Plasma High-density Lipoprotein Levels Research Articles

Genome-wide landscape establishes novel association signals for metabolic traits in the Arab population

While the Arabian population has a high prevalence of metabolic disorders, it has not been included in global studies that identify genetic risk loci for metabolic traits. Determining the transferability of such largely Euro-centric established risk loci is essential to transfer the research tools/resources, and drug targets generated by global studies to a broad range of ethnic populations. Further, consideration of populations such as Arabs, that are characterized by consanguinity and a high level of inbreeding, can lead to identification of novel risk loci. We imputed published GWAS data from two Kuwaiti Arab cohorts (n = 1434 and 1298) to the 1000 Genomes Project haplotypes and performed meta-analysis for associations with 13 metabolic traits. We compared the observed association signals with those established for metabolic traits. Our study highlighted 70 variants from 9 different genes, some of which have established links to metabolic disorders. By relaxing the genome-wide significance threshold, we identified ‘novel’ risk variants from 11 genes for metabolic traits. Many novel risk variant association signals were observed at or borderline to genome-wide significance. Furthermore, 349 previously established variants from 187 genes were validated in our study. Pleiotropic effect of risk variants on multiple metabolic traits were observed. Fine-mapping illuminated rs7838666/CSMD1 rs1864163/CETP and rs112861901/[INTS10,LPL] as candidate causal variants influencing fasting plasma glucose and high-density lipoprotein levels. Computational functional analysis identified a variety of gene regulatory signals around several variants. This study enlarges the population ancestry diversity of available GWAS and elucidates new variants in an ethnic group burdened with metabolic disorders.

Animal Models with Metabolic Syndrome Markers Induced by High Fat Diet and Fructose

Metabolic syndrome is lipid and non-lipid metabolism disorder due to the association of several factors such as physiological, clinical, biochemical, and interrelated factors. People with metabolic syndrome can be diagnosed by fulfilling 3 of 5 criteria, including obesity and increased waist circumference, increased TG levels, increased blood pressure, hyperglycemia, and increased High-Density Lipoprotein (HDL) serum. The high-fat diet disrupts tissue lipid metabolism, so insulin resistance occurs due to lipotoxicity. Besides, some studies use a combination of mixtures (fructose, sucrose) and fat-rich food components to build metabolic characteristics in mice that affect human characteristics. The purpose of this study was to make an animal model with a metabolic syndrome marker induced by the High Fat Diet (HFD) consisting of pork oil and chicken egg yolk, as well as fructose from simple and economical ingredients. This study was an experimental study using experimental animals of male Rattus norvegicus strain wistar, which were grouped into three random treatment groups, namely the control group, HFD group, and High Fat Diet Fructose (HFDF) group. The number of samples used was 27 rats, with nine rats in each group. The animal was induced for four weeks, then measured levels of FPG, HD, and TG. From the research that has been done, it is found that there are significant differences in levels of Fasting Plasma Glucose (FPG), High-Density Lipoprotein (HDL), and Triglycerides (TG) (p

Identification of Reversible Small Molecule Inhibitors of Endothelial Lipase (EL) That Demonstrate HDL-C Increase In Vivo.

Endothelial lipase (EL) hydrolyzes phospholipids in high-density lipoprotein (HDL) resulting in reduction in plasma HDL levels. Studies with murine transgenic, KO, or loss-of-function variants strongly suggest that inhibition of EL will lead to sustained plasma high-density lipoprotein cholesterol (HDL-C) increase and, potentially, a reduced cardiovascular disease (CVD) risk. Herein, we describe the discovery of a series of oxadiazole ketones, which upon optimization, led to the identification of compound 12. Compound 12 was evaluated in a mouse pharmacodynamics (PD) model and demonstrated a 56% increase in plasma HDL-C. In a mouse reverse cholesterol transport study, compound 12 stimulated cholesterol efflux by 53% demonstrating HDL-C functionality.

