Metabolic subtypes of patients with NAFLD exhibit distinctive cardiovascular risk profiles.

BACKGROUND AND AIMS: We previously identified subsets of patients with NAFLD with different metabolic phenotypes. Here we align metabolomic signatures with cardiovascular disease (CVD) and genetic risk factors. APPROACH AND RESULTS: We analyzed serum metabolome from 1154 individuals with biopsy-proven NAFLD, and from four mouse models of NAFLD with impaired VLDL-triglyceride (TG) secretion, and one with normal VLDL-TG secretion. We identified three metabolic subtypes: A (47%), B (27%), and C (26%). Subtype A phenocopied the metabolome of mice with impaired VLDL-TG secretion; subtype C phenocopied the metabolome of mice with normal VLDL-TG; and subtype B showed an intermediate signature. The percent of patients with NASH and fibrosis was comparable among subtypes, although subtypes B and C exhibited higher liver enzymes. Serum VLDL-TG levels and secretion rate were lower among subtype A compared with subtypes B and C. Subtype A VLDL-TG and VLDL-apolipoprotein B concentrations were independent of steatosis, whereas subtypes B and C showed an association with these parameters. Serum TG, cholesterol, VLDL, small dense LDL5,6 , and remnant lipoprotein cholesterol were lower among subtype A compared with subtypes B and C. The 10-year high risk of CVD, measured with the Framingham risk score, and the frequency of patatin-like phospholipase domain-containing protein 3 NAFLD risk allele were lower in subtype A. CONCLUSIONS: Metabolomic signatures identify three NAFLD subgroups, independent of histological disease severity. These signatures align with known CVD and genetic risk factors, with subtype A exhibiting a lower CVD risk profile. This may account for the variation in hepatic versus cardiovascular outcomes, offering clinically relevant risk stratification.

Icosapent ethyl therapy for very high triglyceride levels: a 12-week, multi-center, placebo-controlled, randomized, double-blinded, phase III clinical trial in China.

OBJECTIVES: Eicosapentaenoic acid in its ethyl ester form is the single active component of icosapent ethyl (IPE). This study was a phase III, multi-center trial assessing the safety and efficiency of IPE for treating very high triglyceride (TG) in a Chinese cohort. METHODS: Patients having TG levels (5.6-22.6 mmol/L) were enrolled and randomly assigned to receive a treatment of oral intake of 4 g or 2 g/day of IPE, or placebo. Before and after 12 weeks of treatment, TG levels were assessed and the median was calculated to determine the change between the baseline and week 12. In addition to examining TG levels, the impact of such treatments on other lipid changes was also investigated. The official Drug Clinical Trial Information Management Platform has registered this study (CTR20170362). RESULTS: Random assignments were performed on 373 patients (mean age 48.9 years; 75.1% male). IPE (4 g/day) lowered TG levels by an average of 28.4% from baseline and by an average of 19.9% after correction for placebo (95% CI: 29.8%-10.0%, P < 0.001). In addition, plasma concentration of non-high-density lipoprotein cholesterol (non-HDL-C), very low-density lipoprotein (VLDL) cholesterol, and VLDL-TG remarkedly reduced after IPE (4 g/day) treatment by a median of 14.6%, 27.9%, and 25.2%, respectively compared with participants in placebo group. Compared to the placebo, neither 4 nor 2 g of IPE daily elevated LDL-C levels with statistical significance. IPE was well tolerated by all the treatment groups. CONCLUSIONS: IPE at 4 g/day dramatically lowered other atherogenic lipids without a noticeable increase in LDL-C, thereby decreasing TG levels in an exceptionally high-TG Chinese population.

Saroglitazar, a PPAR-α/γ Agonist, for Treatment of NAFLD: A Randomized Controlled Double-Blind Phase 2 Trial.

