Plasma Triglyceride Levels Research Articles

Evaluation of antihyperlipidemic effect of rosemary oil in streptozotocin-induced diabetic rats

Aim: In this study, the potential effects of rosemary oil on the lipid profile in streptozotocin-induced diabetic rats were examined. Materials and Methods: In this study, thirty-two adult male Wistar Albino rats were used. Working groups were consisted as follows: control group (C, n=6), rosemary group (R, n=6), diabetes group (STZ, n=10) and diabetes+rosemary group (STZ+R, n=10). The rosemary oil was administered at oral dosage of 200 mg/kg daily for duration of three weeks in the groups receiving rosemary oil. Diabetes was performed by subcutaneous injections of streptozotocin at dosage of 40 mg/kg in 0.1 M citrate buffer (pH 4.5) for two consecutive days as a single daily dose. At the end of three weeks, blood samples collected from the all animals were assessed lipid parameters. Results: In this study, plasma levels of triglyceride, total cholesterol, and LDL-cholesterol significantly elevated, alongside plasma HDL-cholesterol levels in diabetes group significantly reduced compared to the control group. However, upon the application of rosemary oil to streptozotocin-induced diabetic rats, a substantial decrease in plasma triglyceride, total cholesterol, and LDL-cholesterol levels was observed, while plasma HDL-cholesterol notably increased. Conclusion: As a result of the current findings, it is concluded that rosemary oil may have antihiperlipidemic properties and could be used as a phytomedicine for the treatment of diabetes.

Basic and translational evidence supporting the role of TM6SF2 in VLDL metabolism.

Transmembrane 6 superfamily member 2 ( TM6SF2 ) gene was identified through exome-wide studies in 2014. A genetic variant from glutamic acid to lysine substitution at amino acid position 167 (NM_001001524.3:c.499G> A) (p.Gln167Lys/p.E167K, rs58542926) was discovered (p.E167K) to be highly associated with increased hepatic fat content and reduced levels of plasma triglycerides and LDL cholesterol. In this review, we focus on the discovery of TM6SF2 and its role in VLDL secretion pathways. Human data suggest TM6SF2 is linked to hepatic steatosis and cardiovascular disease (CVD), hence understanding its metabolic pathways is of high scientific interest. Since its discovery, completed research studies in cell, rodent and human models have defined the role of TM6SF2 and its links to human disease. TM6SF2 resides in the endoplasmic reticulum (ER) and the ER-Golgi interface and helps with the lipidation of nascent VLDL, the main carrier of triglycerides from the liver to the periphery. Consistent results from cells and rodents indicated that the secretion of triglycerides is reduced in carriers of the p.E167K variant or when hepatic TM6SF2 is deleted. However, data for secretion of APOB, the main protein of VLDL particles responsible for triglycerides transport, are inconsistent. The identification of genetic variants that are highly associated with human disease presentation should be followed by the validation and investigation into the pathways that regulate disease mechanisms. In this review, we highlight the role of TM6SF2 and its role in processing of liver triglycerides.

Prevotella and succinate treatments altered gut microbiota, increased laying performance, and suppressed hepatic lipid accumulation in laying hens

BackgroundThis work aimed to investigate the potential benefits of administering Prevotella and its primary metabolite succinate on performance, hepatic lipid accumulation and gut microbiota in laying hens.ResultsOne hundred and fifty 58-week-old Hyline Brown laying hens, with laying rate below 80% and plasma triglyceride (TG) exceeding 5 mmol/L, were used in this study. The hens were randomly allocated into 5 groups and subjected to one of the following treatments: fed with a basal diet (negative control, NC), oral gavage of 3 mL/hen saline every other day (positive control, PC), gavage of 3 mL/hen Prevotella melaninogenica (107 CFU/mL, PM) or 3 mL/hen Prevotella copri (107 CFU/mL, P. copri) every other day, and basal diet supplemented with 0.25% sodium succinate (Succinate). The results showed that PM and P. copri treatments significantly improved laying rate compared to the PC (P < 0.05). The amount of lipid droplet was notably decreased by PM, P. copri, and Succinate treatments at week 4 and decreased by P. copri at week 8 (P < 0.05). Correspondingly, the plasma TG level in Succinate group was lower than that of PC (P < 0.05). Hepatic TG content, however, was not significantly influenced at week 4 and 8 (P > 0.05). PM treatment increased (P < 0.05) the mRNA levels of genes PGC-1β and APB-5B at week 4, and ACC and CPT-1 at week 8. The results indicated enhanced antioxidant activities at week 8, as evidenced by reduced hepatic malondialdehyde (MDA) level and improved antioxidant enzymes activities in PM and Succinate groups (P < 0.05). Supplementing with Prevotella or succinate can alter the cecal microbiota. Specifically, the abundance of Prevotella in the Succinate group was significantly higher than that in the other 4 groups at the family and genus levels (P < 0.05).ConclusionsOral intake of Prevotella and dietary supplementation of succinate can ameliorate lipid metabolism of laying hens. The beneficial effect of Prevotella is consistent across different species. The finding highlights that succinate, the primary metabolite of Prevotella, represents a more feasible feed additive for alleviating fatty liver in laying hens.