Animal Models with Metabolic Syndrome Markers Induced by High Fat Diet and Fructose

Metabolic syndrome is lipid and non-lipid metabolism disorder due to the association of several factors such as physiological, clinical, biochemical, and interrelated factors. People with metabolic syndrome can be diagnosed by fulfilling 3 of 5 criteria, including obesity and increased waist circumference, increased TG levels, increased blood pressure, hyperglycemia, and increased High-Density Lipoprotein (HDL) serum. The high-fat diet disrupts tissue lipid metabolism, so insulin resistance occurs due to lipotoxicity. Besides, some studies use a combination of mixtures (fructose, sucrose) and fat-rich food components to build metabolic characteristics in mice that affect human characteristics. The purpose of this study was to make an animal model with a metabolic syndrome marker induced by the High Fat Diet (HFD) consisting of pork oil and chicken egg yolk, as well as fructose from simple and economical ingredients. This study was an experimental study using experimental animals of male Rattus norvegicus strain wistar, which were grouped into three random treatment groups, namely the control group, HFD group, and High Fat Diet Fructose (HFDF) group. The number of samples used was 27 rats, with nine rats in each group. The animal was induced for four weeks, then measured levels of FPG, HD, and TG. From the research that has been done, it is found that there are significant differences in levels of Fasting Plasma Glucose (FPG), High-Density Lipoprotein (HDL), and Triglycerides (TG) (p <0.05). It can be concluded egg yolks, lard, and fructose in high-fat diets combined with fructose can increase levels of FPG, TG and reduce levels of HDL, which are markers of the metabolic syndrome used in this study.

The Effect of Subdiaphragmatic Vagotomy on Lipid Profile and Insulin Resistance in Diabetic Obese Rats

The aim of the study was to assess of the effect of subdiaphragmatic vagotomy on lipid profile and insulin resistance in diabetic obese rat model. Fifty Male Albino rats were divided into 5 groups. Subdiaphragmatic vagotomy and sham operations were applied on diabetic obese rat model induced by high fat diet for 5 weeks and low dose of streptozotocin (30mg/kg). Serum samples were collected for confirmation of hyperlipidemia and lee obesity index was measured. At the end of the experiment, oral glucose tolerance test, lee obesity index, lipid profile, fasting insulinemia, fasting glucose, insulin resistance (HOMA-IR) and histopathology of pancreases were assessed. Results revealed that Subdiaphragmatic vagotomy significantly improved hyperlipidemia as it normalized plasma triglyceride level, decreased plasma cholesterol level and increased plasma high density lipoprotein level in diabetic and non-diabetic obese vagotomized rats. Vagotomy significantly decreased lee obesity index and perigonadal fat pads weight, decreased fasting insulinemia, decreased HOMA-IR and improved glucose tolerance in diabetic and non-diabetic obese vagotomized rats. These results were confirmed by regression of degenerative changes and restoration of the size of pancreatic islets of Langerhans. In non-diabetic obese vagotomized group, the results of 120 minutes of oral glucose tolerance test and HOMA-IR were close to normal expected values. However, the same parameters were still away from normal expected values although normal histopathological results of pancreases, in diabetic obese vagotomized group. In Conclusion, subdiaphragmatic vagotomy has a promising role in treating obesity. Nevertheless, its role in treating diabetes needs further long-term studies to be approved.

Plasma albumin redox state is superior to conventional biomarkers to indicate the presence of potential protein undernutrition

