Higher Plasma Triglyceride Levels Research Articles

Lipidomics of triglyceride-rich lipoproteins derived from hyperlipidemic patients on inflammation.

Triglyceride-rich lipoproteins (TRLs) can have an important role in atherosclerosis development due to their size and ability to penetrate the endothelium. While high plasma triglyceride (TG) levels and chronic inflammation are relevant in metabolic diseases, it remains unclear whether TGs are atherogenic or which TRL-TG-derived metabolites are responsible for inflammation. Here, we aimed to study the lipidome modifications of TRL particles enriched in TG in patients with hyperlipidemia and their associations with a proinflammatory status both invivo and invitro. Using proton nuclear magnetic resonance (1 H-NMR), we analysed the plasma levels of glycoprotein acetyls and the TRL lipidomic profile of 307 patients with dyslipidemia. THP-1-derived macrophages were used as an invitro model to explore the molecular inflammatory effects mediated by TRL. In vivo, higher TRL-TG levels were associated with higher circulating levels of NMR-measured glycoproteins (Glyc-A, Glyc-B and Glyc-F; p < .001). Lipidomic analysis showed that TRL-TG enrichment led to decreased cholesterol and phospholipid content (p < .01), an increase in omega-9, and a decrease in saturated fatty acids (p < .001). THP-1 macrophages exposed to increasing TRL particle concentrations augmented the secretion of IL-1β and TNF-α, which varied based on particle composition. Particles with higher cholesterol and phospholipid contents exerted higher cytokine secretion. The activation of MAPK, Akt/NFκB, and caspase-1 was concurrent with this proinflammatory response. High TRL-TG levels are associated with a higher systemic inflammatory status and increased particle concentrations. Invitro, higher particle numbers increase proinflammatory cytokine secretion, with cholesterol and phospholipid-rich TRL being more proinflammatory.

Abstract 118: Positive Adipose Liver Crosstalk Protects Adipose MTP Knockout Mice from Hepatic Steatosis on an Obesogenic Diet

Introduction: Our previous study demonstrated that adipocyte MTP regulates intracellular lipolysis by inhibiting ATGL activity. Adipose-specific MTP knockout mice (A- Mttp -/- ) had smaller adipocytes and showed increased thermogenesis and gained less weight on an obesogenic diet. They also exhibited moderately high plasma triglyceride levels and less hepatic steatosis compared to wild-type counterparts. In this study, we have elucidated the mechanism behind less hepatic lipid accumulation and moderately high plasma TG in A- Mttp -/- mice. Methods: We characterized lipoproteins and studied hepatic ApoB production. We have analyzed adipose-liver crosstalk using two strategies 1) lipidomics of adipose tissue, plasma, and liver. 2) adipokine profiling. Further, we have used western blotting and qRT-PCR to check signaling and gene expression. Results: Plasma lipid profiling revealed increased TG content in the VLDL and LDL fraction of A- Mttp -/- mice compared to Mttp f/f mice. Additionally, A- Mttp -/- mice showed significantly increased hepatic triglyceride production compared to the wild type. Lipidomic analysis revealed the movement of fatty acids from adipose tissue to the liver, resulting in significantly higher amounts of oleate, palmitate, linoleate, and stearate in the liver of A- Mttp -/- mice compared to Mttp f/f mice. A- Mttp -/- mice liver also showed significantly increased expression of genes involved in fatty acid uptake and utilization such as Cd36 , Mcad , Fatp2 , and Cpt1a compared to Mttp f/f mice. Further adipokine profiling showed a significantly higher amount of adiponectin and decreased amount of proinflammatory cytokines such as leptin in the plasma of A- Mttp -/- mice compared to Mttp f/f mice. We also found decreased ceramide levels and significantly increased phosphorylation of AMPK in the liver of A- Mttp -/- mice compared to Mttp f/f mice. Conclusion: We conclude that increased availability of substrate for TG production might contribute to increased ApoB secretion by the liver of A- Mttp -/- mice. In addition, positive cytokine profile and increased adiponectin signaling in the liver of A- Mttp -/- mice protects it from hepatic steatosis.

