total cholesterol (r= 0.309, P= 0.001), PCSK9 (r= 0.233, P= 0.01) and total triglyceride (r= 0.61, P= 0.0001) values. The circulating PCSK9 values correlated significantly to LDL-C (r= 0.17, P= 0.05) and total cholesterol (r= 0.23, P= 0.009) values. However, there were not correlations between the levels of serum D and A vitamins, the serum LDL-C, sdLDL-C and total cholesterol values. CONCLUSION: The data showed the correlations between serum vitamin E and PCSK9-related LDLC values lower than the normal range. Furthermore, the results suggested a nutritional need on the patents considering supplementation or fortification of vitamin E for the overweight subjects with higher LDL-C levels.

Small dense low density lipoprotein-cholesterol and cholesterol ratios to predict arterial stiffness progression in normotensive subjects over a 5-year period.

BACKGROUND: Small dense low density lipoprotein-cholesterol (sdLDL-C), cholesterol ratios and carotid-femoral pulse wave velocity (cf-PWV) impart risk for all-cause morbidity and mortality independently of conventional cardiovascular disease (CVD) risk factors. This study was designed to identify feasible indicators for predicting arterial stiffness progression. METHODS: We followed up 816 normotensive participants without diabetes or CVD for nearly 5.0 years. Cholesterol parameters, ratios and other clinical and laboratory data were collected at baseline. cf-PWV were measured at baseline and the end of follow-up. RESULTS: PWV progression subjects had higher levels of PWV parameters, sdLDL-C and TG/HDL-C ratio. sdLDL-C and TG/HDL-C were significantly correlated with all PWV parameters. Multiple regression models showed that sdLDL-C was closely associated with follow-up PWV (ß = 0.222, p < 0.001) and △PWV (ß = 0.275, p < 0.001). TG/HDL-C was only one cholesterol ratios that associated with all PWV parameters. sdLDL-C (OR = 2.070, 95%CI: 1.162 to 3.688, p = 0.014) and TG/HDL-C (OR = 1.355, 95%CI: 1.136 to 1.617, p = 0.001) could significantly determine the progression of PWV after correction for covariates. High sd-LDL-C quantiles subjects were more likely to develop arterial stiffness progression than low quantiles (Tertiles 3 vs Tertiles1, RR = 2.867, 95%CI: 1.106 to 7.434, p = 0.03). CONCLUSION: We founded that sdLDL-C and TG/HDL-C ratio can independently predict arterial stiffness progression in normotensive subjects, and high level sdLDL-C and TG/HDL-C ratio were associated with a higher risk of arterial stiffness.

The role of plasma lipoprotein lipase, hepatic lipase and GPIHBP1 in the metabolism of remnant lipoproteins and small dense LDL in patients with coronary artery disease.

BACKGROUND: The relationship between plasma lipoprotein lipase (LPL), hepatic triglyceride lipase (HTGL), glycosylphosphatidylinositol anchored HDL binding protein1 (GPIHBP1) concentration and the metabolism of remnant lipoproteins (RLP) and small dense LDL (sdLDL) in patients with coronary artery disease (CAD) is not fully elucidated. METHODS: One hundred patients who underwent coronary angiography were enrolled. The plasma LPL, HTGL and GPIHBP1 concentrations were determined by ELISA. The time dependent changes in those lipases, lipids and lipoproteins were studied at a time-point just before, and 15min, 4h and 24h after heparin administration. RESULTS: The LPL concentration exhibited a significant positive correlation with HDL-C, and inversely correlated with TG and RLP-C. The HTGL concentration was positively correlated with RLP-C and sdLDL-C. The HTGL ratio of the pre-heparin/post-heparin plasma concentration and sdLDL-C/LDL-C ratio were significantly greater in CAD patients than in non-CAD patients. GPIHBP1 was positively correlated with LPL and inversely correlated with RLP-C and sdLDL-C. CONCLUSION: The HTGL concentration was positively correlated with RLP-C and sdLDL-C, while LPL and GPIHBP1 were inversely correlated with RLP-C and sdLDL-C. These results suggest that elevated HTGL is associated with increased CAD risk, while elevated LPL is associated with a reduction of CAD risk.