AbstractThe redox state of plasma albumin would reflect albumin synthesis rate, and could be useful to demonstrate the presence of potential protein undernutrition. Aiming to delineate the characteristics of plasma albumin redox state as a nutritional biomarker, adult male Wistar rats were maintained on AIN-93M (14% casein, control diet) or an AIN-93M-based low protein diet (5% casein) ad libitum for 4 weeks, and the two groups were compared by examining plasma albumin redox state, plasma/serum levels of conventional biomarkers for protein nutritional status, and plasma proteome. While no significant difference was seen in body weight at the end of the experimental period, plantaris muscle mass trended lower in the low protein diet group, implicating the manifestation of moderate protein undernutrition. The redox of plasma albumin was shifted to more oxidized state in the low protein diet group, and the shift persisted during the entire experimental period. In contrast, the levels of conventional biomarkers, plasma albumin and prealbumin, were initially decreased in the low protein diet group, and the differences were then dissolved later in the experimental period. Similarly, the levels of other biomarkers, plasma transferrin and serum retinol-binding protein-4, did not differ significantly at the end of the experimental period. Plasma proteomic analysis revealed that the abundances of proteins that constitute high-density lipoprotein (HDL), apolipoprotein A-II and paraoxonase-1, were decreased in the low protein diet group, which were then validated by confirming decreases in plasma HDL level, plasma HDL-cholesterol level, and serum paraoxonase-1 activity in the low protein diet group. According to epidemiological reports, dietary protein intake is positively associated with plasma HDL-cholesterol level, and the risk factors of cardiovascular diseases, including lower HDL-cholesterol level, are closely related to frailty. Thus, it can be conceived that moderate dietary protein insufficiency would increase cardiovascular risks, such as reduction in HDL level and function (paraoxonase-1 activity), which could prime the onset of amyotropic diseases later in life, such as sarcopenia and frailty. Collectively, moderate dietary protein insufficiency would lead to decreased skeletal muscle mass, and also attenuate circulating HDL level and function, which could even aggravate the attenuation of skeletal muscle accretion; the redox state of plasma albumin would be instrumental over conventional biomarkers as an indicator of potentially protein undernourished status.

Transcriptomic profiling of experimental arterial injury reveals new mechanisms and temporal dynamics in vascular healing response

ObjectiveEndovascular interventions cause arterial injury and induce a healing response to restore vessel wall homeostasis. Complications of defective or excessive healing are common and result in increased morbidity and repeated interventions. Experimental models of intimal hyperplasia are vital for understanding the vascular healing mechanisms and resolving the clinical problems of restenosis, vein graft stenosis, and dialysis access failure. Our aim was to systematically investigate the transcriptional, histologic, and systemic reaction to vascular injury during a prolonged time. MethodsBalloon injury of the left common carotid artery was performed in male rats. Animals (n = 69) were euthanized before or after injury, either directly or after 2 hours, 20 hours, 2 days, 5 days, 2 weeks, 6 weeks, and 12 weeks. Both injured and contralateral arteries were subjected to microarray profiling, followed by bioinformatic exploration, histologic characterization of the biopsy specimens, and plasma lipid analyses. ResultsImmune activation and coagulation were key mechanisms in the early response, followed by cytokine release, tissue remodeling, and smooth muscle cell modulation several days after injury, with reacquisition of contractile features in later phases. Novel pathways related to clonal expansion, inflammatory transformation, and chondro-osteogenic differentiation were identified and immunolocalized to neointimal smooth muscle cells. Analysis of uninjured arteries revealed a systemic component of the reaction after local injury, underlined by altered endothelial signaling, changes in overall tissue bioenergy metabolism, and plasma high-density lipoprotein levels. ConclusionsWe demonstrate that vascular injury induces dynamic transcriptional landscape and metabolic changes identifiable as early, intermediate, and late response phases, reaching homeostasis after several weeks. This study provides a temporal “roadmap” of vascular healing as a publicly available resource for the research community.

EFFECT OF IN-OVO INJECTION WITH IRON–METHIONINE CHELATES OR IRON NANO-PARTICLES AND POST HATCH DIETARY FOLIC ACID ON GROWTH PERFORMANCE AND PHYSIOLOGICAL RESPONSES OF BROILER CHICKENS