Revisiting multi-omics-based predictors of the plasma triglyceride response to an omega-3 fatty acid supplementation.

The aim of the present study was to identify the metabolomic signature of responders and non-responders to an omega-3 fatty acid (n-3 FA) supplementation, and to test the ability of a multi-omics classifier combining genomic, lipidomic, and metabolomic features to discriminate plasma triglyceride (TG) response phenotypes. A total of 208 participants of the Fatty Acid Sensor (FAS). Study took 5 g per day of fish oil, providing 1.9-2.2 g eicosapentaenoic acid (EPA) and 1.1 g docosahexaenoic (DHA) daily over a 6-week period, and were further divided into two subgroups: responders and non-responders, according to the change in plasma TG levels after the supplementation. Changes in plasma levels of 6 short-chain fatty acids (SCFA) and 25 bile acids (BA) during the intervention were compared between subgroups using a linear mixed model, and the impact of SCFAs and BAs on the TG response was tested in a mediation analysis. Genotyping was conducted using the Illumina Human Omni-5 Quad BeadChip. Mass spectrometry was used to quantify plasma TG and cholesterol esters levels, as well as plasma SCFA and BA levels. A classifier was developed and tested within the DIABLO framework, which implements a partial least squares-discriminant analysis to multi-omics analysis. Different classifiers were developed by combining data from genomics, lipidomics, and metabolomics. Plasma levels of none of the SCFAs or BAs measured before and after the n-3 FA supplementation were significantly different between responders and non-responders. SCFAs but not BAs were marginally relevant in the classification of plasma TG responses. A classifier built by adding plasma SCFAs and lipidomic layers to genomic data was able to even the accuracy of 85% shown by the genomic predictor alone. These results inform on the marginal relevance of SCFA and BA plasma levels as surrogate measures of gut microbiome in the assessment of the interindividual variability observed in the plasma TG response to an n-3 FA supplementation. Genomic data still represent the best predictor of plasma TG response, and the inclusion of metabolomic data added little to the ability to discriminate the plasma TG response phenotypes.

Beneficial Effects of Natural Alkaloids from Berberis glaucocarpa as Antidiabetic Agents: An In Vitro, In Silico, and In Vivo Approach.

Diabetes, also known as diabetes mellitus (DM), is a metabolic disorder characterized by an abnormal rise in blood sugar (glucose) levels brought on by a complete or partial lack of insulin secretion along with corresponding changes in the metabolism of lipids, proteins, and carbohydrates. It has been reported that medicinal plants play a pivotal role in the treatment of various ailments such as diabetes mellitus, dyslipidemia, and hypertension. The current study involved exploring the acute toxicity and in vivo antidiabetic activity of berberine (WA1), palmatine (WA2), and 8-trichloromethyl dihydroberberine (WA3) previously isolated from Berberis glaucocarpa Stapf using a streptozotocin (STZ)-induced diabetic rat model. Body weight and blood glucose level were assessed on a day interval for 4 weeks. Biochemical parameters, antioxidant enzymes, and oxidative stress markers were also determined. In an acute toxicity profile, the WA1, WA2, and WA3 were determined to be nontoxic up to 500 mg/kg (b.w). After the second and third weeks of treatment (14 and 21 days), the blood glucose levels in the WA1-, WA2-, and WA3-treated groups were significantly lower than those in the diabetic control group (476.81 ± 8.65 mg/dL, n = 8, P < 0.001). On the 21st day, there was a decrease in the blood glucose level and the results obtained were 176.33 ± 4.69, 197.21 ± 4.80, and 161.99 ± 4.75 mg/dL (n = 8, P < 0.001) for WA1, WA2, and WA3 at 12 mg/kg, respectively, as opposed to the diabetic control group (482.87 ± 7.11 mg/dL, n = 8, P < 0.001). Upon comparison with the diabetic group at the end of the study (28 days), a substantial drop in the glucose level of WA3 at 12 mg/kg (110.56 ± 4.11 mg/dL, n = 8, P < 0.001) was observed that was almost near the values of the normal control group. The treated groups (WA1, WA2, and WA3) treated with the samples displayed a significant decline in the levels of HbA1c. Treatment of the samples dramatically lowered the lipid level profile. In groups treated with samples, plasma levels of triglycerides, total cholesterol, and LDL were significantly lowered [F (5, 42) = 100.6, n = 8, P < 0.001]; these levels were also significantly decreased [F (5, 42) = 129.6 and 91.17, n = 8, P < 0.001]. In contrast to the diabetes group, all treated groups had significantly higher HDL levels [F (5, 42) = 15.46, n = 8, P < 0.001]. As a result, hypolipidemic activity was anticipated in the samples. In addition to that, the activity of the antioxidant enzymes superoxide dismutase (SOD) and catalase (CAT) was considerably elevated in the groups treated with the sample compared to the diabetic control group (n = 8, P < 0.001).