BACKGROUND AND AIMS: NAFLD is characterized by insulin resistance and dysregulated lipid and glucose metabolism. Saroglitazar, a dual peroxisome proliferator activated receptor-α/γ agonist, improves insulin sensitivity, and lipid and glycemic parameters. Saroglitazar improved NASH histology in animal studies. In this randomized controlled clinical trial, we evaluated the efficacy and safety of saroglitazar in patients with NAFLD/NASH. APPROACH AND RESULTS: A total of 106 patients with NAFLD/NASH with alanine aminotransferase (ALT) ≥ 50 U/L at baseline and body mass index ≥25 kg/m2 were randomized in a 1:1:1:1 ratio to receive placebo or saroglitazar 1 mg, 2 mg, or 4 mg for 16 weeks. The primary efficacy endpoint was percentage change from baseline in ALT levels at week 16. Liver fat content (LFC) was assessed by MRI proton density fat fraction. The least-squares mean percent change from baseline in ALT at week 16 was -25.5% (5.8), -27.7% (5.9), and -45.8% (5.7), with saroglitazar 1 mg, 2 mg, and 4 mg, respectively, versus 3.4% (5.6) in placebo (P < 0.001 for all). Compared with placebo, saroglitazar 4 mg improved LFC (4.1% [5.9] vs. -19.7% [5.6]), adiponectin (-0.3 µg/mL [0.3] vs. 1.3 µg/mL [0.3]), homeostatic model assessment-insulin resistance (-1.3 [1.8] vs. -6.3 [1.7]), and triglycerides (-5.3 mg/dL [10.7] vs. -68.7 mg/dL [10.3]) (P < 0.05 for all). Saroglitazar 4 mg also improved lipoprotein particle composition and size and reduced lipotoxic lipid species. Saroglitazar was well-tolerated. A mean weight gain of 1.5 kg was observed with saroglitazar 4 mg versus 0.3 kg with placebo (P = 0.27). CONCLUSIONS: Saroglitazar 4 mg significantly improved ALT, LFC, insulin resistance, and atherogenic dyslipidemia in participants with NAFLD/NASH. (ClinicalTrials.gov identifier: NCT03061721.).

Effects of Evolocumab on the Postprandial Kinetics of Apo (Apolipoprotein) B100- and B48-Containing Lipoproteins in Subjects With Type 2 Diabetes.

OBJECTIVE: Increased risk of atherosclerotic cardiovascular disease in subjects with type 2 diabetes is linked to elevated levels of triglyceride-rich lipoproteins and their remnants. The metabolic effects of PCSK9 (proprotein convertase subtilisin/kexin 9) inhibitors on this dyslipidemia were investigated using stable-isotope-labeled tracers. Approach and Results: Triglyceride transport and the metabolism of apos (apolipoproteins) B48, B100, C-III, and E after a fat-rich meal were investigated before and on evolocumab treatment in 13 subjects with type 2 diabetes. Kinetic parameters were determined for the following: apoB48 in chylomicrons; triglyceride in VLDL1 (very low-density lipoprotein) and VLDL2; and apoB100 in VLDL1, VLDL2, IDL (intermediate-density lipoprotein), and LDL (low-density lipoprotein). Evolocumab did not alter the kinetics of apoB48 in chylomicrons or apoB100 or triglyceride in VLDL1. In contrast, the fractional catabolic rates of VLDL2-apoB100 and VLDL2-triglyceride were both increased by about 45%, which led to a 28% fall in the VLDL2 plasma level. LDL-apoB100 was markedly reduced by evolocumab, which was linked to metabolic heterogeneity in this fraction. Evolocumab increased clearance of the more rapidly metabolized LDL by 61% and decreased production of the more slowly cleared LDL by 75%. ApoC-III kinetics were not altered by evolocumab, but the apoE fractional catabolic rates increased by 45% and the apoE plasma level fell by 33%. The apoE fractional catabolic rates was associated with the decrease in VLDL2- and IDL-apoB100 concentrations. CONCLUSIONS: Evolocumab had only minor effects on lipoproteins that are involved in triglyceride transport (chylomicrons and VLDL1) but, in contrast, had a profound impact on lipoproteins that carry cholesterol (VLDL2, IDL, LDL). Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT02948777.

Biochemical Status of Obese Male Adolescents of Different Ethnicity: Discriminant Analysis in the Identification of the Most Informative Indicators.

Parameters of the lipid metabolism and lipid peroxidation-antioxidant defense system in male adolescents with obesity, representatives of European and Mongoloid ethnicity were evaluated. Discriminant analysis revealed the most informative biochemical parameters for obese male adolescents: glutathione-S-transferase, VLDL cholesterol, glutathione peroxidase, reduced glutathione, and SOD activity for obese male Caucasian adolescents and glutathione-S-transferase, VLDL cholesterol, α-tocopherol, and glutathione peroxidase for Mongoloids obese male adolescents. The use of discriminant analysis allows implementing a differentiated ethnicity-oriented approach to prescribing antioxidant drugs in the complex therapy of obesity.