A study was carried out to evaluate the effect of in-ovo injection of iron–methionine chelates (Fe-Meth) or iron nano-particles (FeNPs) and post hatch feeding with diets fortified with folic acid on productive performance and some physiological responses of Ross broiler chickens. A total of 450 fertile eggs were allocated to 5 treatment groups in the incubator, each of which included 3 replicates (30 eggs each). Experimental treatments consisted of a 5 × 2 factorial arrangement design with 5 levels of in-ovo injection solutions at day seven of incubation and two dietary levels of folic acid (FA) (0.0 or 0.5g/kg, diet) after hatching. In-ovo injection treatments were divided into 5 groups: control non- injected (T1), injected with 0.1 ml physiological saline (T2), sham-injected control (T3),injected with 0.1 ml of 75 ppb of iron nano-particles (T4, FeNPs), while the last group (T5) was injected with 0.1 ml of 75 ppb organic iron (Fe- meth). Results showed that in-ovo injection of different iron sources significantly improved live body weight and weight gain of broiler chicks, and enhanced FCR at 3 and 5 weeks of age compared to other groups. Broilers fed folic acid fortified diets displayed significantly heavier Live body weight (LBW) and body weight gain (BWG) than the those fed the control un-supplemented diet. The combined interaction effect of in-ovo iron injection and dietary folic acid supplementation showed the best productive performance figures during the whole experimental period. Different iron sources had no significant effect on all plasma protein fraction, Lipids profile except a higher concentration of high density lipoprotein (HDL) in plasma recorded in-ovo injection of different iron sources compared with different controls. Plasma hemoglobin, globulin fractions(α, β, and γ-globulin), transferrin and Tri-iodothyronine concentration were significantly higher in both injected groups compared to the different control groups. Birds fed FA treatment recorded the lower significant values of plasma cholesterol, triglyceride and LDL, but, the birds fed FA recorded the higher significant value of plasma HDL, plasma hemoglobin, globulin fractions(α, β, and γ-globulin), transferrin and tri-iodothyronine concentration levels compared with birds fed with or without FA. In conclusion, in-ovo injection of Fe-Meth. or FeNPs and fed the diet fortified with FA were sufficient to improve broiler performance or physiological response in broiler chickens.

Apolipoprotein A-I primes beta cells to increase glucose stimulated insulin secretion

The increase of plasma levels of high-density lipoproteins and Apolipoprotein A-I (ApoA-I), its main protein component, has been shown to have a positive action on glucose disposal in type 2 diabetic patients. The current study investigates the unexplored function of ApoA-I to prime beta cells for improved insulin secretion.INS-1E rat clonal beta cells as well as isolated murine islets were used to study the effect of ApoA-I on responsiveness of the beta cells to high glucose challenge. Confocal and transmission electron microscopy were used to dissect ApoA-I mechanisms of action. Chemical endocytosis blockers were used to understand the role of ApoA-I internalization in mediating its positive effect.Pre-incubation of beta cells and isolated murine islets with ApoA-I augmented glucose stimulated insulin secretion. This effect appeared to be due to an increased reservoir of insulin granules at the cell membrane, as confirmed by confocal and transmission electron microscopy. Moreover, ApoA-I induced pancreatic and duodenal homeobox 1 (PDX1) shuttling from the cytoplasm to the nucleus, with the subsequent increase in the proinsulin processing enzyme protein convertase 1 (PC1/3). Finally, the blockade of ApoA-I endocytosis in beta cells resulted in a loss of ApoA-I positive action on insulin secretion.The proposed mechanisms of the phenomenon here described include ApoA-I internalization into beta cells, PDX1 nuclear translocation, and increased levels of proinsulin processing enzymes. Altogether, these events lead to an increased number of insulin granules.

TSPO polymorphism in individuals with alcohol use disorder: Association with cholesterol levels and withdrawal severity.

The translocator protein (TSPO) transports cholesterol into mitochondria and is involved in steroidogenesis. The TSPO polymorphism rs6971 influences binding of cholesterol and other TSPO ligands including positron-emission tomography (PET) imaging radiotracers. Although it is recognized that alcohol increases plasma high-density lipoproteins (HDLs), its effects on total cholesterol and triglycerides along with its relationship to TSPO genotype have not been assessed. Here, we evaluated whether plasma cholesterol and triglycerides are disrupted in alcohol use disorder (AUD) and their association with rs6971 in 932 AUD participants (DSM IV or 5) and 546 controls. AUD participants compared with controls had significantly higher plasma levels of total cholesterol, HDL, and triglycerides, but not of low-density lipoprotein (LDL). In the AUD group only, TSPO rs6971 had a significant effect on plasma levels of cholesterol, LDL, and triglycerides (AA (n = 62) > AG (n = 319) > GG (n = 551)), but not on HDL levels. Additionally, we showed a significant effect of TSPO rs6971 on withdrawal scores (Clinical Institute Withdrawal Assessment for Alcohol [CIWA]), with higher scores in AA (n = 50) compared with AG (n = 238) and GG (n = 428). CIWA scores in AUD participants correlated negatively with LDL and positively with HDL, but not with total cholesterol or triglycerides. These findings corroborate elevated plasma cholesterol and HDL levels in AUD and document significant increases in triglycerides. We also reveal for the first time an association in AUD participants between TSPO rs6971 genotype and plasma cholesterol, LDL, and triglyceride levels (not for HDL) and with withdrawal severity. Mediation analyses revealed that LDL (but not HDL) influenced the association between TSPO and alcohol withdrawal severity.