Effects of the Ketogenic Diet on Metabolic Syndrome

The global prevalence of obesity and metabolic syndrome and its pathophysiologic sequela are currently approaching epidemic proportions, with unacceptable levels in much of Westernized and economically developed society. The clinical stigmata of metabolic syndrome typically include the comorbidities of obesity, hypertension, non-insulin dependent diabetes, and hyperlipidemia with decreased plasma high density lipoprotein concentrations. In addition, a common finding of hyperinsulinemia and insulin resistance typical of high carbohydrate diets often accompanies the syndrome. The incorporation of the insulin sparing ketogenic diet as a dietary strategy for the treatment of metabolic syndrome may bring about improvements in insulin action and substrate utilization in peripheral tissues with at least a partial if not significant resolution of the syndrome. Thus, the ketogenic diet in addition to adaptations toward a healthy lifestyle and pharmacologic therapies have been explored as potential mechanisms to resolve the pathophysiologic sequela of obesity and metabolic syndrome and their impact on the delivery of healthcare. Metabolic syndrome (MetS) is a condition defined as a clustering of risk factors that is strongly associated with obesity, heart disease, and diabetes [22]. It has recently been estimated that the global prevalence of MetS has reached epidemic levels including the U.S.A., where it has been estimated that 20% to 25% of the adult global population meets the diagnostic criterion for MetS [3], which may be established when at least three of the five primary risk factors are present. The risk factors include a large waistline (abdominal or visceral obesity), high plasma triglyceride levels, low plasma HDL cholesterol concentrations, elevated blood pressure, and fasting hyperglycemia. The standard and most effective treatments for MetS to date have been incorporation of lifestyle changes, with dietary interventions being one of the major effective lifestyle modifications utilized to treat both obesity and MetS [14];[41]. The Ketogenic Diet (KD) is one dietary intervention that may have the potential to improve MetS risk factors. Historically, one of the primary uses of the KD has been to treat epilepsy, however, there is substantial evidence that it may also help to improve other conditions and illnesses, including obesity and MetS [30]; [48]; [35]. Despite this potential, certain dietary misconceptions may have prevented or slowed further research on the KD applications to weight control and use of the KD, particularly the emergence of the national dietary guidelines that have now promoted a low-fat, high-carbohydrate diet for several decades [18]; [51]; [52]. The purpose of this paper is to conduct a review of the literature regarding MetS, the KD, and the implications of the KD as a treatment for obesity and MetS. Existing research is systematically reviewed regarding the KD’s potential to address MetS and MetS risk factors. The results of the review indicate the validity of the diet and the need for further research on the KD and its potential to address the benefits, potential risks and clinical efficacy of the KD on reducing the pathophysiologic sequalae of obesity and MetS. MetS = Metabolic Syndrome, KD = ketogenic diet, KB = ketone bodies, including metabolic remnants acetoacetate (AcAc),3-beta-hydroxybutyrate (3HB), and acetone, PSMF = Protein Sparing Modified Fast, HDL, HDL-C= plasma high density cholesterol lipoprotein, LDL, LDL-C = low density cholesterol lipoprotein, TG, TRIG = plasma triglycerides, CRP = C-reactive protein, GLUT4 = Glucose Transporter 4, and insulin-linked cellular entity, ATP = Adenosine tri-phosphate, a high energy phosphate, CCK = cholecystokinin, CR = calorie restricted diet, LFD = low fat diet, LCKD = low calorie ketogenic diet, BP = blood pressure; SBP = systolic blood pressure; DBP = diastolic blood pressure, A(1c) = glycosylated hemoglobin fraction, NHLBI = National Heart, Lung and Blood Institute of the National Institutes of Health

Role of nuclear pregnane X receptor in Cu-induced lipid metabolism and xenobiotic responses in largemouth bass (Micropterus salmoides).