Normal triglyceride concentration and the risk of diabetes mellitus type 2 in the general population of China.

Hypertriglyceridemia and its derivatives are independent predictors of diabetes mellitus type 2 (T2DM). However, the relationship between triglyceride concentrations within the normal range and the incidence of T2DM remains to be clarified. This study investigated the potential relationship between variations in plasma triglyceride levels within the normal range and T2DM onset using data from a longitudinal study of health and retirement in China. Between, 2010 and, 2016, we conducted a retrospective cohort study involving 36,441 individuals with normal triglyceride levels. Using a Cox proportional hazards regression model, we examined the connection between normal triglyceride levels and T2DM incidence. We employed this method with smooth curve fitting to investigate potential nonlinear associations. Subgroup analyses were performed based on age, sex, body mass index, smoking and drinking status, hypertension, and family history of diabetes. A significant linear relationship was observed between normal triglyceride levels and the incidence of T2DM. The hazard ratio for T2DM in individuals with normal triglycerides was 1.81 (95% confidence interval: 1.39, 2.36); P<0.001). Kaplan-Meier analysis further demonstrated a prospective association between the higher tertiles of normal triglyceride levels and the development of T2DM (P<0.001). Subgroup analysis revealed a stronger positive correlation between normal triglyceride levels in females and the risk of T2DM. An increase in triglyceride levels within the normal range is related to a continuous increase in the incidence of T2DM in the general population. These findings show that almost everyone can benefit from reducing triglyceride levels, further emphasizing the importance of lifestyle changes in the general population.

Targeting the PDK/PDH axis to reverse metabolic abnormalities by structure-based virtual screening with in vitro and in vivo experiments

In humans and animals, the pyruvate dehydrogenase kinase (PDK) family proteins (PDKs 1–4) are excessively activated in metabolic disorders such as obesity, diabetes, and cancer, inhibiting the activity of pyruvate dehydrogenase (PDH) which plays a crucial role in energy and fatty acid metabolism and impairing its function. Intervention and regulation of PDH activity have become important research approaches for the treatment of various metabolic disorders.In this study, a small molecule (g25) targeting PDKs and activating PDH, was identified through multi-level computational screening methods. In vivo and in vitro experiments have shown that g25 activated the activity of PDH and reduced plasma lactate and triglyceride level. Besides, g25 significantly decreased hepatic fat deposition in a diet-induced obesity mouse model. Furthermore, g25 enhanced the tumor-inhibiting activity of cisplatin when used in combination. Molecular dynamics simulations and in vitro kinase assay also revealed the specificity of g25 towards PDK2.Overall, these findings emphasize the importance of targeting the PDK/PDH axis to regulate PDH enzyme activity in the treatment of metabolic disorders, providing directions for future related research. This study provides a possible lead compound for the PDK/PDH axis related diseases and offers insights into the regulatory mechanisms of this pathway in diseases.

Environmental exposure to lead and cadmium are associated with triglyceride glucose index

The triglyceride glucose (TyG) index was suggested as a novel reliable surrogate marker for insulin resistance and related cardiovascular-metabolic diseases. We aimed to evaluate the association between the TyG index and environmental exposure to lead (Pb), mercury (Hg), and cadmium (Cd). A total of 9645 adults who enrolled in the Korea National Health and Nutrition Examination Survey in 2005, 2008–2013, and 2016 were included. Fasting plasma glucose and triglyceride levels were used to calculate the TyG index. Multivariate logistic regression model was used to estimate odds ratios (ORs) and 95% confidence intervals (CIs). We noted an increasing trend in the TyG index with increment of blood Pb and Cd concentrations. Participants in the highest quartile of blood Pb and Cd concentrations had higher TyG index values than those in the lowest quartile, with ORs (95% CIs) of 1.32 (1.07–1.63) and 1.29 (1.04–1.59) for Pb and Cd, respectively. Strong associations between blood Pb and Cd concentrations and the TyG index were found in men. Blood Hg concentrations did not show a significant association with the TyG index. Our study suggests that public health strategies for cardiovascular-metabolic disorder prevention should be directed toward individuals exposed to priority heavy metals.