Effect of Crataegus extract supplementation on diabetes induced memory deficits and serum biochemical parameters in male rats

This study was undertaken to investigate the Crataegus extract (CE) eff ;ects on diabetes-induced memory deficit in passive avoidance learning (PAL), blood glucose, and lipid profile panel. Male Wistar rats were divided into five groups: Control (CTRL); Diabetic (DM); and Diabetic animals treated with three doses of CE (100, 300 and 1000 mg/kg) (DM + CE). Streptozotocin (STZ)-induced diabetic rats (50 mg/kg, ip) were orally administrated with CE once a day for 2 weeks. After 2 weeks, PAL task was used to evaluate the passive avoidance learning and memory. At the end of experiment, the level of plasma glucose, triglycerides (TG), cholesterol, low-density lipoprotein (LDL), and high-density lipoprotein (HDL) were determined. Our results showed that the step-through latency (STLr) in diabetic animals was less than the control group (P = 0.0009). Crataegus (300 mg) increased STLr in diabetic animals (P = 0.0418). Diabetic animals spent more time in the dark compartment (TDC) (P = 0.0009). Crataegus (300 and 1000 mg) decreased TDC in diabetic animals (P = 0.0175). Crataegus (100 and 300 mg) decreased blood glucose in diabetic animals (P < 0.001). TG and Cholesterol concentration increased in diabetic animals in comparison with control (P < 0.05). CE (100 and 300 mg) reduced the cholesterol concentration in diabetic animals (P < 0.001). There was no significant difference in the case of LDL among the experimental groups (P > 0.05). CE (1000 mg) increased HDL in diabetic animals (P < 0.05). Our findings demonstrated that CE had the hypolipidemic and hypoglycemic effects and lead to memory improvement in STZ-induced diabetes.

Effects Of Conserved Proline Apoai Variants On Hdl Structure And Function

Background and Aims: Although plasma high density lipoproteins (HDL) and apolipoprotein (apo) AI levels negatively correlate with atherosclerotic cardiovascular disease (CVD), most HDL-raising interventions do not reduce CVD events. Moreover, other studies show that HDL function, e.g., support of macrophage cholesterol efflux, may be more important than the plasma HDL levels. HDL instability is relevant to the activities of plasma LCAT, CETP, PLTP, SR-BI, and HL. The mechanisms and pathways underlying the HDL biogenesis determine its compositions and ultimately its function in vivo. Alignment of the α-helices of apo AI, reveals highly conserved amino acid residues across 31 species. Moreover, proline-initiated amphipathic a-helices are a conserved structural motif among the exchangeable apos. We tested the hypothesis that highly conserved amino acid residues in apo AI are essential to its structure and function.

Association of 584C/T polymorphism in endothelial lipase gene with risk of coronary artery disease.

Coronary artery disease (CAD) is one of the cardiovascular diseases, which is caused by a reduced amount of oxygen and blood that goes to the heart. CAD includes stable angina, unstable angina, myocardial infarction, and sudden cardiac death. It is a common cause of death in both men and women. The environmental and genetic factors are involved in the development of CAD. Multiple gene polymorphisms are risk factors of CAD. To evaluate the association between EL 584C/T polymorphism, CAD risk, and lipid profile in an Egyptian population. This is a case-control study. The patients were classified into three groups: Group A: Control group, this group included 42 apparently healthy people. Group B: included 42 subjects diagnosed with previous myocardial infarction (MI). Group C: included 42 subjects diagnosed with unstable angina (UA). The frequencies of TT and CT genotypes and T allele were higher in control healthy individuals than CAD patients. In addition, the risk of CAD was significantly lower in individuals carrying T allele (P = 0.001). Serum high-density lipoprotein (HDL) levels were significantly higher in healthy individuals and CAD patients (MI and UA patients) carrying EL 584 T allele compared with those carrying CC genotype (P ≤ 0.001). By multiple logistic regression, we found that the protective effect of T allele remained significant (P = 0.005) and it decreased the risk of CAD independent of plasma HDL levels. There was a significant difference between 584C/T polymorphism in the EL gene and CAD and HDL level. T-allele carriers had a higher HDL level and were protected from CAD. T allele was significantly associated with the decreased risk of CAD independent of plasma HDL levels.