Characteristics of serum lipid profiles in patients with primary hypothyroidism / 安徽医科大学学报

Objective To study the changes of serum lipoprotein cholesterol subclass in patients with primary hypothyroidism).Methods 38 cases of primary hypothyroidism were divided into clinical hypothyroidism group (hypothyroidism group,20 cases) and subclinical hypothyroidism group (subclinical hypothyroidism group,18 cases),Another 20 healthy persons (control group) were selected as control group.5 ml of fasting venous blood was extracted,the serum was separated and preserved at-80 ℃.Configuration of density liquid and ultracentrifugation under different background densities was done.Cholesterol oxidase method was used to determine the serum cholesterol,levels of small and low density lipoprotein (sdLDL),high density lipoprotein 2 (HDL2),and HDL3.At the same time,levels of serum triiodothyronine (T3),thyroxine (T4) and thyroid stimulating hormone (TSH) were checked.Statistical analysis of the correlation between the thyroid relevant hormone mentioned above and serum lipoprotein cholesterol subclass was done.Results ① The total cholesterol,triglycerideand LDL cholesterol levels in hypothyroidism group and subclinical hypothyroidism group were higher than that in the control group,However,the HDL level was significantly lower than the control group (P ＜ 0.05);② SdLDL-C in hypothyroidism group and subclinical hypothyroidism group was significantly higher than that in the control group (P ＜ 0.05);serum HDL2-C in hypothyroidism and subclinical hypothyroidism group was significantly lower than that in the control group (P ＜0.05);while the significance of HDL3 was not reached;sdLDL-C,HDL2-C,HDL3-C in hypothyroidism and subclinical hypothyroidism group had no statistical significance;(Primary thyroid dysfunction occurs,the level of sdLDL-C was positively correlated with TSH (r =0.287,P =0.026),and negatively correlated with T4 (r =-0.267,P =0.039);and no correlation with T3;HDL2-C and T3,T4 were positively correlated (r =0.271,0.270,P =0.036,0.037);no significant correlation between HDL3-C and TSH,T3 T4.Conclusion The changes of clinical lipid profile and lipoprotein cholesterol subclass in patients with hypothyroidism are correlated with thyroid function.

Small dense low-density lipoprotein cholesterol was associated with future cardiovascular events in chronic kidney disease patients.

BACKGROUND: Cardiovascular disease (CVD) is often comorbid with chronic kidney disease (CKD). Small low-density lipoprotein cholesterol (sdLDL-C) has also been found to increase risk for CVD. The goal of the present study was to determine the nature of the relationship between sdLDL-C concentration and CVD in patients with CKD. METHODS: One-hundred and forty-five subjects (113 men and 32 women) with CKD (Stage 3 and Stage 4) participated this retrospective study. The concentration of sdLDL-C was measured in samples from 145 CKD patients between 2010 and 2012 during a four-year follow-up period. RESULTS: A total of eight fatal cardiovascular events (CVs) and 46 nonfatal CVs were registered in the four-year follow-up period. Multivariate Cox regression analysis showed that sdLDL-C [1.278, 95 % (1.019-1.598)] and sdLDL-C/LDL-C [2.456, 95 % (1.421-15.784)], at final observation, were independent risks of CVs. A Kaplan-Meier survival analysis showed that patients with sdLDL-C >38 mg/dl (logrank: 4.375, P = 0.037), and sdLDL-C/LDL-C ratio >0.3 levels (logrank: 11.94, P = 0.018) were at increased risk for CVs. CONCLUSION: The results of this study indicated that for patients suffering CKD, a significant relationship exists between an elevated sdLDL-C concentration and the risk of cardiovascular disease.

Fenofibrate, HDL, and cardiovascular disease in Type-2 diabetes: The DAIS trial.