The pregnane X receptor (PXR) is a master xenobiotic-sensing receptor in response to toxic byproducts, as well as a key regulator in intermediary lipid metabolism. Therefore, the present study was conducted to investigate the potential role of PXR in mediating the lipid dysregulation and xenobiotic responses under Cu-induced stress in largemouth bass (Micropterus salmoides). Four groups of largemouth bass (52.66 ± 0.03 g) were treated with control, Cu waterborne (9.44 μmol/L), Cu+RIF (Rifampicin, 100 mg/kg, PXR activator), and Cu+KET (Ketoconazole, 20 mg/kg, PXR inhibitor) for 48 h. Results showed that Cu exposure significantly elevated the plasma stress indicators and triggered antioxidant systems to counteract Cu-induced oxidative stress. Acute Cu exposure caused liver steatosis, as indicated by the significantly higher levels of plasma triglycerides (TG), lipid droplets, and mRNA levels of lipogenesis genes in the liver. Liver injuries were detected, as shown by hepatocyte vacuolization and severe apoptotic signals after Cu exposure. Importantly, Cu exposure significantly stimulated mRNA levels of PXR, suggesting the response of this regulator in the xenobiotic response. The pharmacological intervention of PXR by the agonist and antagonist significantly altered hepatic mRNA levels of PXR, implying that RIF and KET were effective agents of PXR in largemouth bass. Administration of RIF significantly exacerbated liver steatosis, and such alterations were dependent on the regulations on pparγ and cd36 rather than srebp1 signaling, which suggested that PXR-PPARγ might be another pathway for Cu-induced lipid deposition in fish. Whereas, KET administration showed reverse effects on lipid metabolism as indicated by the lower hepatic TG levels, suppressed mRNA levels of pparγ and cd36. Activation of PXR stimulated autophagy and inhibited apoptosis, leading to lower hepatic vacuolization; while inhibition of PXR showed higher apoptotic signals, inhibition of autophagic genes and stimulation of apoptotic genes. Taken together, PXR played a cytoprotective role in Cu-induced hepatotoxicity through regulations on autophagy and apoptosis. Overall, our data has demonstrated for the first time on the dual roles of PXR as a co-regulator in mediating xenobiotic responses and lipid metabolism in fish, which implying the potential of PXR as a therapy target for xenobiotics-induced lipid dysregulation and hepatotoxicity.

IDF21-0315 Gestational Hypertriglyceridemia and Adverse Pregnancy Outcomes: A Search for Cutoffs Using Generalized Additive Models

Background: During pregnancy, there are metabolic adaptations for maternal physiological demands as well as for the growth of the fetus, including the change of lipid metabolism. Plasma triglycerides (TG) increase gradually in response to hormone changes and reach the highest level before delivery. Glycerol and free fatty acid from TG can be transported across placenta to fetal circulation, where they can be used as an energy source or substrates for fat formation by the fetus. Despite these physiological roles, however, high levels of plasma TG have been reported to have an association with several adverse pregnancy outcomes, such as gestational diabetes mellitus (GDM) and large for gestational age (LGA).

Hypertriglyceridemia: A Neglected Risk Factor for Ischemic Stroke?

Hypertriglyceridemia is caused by defects in triglyceride metabolism and generally manifests as abnormally high plasma triglyceride levels. Although the role of hypertriglyceridemia may not draw as much attention as that of plasma cholesterol in stroke, plasma triglycerides, especially nonfasting triglycerides, are thought to be correlated with the risk of ischemic stroke. Hypertriglyceridemia may increase the risk of ischemic stroke by promoting atherosclerosis and thrombosis and increasing blood viscosity. Moreover, hypertriglyceridemia may have some protective effects in patients who have already suffered a stroke via unclear mechanisms. Therefore, further studies are needed to elucidate the role of hypertriglyceridemia in the development and prognosis of ischemic stroke.

Triglyceride-Rich Lipoproteins and Glycoprotein A and B Assessed by 1H-NMR in Metabolic-Associated Fatty Liver Disease.