Very Low-Density Lipoprotein Cholesterol May Mediate a Substantial Component of the Effect of Obesity on Myocardial Infarction Risk: The Copenhagen General Population Study.

BACKGROUND: Individuals with obesity have higher concentrations of very low-density lipoprotein (VLDL) cholesterol and increased risk of myocardial infarction. We hypothesized that VLDL cholesterol explains a fraction of the excess myocardial infarction risk in individuals with obesity. METHODS: We included 29 010 individuals free of myocardial infarction at baseline, nested within 109 751 individuals from the Copenhagen General Population Study. During 10 years of follow-up, 2306 individuals developed myocardial infarction. Cholesterol content in large and small VLDLs, in intermediate-density lipoprotein (IDL), and in LDL was measured directly with nuclear magnetic resonance spectroscopy. RESULTS: Median concentrations of cholesterol in large and small VLDLs were 0.12 mmol/L (interquartile range [IQR], 0.07-0.20 mmol/L; 4.5 mg/dL [IQR, 2.6-6.9 mg/dL]) and 0.6 mmol/L (IQR, 0.5-0.8 mmol/L; 25 mg/dL [IQR, 20-30 mg/dL]) in individuals with obesity vs 0.06 mmol/L (IQR, 0.03-0.1 mmol/L; 2.2 mg/dL [IQR, 1.1-3.8 mg/dL]), and 0.5 mmol/L (IQR, 0.4-0.6 mmol/L; 20 mg/dL (IQR, 16-25 mg/dL]) in individuals with normal weight; in contrast, concentrations of IDL and LDL cholesterol were similar across body mass index (BMI) categories. Cholesterol in large and small VLDLs combined explained 40% (95% CI, 27%-53%) of the excess risk of myocardial infarction associated with higher BMI. In contrast, IDL and LDL cholesterol did not explain excess risk of myocardial infarction, whereas systolic blood pressure explained 17% (11%-23%) and diabetes mellitus explained 8.6% (3.2%-14%). CONCLUSIONS: VLDL cholesterol explains a large fraction of excess myocardial infarction risk in individuals with obesity. These novel findings support a focus on cholesterol in VLDL for prevention of myocardial infarction and atherosclerotic cardiovascular disease in individuals with obesity.

Evaluating Lipid-Lowering Drug Targets for Parkinson's Disease Prevention with Mendelian Randomization.

Long-term exposure to lipid-lowering drugs might affect Parkinson's disease (PD) risk. We conducted Mendelian randomization analyses where genetic variants indexed expected effects of modulating lipid-lowering drug targets on PD. Statin exposure was not predicted to increase PD risk, although results were not precise enough to support benefits for prevention clearly (odds ratio [OR] = 0.83; 95% confidence interval [CI] = 0.65, 1.07). Other target results were null, except for variants indicating Apolipoprotein-A5 or Apolipoprotein-C3 inhibition might confer protection. These findings suggest peripheral lipid variation may not have a prominent role in PD etiology, but some related drug targets could influence PD via alternate pathways. ANN NEUROL 2020;88:1043-1047.

Untargeted Lipidomics Reveals a Specific Enrichment in Plasmalogens in Epicardial Adipose Tissue and a Specific Signature in Coronary Artery Disease.