Hyperinsulinemia and thyroid peroxidase antibody in Chinese patients with papillary thyroid cancer.

This study aimed to investigate if hyperinsulinemia and/or insulin resistance was correlated with the occurrence of papillary thyroid cancer (PTC) in a group of Chinese patients. 258 inpatients were included in the study. According to the postoperative pathology results, all subjects were divided into PTC (n = 153) and control groups (with benign thyroid nodules, n = 105). Body mass index (BMI), fasting glucose, fasting insulin, homeostasis model assessment of insulin resistance (HOMA-IR), thyroid-stimulating hormone (TSH), FT4, FT3, thyroid peroxidase antibody (TPOAb), thyroglobulin antibody (TGAb), serum uric acid (UA), and lipid levels. Fasting insulin levels, HOMA-IR values, TPOAb levels, serum TSH levels, and serum uric acid levels in the PTC group were higher than those in the control group (p < 0.05). However, no significant differences in age, gender, BMI, history of hypertension, and the levels of fasting plasma glucose, FT3, FT4, TGAb, total cholesterol, triglyceride, low-density lipoprotein, and high-density lipoprotein were observed between the two groups (p > 0.05). After the multiple logistic regression analysis, the occurrence of PTC was positively associated with fasting insulin (odds ratio [OR] = 1.048, 95% confidence interval [CI]: 1.003-1.096, p = 0.037) and TPOAb levels (OR = 1.001, 95% CI: 1.000-1.002, p = 0.032). Moreover, TPOAb level was positively correlated with vague margin (r = 0.126, p = 0.045) and negatively correlated with homogeneous echo (r = -0.179, p = 0.004). However, fasting insulin levels were not correlated with pathological characteristics of PTC. Hyperinsulinemia and higher TPOAb levels might be the risk factors of PTC, but not disease severity in Chinese patients.

Revisiting Reverse Cholesterol Transport in the Context of High-Density Lipoprotein Free Cholesterol Bioavailability.

Dysregulated free cholesterol (FC) metabolism has been implicated in nearly all stages of atherosclerosis, the underlying cause of most cardiovascular disease. According to a widely cited model, the burden of macrophage FC in the arterial wall is relieved by transhepatic reverse cholesterol transport (RCT), which comprises three successive steps: (1) macrophage FC efflux to high-density lipoprotein (HDL) and/or its major protein, apolipoprotein AI; (2) FC esterification by lecithin:cholesterol acyltransferase (LCAT); and (3) HDL-cholesteryl ester (CE) uptake via the hepatic HDL-receptor, scavenger receptor class B type 1 (SR-B1). Recent studies have challenged the validity of this model, most notably the role of LCAT, which appears to be of minor importance. In mice, most macrophage-derived FC is rapidly cleared from plasma (t1/2 < 5 min) without esterification by hepatic uptake; the remainder is taken up by multiple tissue and cell types, especially erythrocytes. Further, some FC is cleared by the nonhepatic transintestinal pathway. Lastly, FC movement among lipid surfaces is reversible, so that a higher-than-normal level of HDL-FC bioavailability-defined by high plasma HDL levels concurrent with a high mol% HDL-FC-leads to the transfer of excess FC to cells in vivo. SR-B1-/- mice provide an animal model to study the mechanistic consequences of high HDL-FC bioavailability that provokes atherosclerosis and other metabolic abnormalities. Future efforts should aim to reduce HDL-FC bioavailability, thereby reducing FC accretion by tissues and the attendant atherosclerosis.

LCAT Enzyme Replacement Therapy Reduces LpX and Improves Kidney Function in a Mouse Model of Familial LCAT Deficiency.