High plasma triglyceride (TG) levels and chronic inflammation are important factors related to metabolic-associated fatty liver disease in patients at cardiovascular risk. Using nuclear magnetic resonance (1H-NMR), we aimed to study the triglyceride-rich lipoprotein (TRL) and acute-phase glycoprotein profiles of a cohort of patients with metabolic disease and their relationship with fatty liver. Plasma samples of 280 patients (type 2 diabetes, 81.1%; obesity, 63.3%; and metabolic syndrome, 91.8%) from the University Hospital Lipid Unit were collected for the measurement of small, medium and large TRL particle numbers and sizes and glycoprotein profiles (Glyc-A and Glyc-B) by 1H-NMR. Liver function parameters, including the fatty liver index (FLI) and fibrosis-4 (FIB-4) score, were assessed. Hepatic echography assessment was performed in 100 patients, and they were followed up for 10 years. TRL particle concentrations showed a strong positive association with Glyc-A and Glyc-B (ρ=0.895 and ρ=0.654, p<0.001, respectively) and with the liver function-related proteins ALT ρ=0.293, p<0.001), AST (ρ=0.318, p<0.001) and GGT (ρ=0.284, p<0.001). Likewise, TRL concentrations showed a positive association with FLI (ρ=0.425, p<0.001) but not with FIB-4. During the follow-up period of 10 years, 18 new cases of steatosis were observed among 64 patients who were disease-free at baseline. Baseline TRL particle numbers and glycoprotein levels were associated with the new development of metabolic-associated fatty liver disease (MAFLD) (AUC=0.692, p=0.018 and AUC=0.669, p=0.037, respectively). Overall, our results indicated that TRL number and acute-phase glycoproteins measured by 1H-NMR could be potential biomarkers of the development of hepatic steatosis in patients at metabolic risk.

Effects of lighting patterns in pubertal development and metabolism of female wistar rats

Modern lifestyle is characterized by constant exposure to artificial light, which is associated with alterations in biological rhythms, abnormalities to reproductive cycles and metabolic changes. In this study, we aimed to evaluate the effects of four different lighting patterns on puberty timing and on possible metabolic changes in female Wistar rats. Additionally, we developed a machine learning algorithm to automatically classify the stages of the estrous cycle. Adult Wistar rats mated during a week at a photoperiod station where they were exposed to combined red-green-blue lights (RGB) during the photoperiod that varied its spectral composition (i.e., variable color temperature) during the day (RGB-v; N = 14), RGB during the photoperiod with a fixed light color temperature (RGB-f; N = 13) during the whole photoperiod; constant darkness (DD; N = 13) and constant fixed light (LL; N = 15). Experiments were performed only on female litters from postnatal day (PND) 22 to 50. Body weight, puberty onset, estrous cyclicity and serum metabolic parameters were measured. We also collected pictures of vaginal smears to create a dataset of 15,936 images to construct an automatic classifier based on convolutional neural networks. No significant differences were found in the age of vaginal opening; however, the RGB-v group showed a significantly lower number of complete and consecutives cycles. Also, the RGB-f group showed the first complete estrous cycle significantly earlier than the RGB-v group. Female rats housed in LL condition presented significantly lower mean body weight from PND 33 to PDN 47 compared to the other groups. Furthermore, higher levels of plasma triglycerides were found in the DD group compared to RGB-f and RGB-v. HDL levels were significantly lower in RGB-v compared to RGB-f and LL groups. Total cholesterol was significantly lower in RGB-v compared to all groups. Visceral fat was significantly higher in RGB-f compared to the LL group. These results suggest that both changes in photoperiod and lighting quality affect pubertal development and alter lipid profiles and visceral fat accumulation.

“PlasmaTriglyceridelevelsIncreasetheRiskforRecurrentCardiovascularDiseaseIndependentofHigh-DensityLipoproteinCholesterolLevel”