OBJECTIVE: Epicardial adipose tissue (EAT) is an active endocrine organ that could contribute to the pathophysiology of coronary artery disease (CAD) through the paracrine release of proatherogenic mediators. Numerous works have analyzed the inflammatory signature of EAT, but scarce informations on its lipidome are available. Our objective was first to study the differences between EAT and subcutaneous adipose tissue (SAT) lipidomes and second to identify the specific untargeted lipidomic signatures of EAT and SAT in CAD. Approach and Results: Subcutaneous and EAT untargeted lipidomic analysis was performed in 25 patients with CAD and 14 patients without CAD and compared with paired plasma lipidomic analysis of isolated VLDL (very low-density lipoprotein) and HDL (high-density lipoprotein). Lipidomics was performed on a C18 column hyphenated to a Q-Exactive plus mass spectrometer, using both positive and negative ionization mode. EAT and SAT had independent lipidomic profile, with 95 lipid species differentially expressed and phosphatidylethanolamine 18:1p/22:6 twenty-fold more expressed in EAT compared with SAT false discovery rate =3×10-4). Patients with CAD exhibited more ceramides (P=0.01), diglycerides (P=0.004; saturated and nonsaturated), monoglycerides (P=0.013) in their EAT than patients without CAD. Conversely, they had lesser unsaturated TG (triglycerides; P=0.02). No difference was observed in the 295 lipid species found in SAT between patients with and without CAD. Fifty-one lipid species were found in common between EAT and plasma lipoproteins. TG 18:0/18:0/18:1 was found positively correlated (r=0.45, P=0.019) in EAT and HDL and in EAT and VLDL (r=0.46, P=0.02). CONCLUSIONS: CAD is associated with specific lipidomic signature of EAT, unlike SAT. Plasma lipoprotein lipidome only partially reflected EAT lipidome.

Apolipoprotein CIII Deficiency Protects Against Atherosclerosis in Knockout Rabbits.

OBJECTIVE: Apo (apolipoprotein) CIII mediates the metabolism of triglyceride (TG)-rich lipoproteins. High levels of plasma apoCIII are positively correlated with the plasma TG levels and increase the cardiovascular risk. However, whether apoCIII is directly involved in the development of atherosclerosis has not been fully elucidated. Approach and Results: To examine the possible roles of apoCIII in lipoprotein metabolism and atherosclerosis, we generated apoCIII KO (knockout) rabbits using ZFN (zinc finger nuclease) technique. On a normal standard diet, apoCIII KO rabbits exhibited significantly lower plasma levels of TG than those of WT (wild type) rabbits while total cholesterol and HDL (high-density lipoprotein) cholesterol levels were unchanged. Analysis of lipoproteins isolated by sequential ultracentrifugation revealed that reduced plasma TG levels in KO rabbits were accompanied by prominent reduction of VLDLs (very-low-density lipoproteins) and IDLs (intermediate-density lipoproteins). In addition, KO rabbits showed faster TG clearance rate after intravenous fat load than WT rabbits. On a cholesterol-rich diet, KO rabbits exhibited constantly and significantly lower levels of plasma total cholesterol and TG than WT rabbits, which was caused by a remarkable reduction of ß-VLDLs-the major atherogenic lipoproteins. ß-VLDLs of KO rabbits showed higher uptake by cultured hepatocytes and were cleared faster from the circulation than ß-VLDLs isolated from WT rabbits. Both aortic and coronary atherosclerosis was significantly reduced in KO rabbits compared with WT rabbits. CONCLUSIONS: These results indicate that apoCIII deficiency facilitates TG-rich lipoprotein catabolism, and therapeutic inhibition of apoCIII expression may become a novel means not only for the treatment of hyperlipidemia but also for atherosclerosis.

Sub-acute oral toxicity study of aqueous extract of tobacco leaves (Nicotiana tabacum L.) on lipid profile, the tissue, and serum of the liver and kidney of male Wistar rats.

CONTEXT: Tobacco consumption may pose a very serious threat to the physiological state of the body; yet, fewer records have been documented in that regard. OBJECTIVE: We investigated the impact of aqueous extract of tobacco leaves on the lipid profile, the tissue, and serum levels of the liver and kidney of male Wister rats. MATERIALS AND METHODS: Rats (n = 52; weight = 33 - 47 g; ∼ 2½ weeks old) were acclimatised for 7 days and administered aqueous extract of tobacco leaves at 100, 200, 400, 0 mg/kg of body weight (to group A, B, C, D) for 30 days. RESULTS: Compared with the control group, the kidney tissue and serum (i.e., urea and creatinine) were not influenced, in contrast, indices of the liver such as AST, ALT, and ALP, dose-dependently increased. Changes such as coagulative necrosis resulted in the infiltration of mononuclear inflammatory cells and the vacuolar degeneration of the liver. Beside the reduction in the high-density lipoprotein of the rats, there was an increase in the concentration of triglycerides, very low-density lipoprotein, low-density lipoprotein, and the total cholesterol. CONCLUSION: Thus, extract of tobacco leaves can greatly influence the body lipid profile, beside the serum and tissues of the liver.

Comparative assessment of LDL-C and VLDL-C estimation in familial combined hyperlipidemia using Sampson's, Martin's and Friedewald's equations.