Familial LCAT deficiency (FLD) is due to mutations in lecithin:cholesterol acyltransferase (LCAT), a plasma enzyme that esterifies cholesterol on lipoproteins. FLD is associated with markedly reduced levels of plasma high-density lipoprotein and cholesteryl ester and the formation of a nephrotoxic lipoprotein called LpX. We used a mouse model in which the LCAT gene is deleted and a truncated version of the SREBP1a gene is expressed in the liver under the control of a protein-rich/carbohydrate-low (PRCL) diet-regulated PEPCK promoter. This mouse was found to form abundant amounts of LpX in the plasma and was used to determine whether treatment with recombinant human LCAT (rhLCAT) could prevent LpX formation and renal injury. After 9 days on the PRCL diet, plasma total and free cholesterol, as well as phospholipids, increased 6.1 ± 0.6-, 9.6 ± 0.9-, and 6.7 ± 0.7-fold, respectively, and liver cholesterol and triglyceride concentrations increased 1.7 ± 0.4- and 2.8 ±0.9-fold, respectively, compared with chow-fed animals. Transmission electron microscopy revealed robust accumulation of lipid droplets in hepatocytes and the appearance of multilamellar LpX particles in liver sinusoids and bile canaliculi. In the kidney, LpX was found in glomerular endothelial cells, podocytes, the glomerular basement membrane, and the mesangium. The urine albumin/creatinine ratio increased 30-fold on the PRCL diet compared with chow-fed controls. Treatment of these mice with intravenous rhLCAT restored the normal lipoprotein profile, eliminated LpX in plasma and kidneys, and markedly decreased proteinuria. The combined results suggest that rhLCAT infusion could be an effective therapy for the prevention of renal disease in patients with FLD.

Progressive circuit resistance training improves inflammatory biomarkers and insulin resistance in obese men

BackgroundCircuit resistance training (CRT) is a time-efficient exercise modality for improving skeletal muscle and cardiovascular fitness. But the beneficial role of CRT in obese individuals is still not well understood. This study explores the reducing effects of progressive CRT on inflammatory biomarkers and cardiometabolic risk factors in obese young men. MethodsThirty obese men (Body mass index (BMI): 30.67 ± 3.06; age: 23 ± 3.2 years) were divided into CRT and control groups. The CRT was performed for eight-weeks (3 times/week, 65–85% of 1 repetition maximum). Fasting blood samples were taken pre and post intervention for analyzing apelin, chemerin, serum amyloid A (SAA), C reactive protein concentrations (CRP), lipid profile, and insulin resistance index. The data were assessed by two-way repeated measures ANOVA. ResultsBody mass, BMI and waist to hip ratio (WHR) were significantly decreased after training intervention (P < .05). Compared to the control group, the plasma concentrations of Chemrin (P = .038), SAA (P = .004), insulin (P < .001), insulin resistance index (P < .001), total cholesterol (P = .033), triglyceride (P < .001), and low-density lipoprotein (P = .039), were significantly mitigated in the CRT group, but high-density lipoprotein plasma levels increased in the CRT group compared to that of the control group (P = .035). There was no significant difference between two groups in apelin and CRP (P > .05). Moreover, insulin resistance was positively correlated with apelin (r = 0.56) and chemerin (r = 0.51). Also, chemerin had a positive correlation with SAA (r = 0.49), and WHR (r = 0.54). ConclusionCRT caused an improvement in inflammation and cardiometabolic risk factors in young obese men, and this improvement was accompanied by decreased insulin resistance.

High-density lipoprotein mimetic peptide 4F mitigates amyloid-β-induced inhibition of apolipoprotein E secretion and lipidation in primary astrocytes and microglia.