Background: Plasma triglyceride (TG) levels are known to confer an increased risk of vascular disease in healthy populations, but data in high-risk patients are scarce. In this study we evaluated the risk on recurrent vascular events conferred by increased plasma TG levels in patients with various clinical manifestations of vascular disease. Objective: To assess the Plasma triglyceride levels increase the risk for recurrent Cardiovascular Disease Independent of High-Density Lipoprotein Cholesterol Level. Methods: This study was done in the Department of Cardiology, Community Based Medical College & Hospital, Bangladesh during July 2017 to June 2020. A Meta-analysis of Population Based prospective Studies of 5731 patients with clinically manifest vascular disease. Results: First new vascular events (myocardial infarction, ischemic stroke, vascular death) occurred in 782 subjects during a median follow-up of 4.9 years (interquartile range 2.5–8.1 years). Patients in the highest plasma TG quintile (> 2.24 mmol/L) had a higher risk for recurrent vascular events (HR 1.45; 95%CI 1.13–1.86) compared with the lowest plasma TG quintile (b0.97 mmol/L) after adjustments for age, gender, body mass index, smoking, lipid-lowering medication and low-density lipoprotein-cholesterol. The increased risk associated with increasing plasma TG levels was irrespective of the presence of type 2 diabetes (T2DM), but only present in patients without the metabolic syndrome. Furthermore, the increased risk was particular-ly present in patients with coronary artery disease (CAD) (HR 1.45; 95%CI 1.02–2.08) and was not modified by other lipid levels (p-value for interaction >0.05). Plasma TG still contributed to vascular risk when other lipid levels were at target level. Conclusions: Higher plasma TG levels are associated with increased risk for recurrent vascular events, in par-ticular in CAD patients. This increased risk is independent of the presence of T2DM and the use of lipid-lowering medication and is not modified by other lipid levels.

Characterization of triglyceride rich lipoproteins and glycoproteins assessed by 1H-NMR in metabolic patients and its association with liver steatosis

Background and Aims: High plasma triglyceride (TG) levels and chronic inflammation are important factors related to hepatic damage in patients at cardiovascular risk. Using 1H-NMR, we aimed to characterize the triglyceride rich lipoproteins (TRL) and glycoprotein profiles in a cohort of dyslipidemic patients and study its relation with hepatic damage.

Correlation of HbA1c levels with Triglyceride, LDL and HDL levels in Type 2 Diabetes Mellitus Patients

Diabetes mellitus (DM) is a group of metabolic diseases with characteristics of increased blood glucose levels that occur due to abnormal insulin secretion, insulin action or both. It is necessary to monitor long-term glycemic status by measuring HbA1c levels to determine the quality of long-term blood glucose control. People with Type 2 DM are more at risk of suffering from cardiovascular disease characterized by dyslipidemia, with a characteristic description of high plasma triglyceride levels, elevated LDL levels and decreased HDL levels. The purpose of this study was to determine the relationship between HbA1c levels and levels of triglycerides, LDL and HDL. This study was an analytic observational study using a cross-sectional design. Data on each variable is secondary data obtained from patients with Type 2 DM at Jakarta Friendship Hospital for the period January-December 2018. The research sample used was 97 data of Type 2 DM patients. Chi-Square test showed an association between HbA1c levels and triglyceride levels with a value of p = 0.046 (&lt; 0.05), there was a relationship between HbA1c levels and LDL levels with p = 0.742 (p &gt; 0.05), and there was a relationship between HbA1c levels and HDL levels with p = 0.241 (p &gt; 0.05). The conclusion obtained in this study is that there is a significant relationship between HbA1c levels and triglyceride levels and there was no significant relationship between HbA1c levels and LDL and HDL levels.

Female Songbirds Can Initiate the Transition from a Migratory to a Reproductive Physiology during Spring Migration.

AbstractThe high energetic costs of both migration and reproduction and the physiological changes to support these costs suggest that these life-history stages should be compartmentalized with little overlap between stages. In contrast, previous studies have shown that male birds can initiate reproductive development during migration before arrival on the breeding grounds with increases in plasma testosterone levels and testis size. However, sex differences in seasonal gonadal function are now recognized as profound, and few studies to date have shown that females can initiate the costly, but critical, estrogen-dependent final stages of gonadal maturation and changes in liver function (yolk precursor synthesis, vitellogenesis) while on migration. Here, we show that female yellow warblers (Setophaga petechia) arrive on the breeding grounds with elevated plasma triglyceride levels compared with males. Some females had plasma triglyceride levels of 5-7 mmol L-1, suggesting that they arrived in a relatively advanced stage of yolk precursor production. Furthermore, we show that females that arrived with higher plasma triglyceride levels took less time to initiate their first clutch. Adaptive plasticity in the timing of the transition from a migratory to a reproductive physiology might help migrant birds buffer against a mismatch between timing of arrival and conditions on the breeding grounds and allow them to advance timing of breeding to maximize breeding productivity.