BACKGROUND: Sampson et al. developed a novel method to estimate very low-density lipoprotein cholesterol (VLDL-C) and low-density lipoprotein cholesterol (LDL-C) in the setting of hypertriglyceridemia. Familial Combined Hyperlipidemia (FCHL) is a common primary dyslipidemia in which lipoprotein composition interferes with LDL-C estimation. This study aimed to evaluate performance of LDL-C using this new method (LDL-S) compared with LDL-C estimated by Friedewald's and Martin eq. (LDL-F, LDL-M) in FCHL. METHODS: Data were collected from 340 subjects with confirmed FCHL. Concordance for VLDL-C measured by ultracentrifugation and LDL-C estimated using these measures compared to Sampson's, Martin's and Friedewald's equations was performed using correlation coefficients, root mean squared error (RMSE) and bias. Also, concordance of misclassified metrics according to LDL-C (< 70 and < 100 mg/dL) and Apo B (< 80 and < 65 mg/dL) thresholds were assessed. RESULTS: Sampson's equation was more accurate (RMSE 11.21 mg/dL; R2 = 0.88) compared to Martin's (RMSE 13.15 mg/dL; R2 = 0.875) and the Friedewald's equation (RMSE 13.7 mg/dL; R2 = 0.869). When assessing performance according to LDL-C, Sampson's had highest correlation and lowest RMSE compared to other equations (RMSE 19.99 mg/dL; R2 = 0.840). Comparing performance strength across triglyceride levels, Sampson's showed consistently improved correlations compared to Martin's and Friedewald's formulas for increasing triglycerides and for the FCHL phenotype of mixed dyslipidemia. Sampson's also had improved concordance with treatment goals. CONCLUSIONS: In FCHL, VLDL-C and LDL-C estimation using Sampson's formula showed higher concordance with lipid targets assessed using VLDL-C obtained by ultracentrifugation compared with Friedewald's and Martin's equations. Implementation of Sampson's formula could improve treatment monitoring in FCHL.

Association of remnant cholesterol with nonalcoholic fatty liver disease: a general population-based study.

BACKGROUND: Remnant cholesterol (RC) mediates the progression of coronary artery disease, diabetic complications, hypertension, and chronic kidney disease. Limited information is available on the association of RC with nonalcoholic fatty liver disease (NAFLD). This study aimed to explore whether RC can be used to independently evaluate the risk of NAFLD in the general population and to analyze the predictive value of RC for NAFLD. METHODS: The study included 14,251 subjects enrolled in a health screening program. NAFLD was diagnosed by ultrasound, and the association of RC with NAFLD was assessed using the receiver operating characteristic (ROC) curve and logistic regression equation. RESULTS: Subjects with elevated RC had a significantly higher risk of developing NAFLD after fully adjusting for potential confounding factors (OR 1.77 per SD increase, 95% CI 1.64-1.91, P trend< 0.001). There were significant differences in this association among sex, BMI and age stratification. Compared with men, women were facing a higher risk of RC-related NAFLD. Compared with people with normal BMI, overweight and obesity, the risk of RC-related NAFLD was higher in thin people. In different age stratifications, when RC increased, young people had a higher risk of developing NAFLD than other age groups. Additionally, ROC analysis results showed that among all lipid parameters, the AUC of RC was the largest (women: 0.81; men: 0.74), and the best threshold for predicting NAFLD was 0.54 in women and 0.63 in men. CONCLUSIONS: The results obtained from this study indicate that (1) in the general population, RC is independently associated with NAFLD but not with other risk factors. (2) Compared with traditional lipid parameters, RC has a better predictive ability for NAFLD in men.

Pemafibrate decreases triglycerides and small, dense LDL, but increases LDL-C depending on baseline triglycerides and LDL-C in type 2 diabetes patients with hypertriglyceridemia: an observational study.