Biological sex-related differences in the postprandial triglyceride response to intermittent hypoxaemia in young adults: a randomized crossover trial.

Obstructive sleep apnoea is characterized by chronic intermittent hypoxaemia and is independently associated with an increased risk of metabolic comorbidities (e.g. type II diabetes and ischaemic heart disease). These comorbidities could be attributable to hypoxaemia-induced alterations in blood lipid profiles. However, it remains unclear whether intermittent hypoxaemia alters triglyceridaemia differently between biological sexes. Therefore, we used a randomized crossover design to examine whether 6h of moderate intermittent hypoxaemia (15hypoxaemic cycles/h, 85% oxyhaemoglobin saturation) alters plasma triglyceride levels differently between men and women after a high-fat meal. Relative to men, women displayed lower levels of total triglycerides, in addition to denser triglyceride-rich lipoprotein triglycerides (TRL-TG; mainly very low-density lipoprotein triglycerides and chylomicron remnant triglycerides) and buoyant TRL-TG (mainly chylomicron triglycerides) during normoxia (ambient air) and intermittent hypoxaemia (sex × time: all P ≤ 0.008). Intermittent hypoxaemia led to higher triglyceride levels (condition: all P ≤ 0.016); however, this effect was observed only in men (sex × condition: all P ≤ 0.002). Compared with normoxia, glucose levels were higher in men and lower in women during intermittent hypoxaemia (sex × condition: P<0.001). The different postprandial responses between biological sexes occurred despite similar reductions in mean oxyhaemoglobin saturation and similar elevations in insulin levels, non-esterified fatty acid levels and mean heart rate (sex × condition: all P ≥ 0.185). These results support growing evidence showing that intermittent hypoxaemia impacts men and women differently, and they might help to explain biological sex-related discrepancies in the rate of certain comorbidities associated with intermittent hypoxaemia. KEY POINTS: Intermittent hypoxaemia is a key characteristic of obstructive sleep apnoea and alters lipid metabolism in multiple tissues, resulting in increased circulating triglyceride levels, an important risk factor for cardiometabolic diseases. Circulating triglyceride levels are regulated differently between biological sexes, with women typically displaying much lower fasting and postprandial triglyceride levels than men, partly explaining why women of all ages experience lower mortality rates from cardiometabolic diseases. In this study, healthy young men and women consumed a high-fat meal and were then exposed to 6h of intermittent hypoxaemia or ambient air. We show that postprandial triglyceride levels are significantly lower in women compared with men and that intermittent hypoxaemia leads to higher postprandial triglyceride levels in men only. These results might help us to understand better why women living with obstructive sleep apnoea experience lower rates of cardiometabolic diseases (e.g. type II diabetes and ischaemic heart disease) than men living with obstructive sleep apnoea.

Gastrodin Suppresses the Progression of Atherosclerosis and Vascular Inflammation by Regulating TLR4/NF-κB Pathway.

Elevated levels of plasma triglycerides (TG) and cholesterol have been shown to contribute to the pathogenesis of several cardiovascular risk factors, such as atherosclerosis, a primary cause of mortality. Gastrodin (Gas) is an effective polyphenol extracted from Chinese natural herbal Gastrodiae elata Blume, which has been documented to be effective against atherosclerosis. However, the related mechanisms remain largely unclear. The current investigation elucidated the involvement of Gas in the development of AS generated by a high-fat diet in mice lacking the apolipoprotein E gene (ApoE-/-). The findings of our study indicate that the administration of Gas had a beneficial effect on hyperlipidemia in mice that were given a high-fat diet and lacked the ApoE gene. Specifically, Gas supplementation resulted in a reduction in blood levels of oxidized low-density lipoprotein (ox-LDL), interleukin-6 (IL-6), monocyte chemoattractant protein-1 (MCP-1), and tumor necrosis factor-alpha (TNF-α). Additionally, the administration of Gas resulted in the suppression of lesions in the en face aortas of ApoE KO mice, accompanied by a modest improvement in lipid profiles. The intervention demonstrated the capacity to impede the development of atherosclerotic lesions and promote characteristics associated with plaque stability. The administration of Gas prevented inflammation in the aorta by decreasing the expression of IL-6, TNF-α, and MCP-1. Additionally, Gas had a mitigating effect on TLR4/NF-κB pathway components in the aorta of ApoE-/- mice. Furthermore, it has been shown that Gas has the potential to mitigate the harm caused to human umbilical vein endothelial cells (HUVECs) by ox-LDL, perhaps via inhibiting inflammation through the TLR4/NF-κB pathway. This study shows that Gas may potentially mitigate the development of atherosclerosis via its pleiotropic effects, including improvements in lipid profiles and anti-inflammatory properties.