Angiopoietin-like 3 inhibition of endothelial lipase is not modulated by angiopoietin-like 8

High plasma triglyceride (TG) levels and low HDL-C levels are risk factors for atherosclerosis and cardiovascular disease. Both plasma TG and HDL-C levels are regulated in part by the circulating inhibitor, angiopoietin-like 3 (ANGPTL3). ANGPTL3 inhibits the phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL, thus decreasing plasma HDL levels. ANGPTL3 also inhibits LPL, the lipase primarily responsible for the clearance of TGs from the circulation. Previous studies have shown that ANGPTL3 requires complex formation with the related ANGPTL protein, angiopoietin-like 8 (ANGPTL8), to efficiently inhibit LPL, but the role of ANGPTL8 in EL inhibition is not known. In this study, we characterized inhibition and binding of EL by ANGPTL3 and investigated the role of ANGPTL8 in EL inhibition. We found that inhibition of EL by ANGPTL3 was dose dependent and temperature dependent. Interestingly, this inhibition was diminished when EL was bound to endothelial cells or in the presence of heparin. Unlike previous findings with LPL, we found that ANGPTL8 did not significantly alter the binding or the inhibition of EL by ANGPTL3. In addition, we found that a common ANGPTL8 variant, which encodes an R59W mutation, altered the ability of ANGPTL3 to bind and inhibit LPL but not EL. Together, our data indicate that ANGPTL8 is not necessary for EL inhibition. We conclude that ANGPTL8 is specific for the regulation of TG-rich lipoproteins through the LPL pathway and that therapeutically targeting ANGPTL8 for the treatment of hypertriglyceridemia or cardiovascular disease may have different outcomes than targeting ANGPTL3.

High-fat diet-associated cognitive decline: Is zinc finger protein 1 (ZPR1) the molecular connection?

Zinc finger protein 1 (ZPR1) is required for cellular replication and viability. Recently, ZPR1 variant rs964184 has been repeatedly linked to high plasma triglyceride levels, metabolic syndrome, type 2 diabetes mellitus (T2DM), and nonalcoholic fatty liver disease (NAFLD), suggesting its involvement in lipid metabolism. This article attempts to explain how ZPR1 contributes to the mechanism of high-fat diet-associated cognitive decline through three premises: i) high-fat diet results in cognitive decline, ii) ZPR1 deficiency also results in cognitive decline, and iii) high-fat diet results in ZPR1 deficiency. Therefore, ZPR1 has the potential to be the connection between high-fat diet and cognitive decline. The two modalities of cognitive decline caused by low concentrations of ZPR1 are reduced brain-derived growth factor (BDNF) synthesis and neuron death, both occurring in the hippocampus. Downregulation of ZPR1 may lead to decreased synthesis of BDNF due to reduced concentrations of peroxisome proliferator-activated receptor-gamma (PPAR-γ), tropomyosin receptor kinase B (Trk B), and cAMP response element-binding protein (CREB), resulting in reduced ability to form and retain long-term memory as well as reduced neuroplasticity. Likewise, low concentrations of ZPR1 facilitate neuron death by producing lower amount of spinal motor neuron (SMN) protein, causing genomic instability, activating mixed-lineage protein kinase 3 (MLK3), mitogen-activated protein kinase 7 (MKK7), and c-Jun N-terminal kinase 3 (JNK3) signal cascade, and ultimately resulting in the activation of Caspase 3.