BACKGROUND: Pemafibrate, a selective PPARα modulator, has the beneficial effects on serum triglycerides (TGs) and very low density lipoprotein (VLDL), especially in patients with diabetes mellitus or metabolic syndrome. However, its effect on the low density lipoprotein cholesterol (LDL-C) levels is still undefined. LDL-C increased in some cases together with a decrease in TGs, and the profile of lipids, especially LDL-C, during pemafibrate administration was evaluated. METHODS: Pemafibrate was administered to type 2 diabetes patients with hypertriglyceridemia. Fifty-one type 2 diabetes patients (mean age 62 ± 13 years) with a high rate of hypertension and no renal insufficiency were analyzed. Pemafibrate 0.2 mg (0.1 mg twice daily) was administered, and serum lipids were monitored every 4-8 weeks from 8 weeks before administration to 24 weeks after administration. LDL-C was measured by the direct method. Lipoprotein fractions were measured by electrophoresis (polyacrylamide gel, PAG), and LDL-migration index (LDL-MI) was calculated to estimate small, dense LDL. RESULTS: Pemafibrate reduced serum TGs, midband and VLDL fractions by PAG. Pemafibrate increased LDL-C levels from baseline by 5.3% (- 3.8-19.1, IQR). Patients were divided into 2 groups: LDL-C increase of > 5.3% (group I, n = 25) and < 5.3% (group NI, n = 26) after pemafibrate. Compared to group NI, group I had lower LDL-C (2.53 [1.96-3.26] vs. 3.36 [3.05-3.72] mmol/L, P = 0.0009), higher TGs (3.71 [2.62-6.69] vs. 3.25 [2.64-3.80] mmol/L), lower LDL by PAG (34.2 [14.5, SD] vs. 46.4% [6.5], P = 0.0011), higher VLDL by PAG (28.2 [10.8] vs. 22.0% [5.2], P = 0.0234), and higher LDL-MI (0.421 [0.391-0.450] vs. 0.354 [0.341-0.396], P < 0.0001) at baseline. Pemafibrate decreased LDL-MI in group I, and the differences between the groups disappeared. These results showed contradictory effects of pemafibrate on LDL-C levels, and these effects were dependent on the baseline levels of LDL-C and TGs. CONCLUSIONS: Pemafibrate significantly reduced TGs, VLDL, midband, and small, dense LDL, but increased LDL-C in diabetes patients with higher baseline TGs and lower baseline LDL-C. Even if pre-dose LDL-C remains in the normal range, pemafibrate improves LDL composition and may reduce cardiovascular disease risk.

The effect of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis.

BACKGROUND: To our knowledge, data on the effects of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis are limited. This study was conducted to determine the effects of vitamin D supplementation on clinical symptoms and metabolic profiles in patients with endometriosis. METHODS: The current randomized, double-blind, placebo-controlled trial was conducted among 60 patients (aged 18-40 years old) with endometriosis. Participants were randomly allocated into two groups (30 participants each group) to receive either 50,000 IU vitamin D or placebo each 2 weeks for 12 weeks. RESULTS: Vitamin D supplementation significantly decreased pelvic pain (ß - 1.12; 95% CI, -2.1, -0.09; p=.03) and total-/HDL-cholesterol ratio (ß - 0.29; 95% CI, -0.57, -0.008; p=.04) compared with the placebo. Moreover, vitamin D intake led to a significant reduction in high-sensitivity C-reactive protein (hs-CRP) (ß - 0.64 mg/L; 95% CI, -0.97, -0.30; p<.001) and a significant increase in total antioxidant capacity (TAC) (ß 47.54 mmol/L; 95% CI, 19.98, 75.11; p=.001) compared with the placebo. CONCLUSIONS: Overall, our study demonstrated that vitamin D intake in patients with endometriosis resulted in a significant improvement of pelvic pain, total-/HDL-cholesterol ratio, hs-CRP and TAC levels, but did not affect other clinical symptoms and metabolic profiles.

Metabolic syndrome in rheumatoid arthritis patients: Relationship among its clinical components.