BACKGROUND: There are conflicting reports on the role of fibrates in CVD-risk. Several studies indicate beneficial effects of fibrates on CVD risk in type-2 diabetic patients. We tested how fenofibrate changes lipoprotein subfractions and glucose homeostasis in type-2 diabetic patients. STUDY DESIGN: Selected markers of lipid and glucose homeostasis and inflammation were measured in 204 diabetic patients who participated in the Diabetes Atherosclerosis Intervention Study (DAIS) and were randomly assigned to 200 mg fenofibrate or placebo. Percent changes from baseline until a minimum of 3 years (average 39.6 months) on therapy (end of study) were calculated for all study parameters. RESULTS: The concentrations of total LDL-C and small dense LDL-C (sdLDL-C) did not change on fenofibrate compared to placebo. Compared to placebo, fenofibrate significantly decreased concentrations of triglyceride and remnant-like particle cholesterol (RLP-C) and activity of lipoprotein-associated phospholipase A2 (Lp-PLA2), while significantly increased concentrations of HDL-C. In contrast to other lipid-modifying drugs (e.g. statins) which increase HDL-C by increasing large (α-1) HDL particles, fenofibrate increased HDL-C by increasing the smaller, less antiatherogenic HDL-C particles, α-3 and α-4. Furthermore, despite lowering TG levels by 20%, fenofibrate failed to decrease pre-ß1 levels. On fenofibrate, glycated serum-protein levels increased moderately, while insulin and adiponectin levels did not change. CONCLUSION: On fenofibrate, lipid homeostasis improved and Lp-PLA2 activity decreased while there was no improvement in glucose homeostasis. Despite increasing HDL-C and decreasing triglyceride levels, fenofibrate failed to improve the antiatherogenic properties of the HDL subpopulation profile.

Serum sdLDL-C and Cellular SREBP2-dependent Cholesterol Levels; is there a Challenge on Targeting PCSK9?

BACKGROUND: Serum small dense LDL-cholesterol (sdLDL-C) value is suggested to bean important risk factor for atherosclerosis. Since sdLDL-C changes may be related to PCSK9 and SREBP-2 functions, the aim of this study was to investigate correlations between sdLDL-C, circulating PCSK9, SREBP-2 expression and some lipid parameters in serum and butty coat fraction of healthy subjects. METHODS: One hundred and twenty-four subjects were randomly included in the study. The lipid profile was measured using routine laboratory methods. The serum sdLDL-C level was calculated by a heparin-related precipitation technique. The cellular LDL-C/protein and cholesterol/protein values were measured after lysing of cells with methanol/chloroform binary solvent. The circulating PCSK9 level was measured using ELISA technique. The SREBP-2 expression level was estimated using theRT-qPCR technique. RESULTS: Data showed significant correlations between LDL-C, TG and sdLDL-C levels (r=0.34, p=0.001; r=0.2, p=0.04). The circulating PCSK9 level was correlated to LDL-C (r=0.29, p=0.04), but not to sdLDL-C (r=-0.08, p=0.57). Also, cellular LDL-C value was not related to serum LDL-C level (r=-0.12, p=0.39). Furthermore, there was an inverse correlation between cellular LDL-C/protein value and estimated de novo cholesterol/protein value (r= -0.5, p=0.001). Similar results were observed for cellular LDL-C/protein value and SREBP-2 expression level (r= -0.52, p=0.004). CONCLUSIONS: We concluded that the serum sdLDL-C value is not related to circulating PCSK9. Furthermore, SREBP-2 regulatory system was able to elevate the cellular cholesterol level after reducing LDL influx. We suggest to investigate the cellular sdLDL fate and lipid synthesis pathways in PCSK9-targeting studies.

Association of plasma small dense LDL cholesterol with PCSK9 levels in patients with angiographically proven coronary artery disease.

BACKGROUND AND AIMS: Proprotein convertase subtilisin-kexin type 9 (PCSK9) is a novel regulator of low-density lipoprotein (LDL) metabolism. Recently, small dense LDL (sdLDL) particles have been suggested to be a very atherogenic subspecies of LDL. To date, the association of sdLDL with PCSK9 is still unclear. The aim of the present study is to determine the association of sdLDL, as assayed by sdLDL-cholesterol (sdLDL-C), with PCSK9 in a cohort of subjects undergoing coronary angiography. METHODS AND RESULTS: Four hundred and ninety consecutive subjects were enrolled and classified into stable coronary artery disease (CAD) and non-CAD group. LDL separation was performed by Lipoprint System: 7 LDL subfractions were obtained and LDL score (% sdLDL) was calculated. The plasma PCSK9 levels were measured by ELISA. The data indicated that PCSK9 levels were significantly increased by sdLDL-C quartiles (p = 0.028). In age- and sex-adjusted analysis plasma sdLDL-C was positively correlated with PCSK9 levels (r = 0.157, p < 0.01). To rule out the confounding effect of dyslipidemia, we performed the analysis in subjects with and without dyslipidemia separately. Interestingly, the positive correlation of sdLDL-C with PCSK9 was only significant in patients with dyslipidemia and stable CAD (r = 0.177, p < 0.01). In a model adjusting for traditional risk factors including dyslipidemia, PCSK9 was an independent predictor of high sdLDL-C in CAD group (OR = 12.919, 95% CI 1.427-116.952) but not in non-CAD group. CONCLUSION: This study firstly demonstrated that plasma sdLDL-C was positively related to PCSK9 in patients with stable CAD, suggesting an interaction between sdLDL-C and PCSK9 in atherosclerotic coronary disease.