Increased Diurnal Salivary Cortisol and Morning Serum Triglycerides and Decreased Apo A1 Concentrations in Children and Adolescents with Clinical Depression

Data available on possible associations of lipids, steroid levels, and depression are conflicting. This study investigated their possible associations in a sample of youth with depression. Ninety-eight youth with depression and individually matched healthy volunteers on the basis of age and sex were enrolled for the study. The two groups had nearly similar body mass index. After fasting overnight, they underwent blood sampling for triglycerides (TG), total cholesterol, low-density lipoprotein, high-density lipoprotein (HDL)-cholesterol, apolipoprotein A1 (apo A1) and B (apo B), lipoprotein A (LpA), morning cortisol, total testosterone (TT), estradiol (E2), and DHEAS measurements. All participants were evaluated with the semi-structured psychiatric K-SADS-PL interview and filled out the self-rating Children’s Depression Inventory (CDI). Salivary cortisol was also determined serially five times a day. Children with depression showed significantly higher levels of plasma TG (p = 0.006), lower apolipoprotein A1 (p = 0.043), higher morning cortisol (p = 0.011) and TT (p = 0.001), as well as lower E2 levels (p = 0.032) compared to those of controls. Positive correlations for the total sample was observed between TG (R = 0.24, p = 0.018), TT (R = 0.35, p

Non- high-density lipoprotein cholesterol and cardiovascular disease in patients with diabetic dyslipidaemia

Elevated levels of blood lipids are one of the major risk factors for cardiovascular (CV) disease in patients with type 2 diabetes mellitus. Diabetic dyslipidaemia is characterised by the presence of potentially atherogenic lipids, including high levels of plasma triglycerides (TGs), mild-to-moderately elevated levels of low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C). Statin therapy to reduce LDL-C levels is the mainstay of treatment practice to reduce CV risk. However, despite achieving targets for LDL-C, patients with diabetic dyslipidaemia remain at a high risk of residual CV events. Hence there is a need to target other components (i.e. elevated TGs) of the atherogenic dyslipidaemia that are not affected by treatment with statins. This review highlights the clinical benefits of using non-HDL-C, a single marker that includes all atherogenic lipoproteins, as a leading treatment target to reduce the residual CV risk.

Triglycerides and remnant cholesterol associated with risk of aortic valve stenosis: Mendelian randomization in the Copenhagen General Population Study.

We tested the hypothesis that higher levels of plasma triglycerides and remnant cholesterol are observationally and genetically associated with increased risk of aortic valve stenosis. We included 108 559 individuals from the Copenhagen General Population Study. Plasma triglycerides, remnant cholesterol (total cholesterol minus low-density lipoprotein and high-density lipoprotein cholesterol), and 16 genetic variants causing such increased or decreased levels were determined. Incident aortic valve stenosis occurred in 1593 individuals. Observationally compared to individuals with triglycerides <1 mmol/L (<89 mg/dL), the multifactorially adjusted hazard ratio for aortic valve stenosis was 1.02 [95% confidence interval (CI) 0.87-1.19] for individuals with triglycerides of 1.0-1.9 mmol/L (89-176 mg/dL), 1.22 (1.02-1.46) for 2.0-2.9 mmol/L (177-265 mg/dL), 1.40 (1.11-1.77) for 3.0-3.9 mmol/L (266-353 mg/dL), 1.29 (0.88-1.90) for 4.0-4.9 mmol/L (354-442 mg/dL), and 1.52 (1.02-2.27) for individuals with triglycerides ≥5 mmol/L (≥443 mg/dL). By age 85, the cumulative incidence of aortic valve stenosis was 5.1% for individuals with plasma triglycerides <2.0 mmol/L (77 mg/dL), 6.5% at 2.0-4.9 mmol/L (177-442 mg/dL), and 8.2% for individuals with plasma triglycerides ≥5.0 mmol/L (443 mg/dL). The corresponding values for remnant cholesterol categories were 4.8% for <0.5 mmol/L (19 mg/dL), 5.6% for 0.5-1.4 mmol/L (19-57 mg/dL), and 7.4% for ≥1.5 mmol/L (58 mg/dL). Genetically, compared to individuals with allele score 13-16, odds ratios for aortic valve stenosis were 1.30 (95% CI 1.20-1.42; Δtriglycerides +12%; Δremnant cholesterol +11%) for allele score 17-18, 1.41 (1.31-1.52; +25%; +22%) for allele score 19-20, and 1.51 (1.22-1.86; +51%; +44%) for individuals with allele score 21-23. Higher triglycerides and remnant cholesterol were observationally and genetically associated with increased risk of aortic valve stenosis.