BACKGROUND: Metabolic syndrome (MetS) prevalence in rheumatoid arthritis (RA) patients is known to vary considerably across the world. This study aimed to determine the prevalence of MetS in RA patients from western Mexico and to analyze the interrelation of the MetS components with the clinical variables of RA. METHODS: This case-control study included 216 RA patients and 260 control subjects (CS). MetS prevalence was determined according to the NCEP/ATP III and the Latin American Consensus of the Latin American Diabetes Association (ALAD) criteria. RESULTS: MetS was observed in 30.6% RA patients and 33.3% of controls (p > 0.05) according to NCEP/ATP III and 28.7% in RA patients and 31.1% for controls using ALAD criteria. Total cholesterol, LDL-C, and Castelli's I-II indexes were lower in RA (p < 0.001) than in CS. The RA patients with MetS had more swollen joints than those without MetS (p = 0.018). In RA patients with MetS, DAS-28 score correlated with smoking index (rho = 0.4601, p = 0.0004) and VLDL-C (rho = 0.3108, p = 0.0056); similarly, rheumatoid factor (RF) correlated with age (rho = 0.2031, p = 0.0027), smoking index (rho = 0.3404, p < 0.0001), triglycerides (rho = 0.1958, p = 0.0039), and VLDL-C (rho = 0.1761, p = 0.0162). CONCLUSIONS: The MetS prevalence in RA patients from western Mexico is not higher than controls; however, in RA patients with MetS, some inflammatory markers are associated with MetS components; thus, the control of MetS in RA could be beneficial to regulate disease activity.

Influence of hs-CRP, IL-6 and TNF-α and it's role in dyslipidemia and type 2 diabetes in population of Karachi, Pakistan.

The present study was conducted to estimate the prevalence of pro-inflammatory cytokine interleukin-6, highly sensitive C-reactive protein, and tumor necrotic factor alpha and evaluate the association and role of these inflammatory markers in the pathogenesis of type 2 diabetes mellitus. A retrospective case-control study was conducted in Karachi. 400 individuals participated in the study having 200 diabetic patients and 200 controls. The subjects' profile and anthropometric indices were recorded and the levels of FPG, fasting insulin, lipid profile, IL-6, and hs-CRP were determined. Insulin resistance, beta-cell function and sensitivity were calculated by HOMA analysis using the HOMA calculator. Using independent t-test BMI, percent body fats, HbA1c, FPG, and fasting insulin were found significant (p<0.05). HOMA-IR, percent beta cell, total cholesterol, triglyceride, and HDL showed significant (p<0.05) results among cases and controls. Similarly, TNF-α and hs-CRP were also found significant (p<0.05) in cases than controls. Multiple linear regression was performed to predict the values of FPG, fasting plasma insulin, and IL-6. All models were statistically significant (p<0.05). The current study reveals that inflammation is the fundamental mechanism in obesity-induced insulin resistance, and T2DM, expanded fat stores in the body, and sedentary lifestyle are involved in the alteration of metabolic processes.

Angiopoietin-like protein 3 governs LDL-cholesterol levels through endothelial lipase-dependent VLDL clearance.

Angiopoietin-like protein (ANGPTL)3 regulates plasma lipids by inhibiting LPL and endothelial lipase (EL). ANGPTL3 inactivation lowers LDL-C independently of the classical LDLR-mediated pathway and represents a promising therapeutic approach for individuals with homozygous familial hypercholesterolemia due to LDLR mutations. Yet, how ANGPTL3 regulates LDL-C levels is unknown. Here, we demonstrate in hyperlipidemic humans and mice that ANGPTL3 controls VLDL catabolism upstream of LDL. Using kinetic, lipidomic, and biophysical studies, we show that ANGPTL3 inhibition reduces VLDL-lipid content and size, generating remnant particles that are efficiently removed from the circulation. This suggests that ANGPTL3 inhibition lowers LDL-C by limiting LDL particle production. Mechanistically, we discovered that EL is a key mediator of ANGPTL3's novel pathway. Our experiments revealed that, although dispensable in the presence of LDLR, EL-mediated processing of VLDL becomes critical for LDLR-independent particle clearance. In the absence of EL and LDLR, ANGPTL3 inhibition perturbed VLDL catabolism, promoted accumulation of atypical remnants, and failed to reduce LDL-C. Taken together, we uncover ANGPTL3 at the helm of a novel EL-dependent pathway that lowers LDL-C in the absence of LDLR.

Association of Lipid Levels with Mefloquine and Carboxy-Mefloquine Concentrations in Patients with Uncomplicated Falciparum Malaria.

Mefloquine shows a high capacity to bind plasma proteins, which influences the amount of drug in erythrocytes. The study investigated the association of lipids levels with plasma concentrations of mefloquine and carboxy-mefloquine in 85 Brazilian patients with uncomplicated falciparum malaria. There were no significant associations between the total cholesterol or triglycerides with plasma concentrations of mefloquine and of carboxy-mefloquine. Lipoprotein levels explained 25.68% and 18.31% of mefloquine and carboxy-mefloquine plasma concentrations, respectively.