How to descript a clinical case correctly: For inquiry scientists and demanding doctors

The article presents step by step international CARE guidelines (CAse REport), which regulate the structure of the description of a clinical case and include a checklist of 13 points. This form of presentation of the material does not create any difficulties in understanding, does not require a long period of time to prepare a publication for the author, demonstrating a unique personalized experience and informing the medical community about interesting clinical manifestations, diagnostic or therapeutic approaches within a particular nosology, as well as describing rare or newly reported side effects of drugs or features of their prescription. Below as an example presented a clinical observation of a young man with diabetes mellitus of complex origin, which was diagnosed after the initial diagnosis of type 2 diabetes mellitus, which was later supplemented with recurrent pancreatitis, pancreatic cyst development and alcohol abuse with underlying severe hypertriglyceridemia (up to 67 mmol/l). Given the limited choice of glucose-lowering therapy, inability to prescribe metformin, glucagon-like peptide-1 agonists, infeasibility to use dipeptidyl peptidase 4 inhibitors and gliflozins (history of episodes of balanoposthitis), after a detailed discussion with the patient, a decision was made to prescribe a combination insulin drug – biphasic Lispro (RinLis Mix 25, Geropharm, Russia), which, together with fundamental lifestyle changes, strong alcohol avoidance, and regular medical follow-ups, allowed him to achieve glycemic targets and reduce plasma triglyceride levels, which once again supported the versatility of insulin as hypoglycemic agent, easiness to use and comprehensive glycemic control, if pre-mixed ultra-fast-acting insulin analogue and its protaminized analogue are prescribed. The prescription of insulin premix in this case is also justified in terms of clinical guidelines, as the man led a regular lifestyle, had low physical activity, an HbA1c level greater than 1.5% of the target value, as well as fasting and postprandial hyperglycemia.

Genetic inhibition of angiopoietin-like protein-3, lipids, and cardiometabolic risk.

RNA-based, antibody-based, and genome editing-based therapies are currently under investigation to determine if the inhibition of angiopoietin-like protein-3 (ANGPTL3) could reduce lipoprotein-lipid levels and atherosclerotic cardiovascular disease (ASCVD) risk. Mendelian randomisation (MR) was used to determine whether genetic variations influencing ANGPTL3 liver gene expression, blood levels, and protein structure could causally influence triglyceride and apolipoprotein B (apoB) levels as well as coronary artery disease (CAD), ischaemic stroke (IS), and other cardiometabolic diseases. RNA sequencing of 246 explanted liver samples and genome-wide genotyping was performed to identify single-nucleotide polymorphisms (SNPs) associated with liver expression of ANGPTL3. Genome-wide summary statistics of plasma protein levels of ANGPTL3 from the deCODE study (n = 35 359) were used. A total of 647 carriers of ANGPTL3 protein-truncating variants (PTVs) associated with lower plasma triglyceride levels were identified in the UK Biobank. Two-sample MR using SNPs that influence ANGPTL3 liver expression or ANGPTL3 plasma protein levels as exposure and cardiometabolic diseases as outcomes was performed (CAD, IS, heart failure, non-alcoholic fatty liver disease, acute pancreatitis, and type 2 diabetes). The impact of rare PTVs influencing plasma triglyceride levels on apoB levels and CAD was also investigated in the UK Biobank. In two-sample MR studies, common genetic variants influencing ANGPTL3 hepatic or blood expression levels of ANGPTL3 had a very strong effect on plasma triglyceride levels, a more modest effect on low-density lipoprotein cholesterol, a weaker effect on apoB levels, and no effect on CAD or other cardiometabolic diseases. In the UK Biobank, the carriers of rare ANGPTL3 PTVs providing lifelong reductions in median plasma triglyceride levels [-0.37 (interquartile range 0.41) mmol/L] had slightly lower apoB levels (-0.06 ± 0.32 g/L) and similar CAD event rates compared with non-carriers (10.2% vs. 10.9% in carriers vs. non-carriers, P = .60). PTVs influencing ANGPTL3 protein structure as well as common genetic variants influencing ANGPTL3 hepatic expression and/or blood protein levels exhibit a strong effect on circulating plasma triglyceride levels, a weak effect on circulating apoB levels, and no effect on ASCVD. Near-complete inhibition of ANGPTL3 function in patients with very elevated apoB levels may be required to reduce ASCVD risk.