Small dense LDL cholesterol measured by homogeneous assay in Japanese healthy controls, metabolic syndrome and diabetes patients with or without a fatty liver.

BACKGROUND: Serum small dense LDL-cholesterol (sdLDL-C) levels in healthy controls and the cases with diabetes (T2DM) and metabolic syndrome (MetS) with or without a fatty liver in a large, typical Japanese population was determined. METHODS: The plasma lipids and lipoproteins, including sdLDL-C by homogeneous assay, were determined in controls, MetS and T2DM patients (n=5255). The cases with MetS and preliminary MetS (pre-MetS) as well as T2DM and preliminary T2DM (pre-DM) were selected based on the Japanese criteria for MetS and T2DM. Fatty liver was diagnosed using the ultrasonography. RESULTS: The 75th percentile values for sdLDL-C were 27.5mg/dl for men and 23.3mg/dl for women and increased with age. The concentrations of sdLDL-C and sdLDL-C/LDL-C were significantly higher in pre-MetS and pre-T2DM patients than healthy controls as well as in MetS and T2DM patients. Significantly higher sdLDL-C was found in cases with a fatty liver than without a fatty liver in all five groups. CONCLUSIONS: Significantly elevated sdLDL-C levels were found in pre-MetS, MetS and pre-T2DM, T2DM patients compared to the healthy controls. Fatty liver significantly enhanced serum sdLDL-C levels and the multiple regression analyses ascertained that fatty liver was an independent determinant for sdLDL-C.

Plasma proprotein convertase subtilisin kexin type 9 levels are related to markers of cholesterol synthesis in familial combined hyperlipidemia.

BACKGROUND AND AIMS: Two recent independent studies showed that patients with familial combined hyperlipidemia (FCHL) have elevated plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) and markers of cholesterol synthesis. Both PCSK9 expression and cholesterol synthesis are downstream effects of hepatic activation of sterol regulatory element binding protein 2 (SREBP2). The present study was conducted to study the relationship between plasma PCSK9 and markers of cholesterol synthesis in FCHL. METHODS AND RESULTS: Markers of cholesterol synthesis (squalene, desmosterol, lathosterol), cholesterol absorption (campesterol, sitosterol, cholestanol) and PCSK9 were measured in plasma of FCHL patients (n = 103) and their normolipidemic relatives (NLR; n = 240). Plasma PCSK9, lathosterol and desmosterol levels were higher in FCHL patients than their NLR (p < 0.001, age and sex adjusted). Heritability calculations demonstrated that 35% of the variance in PCSK9 levels could be explained by additive genetic effects (p < 0.001). Significant age- and sex-adjusted correlations were observed for the relationship between PCSK9 and lathosterol, both unadjusted and adjusted for cholesterol, in the overall FCHL population (both p < 0.001). Multivariate regression analyses, with PCSK9 as the dependent variable, showed that the regression coefficient for FCHL status decreased by 25% (from 0.8 to 0.6) when lathosterol was included. Nevertheless, FCHL status remained an independent contributor to plasma PCSK9 (p < 0.001). CONCLUSIONS: The present study confirms the previously reported high and heritable PCSK9 levels in FCHL patients. Furthermore, we now show that high PCSK9 levels are, in part, explained by plasma lathosterol, suggesting that SREBP2 activation partly accounts for elevated PCSK9 levels in FCHL.