Materno-fetal cholesterol transport during pregnancy.

Cholesterol is a major nutrient required for fetal growth. It is also a precursor for the synthesis of steroid hormones and essential for the development and maturation of fetal organs. During pregnancy, the placenta controls the transport of cholesterol from the mother to the fetus and vice versa. Cholesterol originating from the maternal circulation has to cross two main membrane barriers to reach the fetal circulation: Firstly, cholesterol is acquired by the apical side of the syncytiotrophoblast (STB) from the maternal circulation as high-density lipoprotein (HDL)-, low-density lipoprotein (LDL)- or very-low-density lipoprotein (VLDL)-cholesterol and secreted at the basal side facing the villous stroma. Secondly, from the villous stroma cholesterol is taken up by the endothelium of the fetal vasculature and transported to the fetal vessels. The proteins involved in the uptake of HDL-, LDL-, VLDL- or unesterified-cholesterol are scavenger receptor type B class 1 (SR-B1), cubulin, megalin, LDL receptor (LDLR) or Niemann-Pick-C1 (NPC1) which are localized at the apical and/or basal side of the STB or at the fetal endothelium. Through interaction with apolipoproteins (e.g. apoA1) cholesterol is effluxed either to the maternal or fetal circulation via the ATP-binding-cassette (ABC)-transporter A1 and ABCG1 localized at the apical/basal side of the STB or the endothelium. In this mini-review, we summarize the transport mechanisms of cholesterol across the human placenta, the expression and localization of proteins involved in the uptake and efflux of cholesterol, and the expression pattern of cholesterol transport proteins in pregnancy pathologies such as pre-eclampsia, gestational diabetes mellitus and intrauterine growth retardation.

Combination therapy with pemafibrate (K-877) and pitavastatin improves vascular endothelial dysfunction in dahl/salt-sensitive rats fed a high-salt and high-fat diet.

BACKGROUND: Statins suppress the progression of atherosclerosis by reducing low-density lipoprotein (LDL) cholesterol levels. Pemafibrate (K-877), a novel selective peroxisome proliferator-activated receptor α modulator, is expected to reduce residual risk factors including high triglycerides (TGs) and low high-density lipoprotein (HDL) cholesterol during statin treatment. However, it is not known if statin therapy with add-on pemafibrate improves the progression of atherosclerosis. The aim of this study was to assess the effect of combination therapy with pitavastatin and pemafibrate on lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. METHODS: Seven-week-old male Dahl salt-sensitive (DS) rats were divided into the following five treatment groups (normal diet (ND) plus vehicle, high-salt and high-fat diet (HD) plus vehicle, HD plus pitavastatin (0.3 mg/kg/day), HD plus pemafibrate (K-877) (0.5 mg/kg/day), and HD plus combination of pitavastatin and pemafibrate) and treated for 12 weeks. At 19 weeks, endothelium-dependent relaxation of the thoracic aorta in response to acetylcholine was evaluated. RESULTS: After feeding for 12 weeks, systolic blood pressure and plasma levels of total cholesterol were significantly higher in the HD-vehicle group compared with the ND-vehicle group. Combination therapy with pitavastatin and pemafibrate significantly reduced systolic blood pressure, TG levels, including total, chylomicron (CM), very LDL (VLDL), HDL-TG, and cholesterol levels, including total, CM, VLDL, and LDL-cholesterol, compared with vehicle treatment. Acetylcholine caused concentration-dependent relaxation of thoracic aorta rings that were pre-contracted with phenylephrine in all rats. Relaxation rates in the HD-vehicle group were significantly lower compared with the ND-vehicle group. Relaxation rates in the HD-combination of pitavastatin and pemafibrate group significantly increased compared with the HD-vehicle group, although neither medication alone ameliorated relaxation rates significantly. Western blotting experiments showed increased phosphorylated endothelial nitric oxide synthase protein expression in aortas from rats in the HD-pemafibrate group and the HD-combination group compared with the HD-vehicle group. However, the expression levels did not respond significantly to pitavastatin alone. CONCLUSIONS: Combination therapy with pitavastatin and pemafibrate improved lipid profiles and endothelial dysfunction in hypertension and insulin resistance model rats. Pemafibrate as an add-on strategy to statins may be useful for preventing atherosclerosis progression.