Alterations in Th17 Cells and Non-Classical Monocytes as a Signature of Subclinical Coronary Artery Atherosclerosis during ART-Treated HIV-1 Infection.

Cardiovascular disease (CVD) remains an important comorbidity in people living with HIV-1 (PLWH) receiving antiretroviral therapy (ART). Our previous studies performed in the Canadian HIV/Aging Cohort Study (CHACS) (>40 years-old; Framingham Risk Score (FRS) > 5%) revealed a 2-3-fold increase in non-calcified coronary artery atherosclerosis (CAA) plaque burden, measured by computed tomography angiography scan (CTAScan) as the total (TPV) and low attenuated plaque volume (LAPV), in ART-treated PLWH (HIV+) versus uninfected controls (HIV-). In an effort to identify novel correlates of subclinical CAA, markers of intestinal damage (sCD14, LBP, FABP2); cell trafficking/inflammation (CCL20, CX3CL1, MIF, CCL25); subsets of Th17-polarized and regulatory (Tregs) CD4+ T-cells, classical/intermediate/non-classical monocytes, and myeloid/plasmacytoid dendritic cells were studied in relationship with HIV and TPV/LAPV status. The TPV detection/values coincided with higher plasma sCD14, FABP2, CCL20, MIF, CX3CL1, and triglyceride levels; lower Th17/Treg ratios; and classical monocyte expansion. Among HIV+, TPV+ versus TPV- exhibited lower Th17 frequencies, reduced Th17/Treg ratios, higher frequencies of non-classical CCR9lowHLADRhigh monocytes, and increased plasma fibrinogen levels. Finally, Th17/Treg ratios and non-classical CCR9lowHLADRhigh monocyte frequencies remained associated with TPV/LAPV after adjusting for FRS and HIV/ART duration in a logistic regression model. These findings point to Th17 paucity and non-classical monocyte abundance as novel immunological correlates of subclinical CAA that may fuel the CVD risk in ART-treated PLWH.

Unlocking the mysteries of VLDL: exploring its production, intracellular trafficking, and metabolism as therapeutic targets

Reducing circulating lipid levels is the centerpiece of strategies for preventing and treating atherosclerotic cardiovascular disease (ASCVD). Despite many available lipid-lowering medications, a substantial residual cardiovascular risk remains. Current clinical guidelines focus on plasma levels of low-density lipoprotein (LDL). Recent attention has been given to very low-density lipoprotein (VLDL), the precursor to LDL, and its role in the development of coronary atherosclerosis. Preclinical investigations have revealed that interventions targeting VLDL production or promoting VLDL metabolism, independent of the LDL receptor, can potentially decrease cholesterol levels and provide therapeutic benefits. Currently, methods, such as mipomersen, lomitapide, and ANGPTL3 inhibitors, are used to reduce plasma cholesterol and triglyceride levels by regulating the lipidation, secretion, and metabolism of VLDL. Targeting VLDL represents an avenue for new lipid-lowering strategies. Interventions aimed at reducing VLDL production or enhancing VLDL metabolism, independent of the LDL receptor, hold promise for lowering cholesterol levels and providing therapeutic benefits beyond LDL in the management of ASCVD.

A novel fully human anti-NT-ANGPTL3 antibody from phage display library exhibits potent ApoB, TG, and LDL-C lowering activities in hyperlipidemia mice.

Dyslipidemia is characterized by elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), triglycerides (TG), and TG-rich lipoprotein (TGRLs) in circulation, and is closely associated with the incidence and development of cardiovascular disease. Angiopoietin-like protein 3 (ANGPTL3) deficiency has been identified as a cause of familial combined hypolipidemia in humans, which allows it to be an important therapeutic target for reducing plasma lipids. Here, we report the discovery and characterization of a novel fully human antibody F1519-D95aA against N-terminal ANGPTL3 (NT-ANGPTL3), which potently inhibits NT-ANGPTL3 with a KD as low as 9.21 nM. In hyperlipidemic mice, F1519-D95aA shows higher apolipoprotein B (ApoB) and TG-lowering, and similar LDL-C reducing activity as compared to positive control Evinacumab (56.50% vs 26.01% decrease in serum ApoB levels, 30.84% vs 25.28% decrease in serum TG levels, 23.32% vs 22.52% decrease in serum LDLC levels, relative to vehicle group). Molecular docking and binding energy calculations reveal that the F1519-D95aA-ANGPTL3 complex (10 hydrogen bonds, -65.51 kcal/mol) is more stable than the Evinacumab-ANGPTL3 complex (4 hydrogen bonds, -63.76 kcal/mol). Importantly, F1519-D95aA binds to ANGPTL3 with different residues in ANGPTL3 from Evinacumab, suggesting that F1519-D95aA may be useful for the treatment of patients resistant to Evinacumab. In conclusion, F1519-D95aA is a novel fully human anti-NT-ANGPTL3 antibody with potent plasma ApoB, TG, and LDL-C lowering activities, which can potentially serve as a therapeutic agent for hyperlipidemia and relevant cardiovascular diseases.