The apolipoprotein E (apoE) ε4 allele is the primary genetic risk factor for late-onset Alzheimer's disease (AD). ApoE in the brain is produced primarily by astrocytes; once secreted from these cells, apoE binds lipids and forms high-density lipoprotein (HDL)-like particles. Accumulation of amyloid-β protein (Aβ) in the brain is a key hallmark of AD, and is thought to initiate a pathogenic cascade leading to neurodegeneration and dementia. The level and lipidation state of apoE affect Aβ aggregation and clearance pathways. Elevated levels of plasma HDL are associated with lower risk and severity of AD; the underlying mechanisms, however, have not been fully elucidated. This study was designed to investigate the impact of an HDL mimetic peptide, 4F, on the secretion and lipidation of apoE. We found that 4F significantly increases apoE secretion and lipidation in primary human astrocytes as well as in primary mouse astrocytes and microglia. Aggregated Aβ inhibits glial apoE secretion and lipidation, causing accumulation of intracellular apoE, an effect that is counteracted by co-treatment with 4F. Pharmacological and gene editing approaches show that 4F mediates its effects partially through the secretory pathway from the endoplasmic reticulum to the Golgi apparatus and requires the lipid transporter ATP-binding cassette transporter A1. We conclude that the HDL mimetic peptide 4F promotes glial apoE secretion and lipidation and mitigates the detrimental effects of Aβ on proper cellular trafficking and functionality of apoE. These findings suggest that treatment with such an HDL mimetic peptide may provide therapeutic benefit in AD. Read the Editorial Highlight for this article on page580.

Association of serum paraoxonase activity with lipid profile, APO-A and APO-B in subjects with different levels of HDL

BackgroundCoronary heart diseases are inversely related to plasma high-density lipoprotein (HDL) level. Paraoxonase-1 (PON1) is mainly associated with HDL and plays a vital role in protection of low-density lipoprotein (LDL) and HDL. The aim of this study was to investigate the association between paraoxonase activity (PON1) with lipid profile, apoA-І, apoB and apoB/apoA-І ratio in subjects with different level of HDL cholesterol (HDL-C). Methods135 subjects, 20–60 years old, contributed to this study. The subjects were divided into three groups (45 in each group) with different levels of HDL-C (High, Normal and Low). For each group, the activity of PON1 was measured using paraoxon as a substrate. Moreover, the serum level of lipid profile, ApoA and apoB were measured. The statistical analysis was performed using SPSS software. ResultsPON-1 activity and apoA-І level were decreased in subjects with lower level of HDL-C (P < 0.001). ApoB and apoB/apoA-І ratio were higher in subjects with lower level of HDL-C (P < 0.001). Serum PON-1 activity was positively correlated with TC, TG, apo A-B, and LDL-C levels (P < 0.01). ConclusionsIn conclusion, determination of serum PON1 activity and lipoproteins may play important role in earlier prediction of CAD and help to design a therapeutic for treatment of CAD toward PON1 activity regulation.

Synthesis and in Vivo Lipid-Lowering Activity of Novel Imidazoles-5-carboxamide Derivatives in Triton-WR-1339-Induced Hyperlipidemic Wistar Rats.

A new series of imidazole-5-carboxamide derivatives were prepared and tested for their anti-hyperlipidemic activity in Triton-WR-1339-induced hyperlipidemic Wistar rats. The purpose of this research was to improve benzophenone carboxamides water solubility maintaining at the same time the antihyperlipidemic activity. Compounds 4, 6, 10, and 11 were synthesized through a coupling reaction between imidazoles-5-carbonyl chloride and amino benzophenones. The tested animals (n=48) were divided into six groups: the first group (hyperlipidemic control group; HCG) received an intraperitoneal injection (i.p.) of (300 mg/kg) Triton WR-1339. The second group received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of bezafibrate (100 mg/kg) (bezafibrate; BF). The third, fourth, fifth, and sixth groups received i.p. injection of Triton WR-1339 followed by an intra-gastric administration of (30 mg/kg) of compounds 4, 6, 10, and 11, respectively. At a dose of 30 mg/kg body weight compounds 4, 6, 10, and 11 significantly (p<0.0001) decreased the plasma level of triglyceride (TG), low-density lipoprotein (LDL) and total cholesterol (TC) levels after 18 h of treatment. Additionally, compounds 4, 6, 11 and bezafibrate (100 mg/kg) significantly (p<0.0001) increased the plasma level of high-density lipoprotein (HDL) levels, which is known for its preventive role against atherogenesis. These results demonstrate the possibility of pharmacokinetic properties improvement maintaining the biological and pharmacological profile of these compounds.