The protective role of virgin olive oil and vitamin E on mercury-induced hepatic, renal, testicular and adrenal toxicity in the rabbit (Oryctolagus cuniculus)

This study aimed to strengthen the antioxidant defenses against the toxic effect of mercury, by administering a synthetic antioxidant (vitamin E) and a natural product rich in antioxidant compounds (virgin olive oil) to rabbits. Hepatic and renal biomarker levels, cortisol and testosterone synthesis, mercury concentration, relative weight of organs, and tissue architecture were studied. The results showed a significant decrease in the plasma alkaline phosphatase (ALP), plasma aspartate aminotransferase (AST), serum alanine aminotransferase (ALT), plasma testosterone levels, and relative weight of the liver, testes, and adrenal in the mercury treated group (group M), while the other indices were significantly increased in the m-group compared to the control (group C). However, the group treated with olive oil combined with mercury (group O) showed a significant decrease in the ALP, AST, ALT, testosterone levels, and adrenal relative weight, while plasma creatinine, uric acid levels, mercury concentration in organs, and the kidney relative weight were significantly increased. Vitamin E supplementation (group E) led to a significant decrease in the ALP, testosterone levels, and adrenal relative weight, a significant increase was observed in plasma levels of triglycerides, creatinine, and uric acid. Histological sections of the liver, kidney, testis, and adrenal of group M showed severe tissue damage, while the other groups showed less important tissue alterations demonstrating that supplementation with natural or synthetic antioxidants can protect against the toxicity of heavy metals such as mercury, improving the health of rabbits.

Plasma cholesterol and triglyceride levels in black-necked pheasants, gray and chukar partridges with cannibalism treated with silymarin and tryptophan

Plasma cholesterol and triglyceride levels were studied in black-necked pheasants, gray partridges and chukar partridges divided into 4 groups (n=12 in each group; n=6 by sex): first group (negative control) – clinically healthy birds, second group – birds treated with tryptophan, third group – birds treated with sylimarin, fourth group (positive control) – birds with signs of cannibalism. In the pheasants and chukars with signs of cannibalism, cholesterol levels were higher than these in the control group. On the opposite, the triglyceride levels in the other three groups of birds with canniba­lism were substantially lower than those in the healthy group. Supplementation with tryptophan tended to increase blood cholesterol and triglycerides in pheasants, gray and chukar partridges. In the groups treated with silymarin, the levels of the studied indicators were significantly higher in comparison to birds with cannibalism.

Pancreatitis as a Main Consequence of APOC2-Related Hypertriglyceridemia: The Role of Nonsense and Frameshift Variants.

APOC2-related hypertriglyceridemia occurs due to biallelic variants of this gene. Here, genotype-phenotype architecture of all pathogenic APOC2 variants is investigated among heterozygous and homozygous individuals. Clinical heterogeneity of various types of the variants is also described, and pancreatitis in more than half of homozygotes carrying chain-termination variants is highlighted as well. For this study, patients were selected who had a plasma triglyceride level above 250 mg/dL. The coding and intronic regions of the APOC2 gene were amplified using the Sanger sequencing to investigate the presence of variants. The genotypes, lipid profiles, and detailed clinical features were documented for all APOC2-related patients and heterozygous individuals. Pathogenicity of the variants was predicted and categorized using available bioinformatics tools such as MutationTaster and PolyPhen-2 and ACMG criteria. MetaDome and Phyre2 were applied for structural and functional in silico analyses. 40% (12 out of 30) of APOC2 variants were chain-termination (nonsense and frameshift) variants. These types of variants were determined in 60.53% of patients. 55% of these patients showed pancreatitis followed by lipemia retinalis (29%), abdominal pain (24%), hepatosplenomegaly (24%), and xanthomas (18%). The mean age of onset was about 22 years old. In at least 50% of 38 homozygous individuals, the TG level was more than 2000 mg/dL. More than 25% of heterozygous individuals showed at least one symptom. Pancreatitis and a severe form of HTG were found in 5 and 2% of heterozygous individuals, respectively. The main clinical features of APOC2-related hypertriglyceridemia include pancreatitis, lipemia retinalis, abdominal pain, hepatosplenomegaly, and xanthomas. Nonsense and frameshift homozygous variants usually lead to a severe form of hypertriglyceridemia. Pancreatitis is one of the main consequences of these types of mutations; thus, it is important to consider this point when evaluating asymptomatic individuals. Heterozygous individuals may become symptomatic due to the role of unknown modifying agent including environmental genetic factors.

Simultaneous quantitative LC-MS/MS analysis of 13 apolipoproteins and lipoprotein (a) in human plasma.

Numerous studies have revealed a close correlation between the levels of apolipoproteins (Apos) (including lipoprotein(a) [Lp(a)]) and an increased risk of cardiovascular disease in recent decades. However, clinically, lipid profiling remains limited to the conventional plasma levels of cholesterol, triglyceride, ApoA1, and ApoB, which brings the necessity to quantify more apolipoproteins in human plasma. In this study, we simultaneously quantified 13 apolipoproteins and Lp(a) in 5 μL of human plasma using the LC-MS/MS platform. A method was developed for the precise detection of Lp(a), ApoA1, A2, A5, B, C1, C2, C3, D, E, H, L1, M, and J. Suitable peptides were selected and optimized to achieve clear separation of each peak. Method validation consisting of linearity, sensitivity, accuracy and precision, recovery, and matrix effects was evaluated. The intra-day CV ranged from 0.58% to 14.2% and the inter-day CV ranged from 0.51% to 13.3%. The recovery rates ranged from 89.8% to 113.7%, while matrix effects ranged from 85.4% to 113.9% for all apolipoproteins and Lp(a). Stability tests demonstrated that these apolipoproteins remained stable for 3 days at 4 °C and 7 days at -20 °C. This validated method was successfully applied to human plasma samples obtained from 45 volunteers. The quantitative results of ApoA1, ApoB, and Lp(a) exhibited a close correlation with the results from the immunity transmission turbidity assay. Collectively, we developed a robust assay that can be used for high-throughput quantification of apolipoproteins and Lp(a) simultaneously for investigating related risk factors in patients with dyslipidemia.

Evaluation of the anti-obesity effect of Sambucus nigra L. (elderberry) and Vitex agnus-castus L. (chasteberry) extracts in high-fat diet-induced obese rats.

The aim of this study was to investigate the effects of S. nigra L. and V. agnus-castus L. plants on obesity in vivo. Extracts were prepared from S. nigra leaves, flowers, fruits and from V. agnus-castus leaves, flowers, and fruits using 100% water and 70% ethanol. The total phenol and flavonoid contents of the extracts were quantified spectrophotometrically. The findings revealed that the ethanol extracts of V. agnus-castus and S. nigra flowers had the highest phenolic content, while the ethanol extracts of S. nigra flowers and V. agnus-castus leaves had the highest flavonoid content. Qualification and quantification of the phenolic contents of the extracts were carried out using liquid chromatography-high resolution mass spectrometry (LC-HRMS) analyses. The study investigated the effects of various extracts on plasma levels of leptin, insulin, triiodothyronine (T3), thyroxine (T4), triglycerides, high-density lipoprotein (HDL), low-density lipoprotein (LDL) and lipase enzyme in obesity-induced rats. The results showed that the ethanol extract of V. agnus-castus flowers, as well as the ethanol and water extracts of V. agnus-castus leaves, resulted in body weight reduction in rats with obesity. Additionally, these extracts were found to decrease serum levels of LDL, triglycerides, leptin, lipase, TNF-α, and IL-1β while increasing levels of HDL and adiponectin. The LC-HRMS results demonstrated that all three extracts exhibited relatively high concentrations of luteolin-7-glycoside and kaempferol, in comparison to the other extracts. The ethanol extract of V. agnus-castus flowers contained 653.04mg/100g of luteolin-7-glycoside and 62.63mg/100g of kaempferol. The ethanol extract of V. agnus-castus leaves contained 1,720.26mg/100g of luteolin-7-glycoside and 95.85mg/100g of kaempferol. The water extract of V. agnus-castus leaves contained 690.49mg/100g of luteolin-7-glycoside and 194.41mg/100g of kaempferol. The study suggests that the ethanol extract of V. agnus-castus flowers and leaves, as well as the water extract of V. agnus-castus leaves, may have potential benefits in treating obesity. However, further controlled clinical studies are necessary to evaluate the clinical efficacy of V. agnus-castus in treating obesity and investigate the in vivo anti-obesogenic effects of luteolin-7-glycoside and kaempferol separately, both in their pure form and in combination.