Obstructive sleep apnea in obese adolescents referred for bariatric surgery: association with metabolic and cardiovascular variables

Backgroundobstructive sleep apnea syndrome (OSA) is a well-described disease entity in adults, with a higher prevalence in severely obese individuals, while at the same time associated with several comorbidities independently of BMI. Literature regarding OSA in severely obese adolescents is qualitatively and quantitatively limited, possibly resulting in suboptimal diagnosis and treatment. Methodspolysomnographic, demographic, anthropometric, and comorbidity-related data were prospectively collected in 56 adolescents with morbid obesity refractory to conservative treatment who presented for surgical therapy. Differences between adolescents with no/mild (apnea–hypopnea index (AHI) 0–4.9) and moderate/severe OSA (AHI ≥ 5.0) were evaluated using independent-samples t, chi-square or Fisher's exact tests. Multivariable linear regression analysis was performed to evaluate the association of several variables with AHI, corrected for BMI z-score. Resultsof the 53 included subjects, 48 (90.6%) showed some degree of sleep disordered breathing and 20 (37.7%) had moderate/severe OSA. Patients with moderate/severe OSA had on average a higher neck circumference (42.4 versus 40.1 cm, p = 0.008), higher BMI z-score (3.7 versus 3.4, p = 0.003), higher plasma triglyceride level (2.2 versus 1.5 mmol/L, p = 0.012), and lower IGF (29.6 versus 40.2 mmol/L, p = 0.010) than those with no/mild OSA. BMI z-score and plasma triglyceride levels were independently related to AHI. ConclusionsOSA is highly prevalent amongst morbidly obese adolescents and is strongly associated with BMI z-score. Elevated plasma triglyceride levels are associated with AHI, independent of BMI z-score.

A lipoprotein lipase–GPI-anchored high-density lipoprotein–binding protein 1 fusion lowers triglycerides in mice: Implications for managing familial chylomicronemia syndrome

Lipoprotein lipase (LPL) is central to triglyceride metabolism. Severely compromised LPL activity causes familial chylomicronemia syndrome (FCS), which is associated with very high plasma triglyceride levels and increased risk of life-threatening pancreatitis. Currently, no approved pharmacological intervention can acutely lower plasma triglycerides in FCS. Low yield, high aggregation, and poor stability of recombinant LPL have thus far prevented development of enzyme replacement therapy. Recently, we showed that LPL monomers form 1:1 complexes with the LPL transporter glycosylphosphatidylinositol-anchored high-density lipoprotein–binding protein 1 (GPIHBP1) and solved the structure of the complex. In the present work, we further characterized the monomeric LPL/GPIHBP1 complex and its derivative, the LPL–GPIHBP1 fusion protein, with the goal of contributing to the development of an LPL enzyme replacement therapy. Fusion of LPL to GPIHBP1 increased yields of recombinant LPL, prevented LPL aggregation, stabilized LPL against spontaneous inactivation, and made it resistant to inactivation by the LPL antagonists angiopoietin-like protein 3 (ANGPTL3) or ANGPTL4. The high stability of the fusion protein enabled us to identify LPL amino acids that interact with ANGPTL4. Additionally, the LPL–GPIHBP1 fusion protein exhibited high enzyme activity in in vitro assays. Importantly, both intravenous and subcutaneous administrations of the fusion protein lowered triglycerides in several mouse strains without causing adverse effects. These results indicate that the LPL–GPIHBP1 fusion protein has potential for use as a therapeutic for managing FCS.

An association between niacin skin flush response and plasma triglyceride levels in patients with schizophrenia

The available data suggest that abnormalities of arachidonic acid-related signaling may be of relevance in attenuated niacin-induced flush responses and lipid and glucose metabolism disturbances, which are all common among individuals with schizophrenia. We previously demonstrated attenuated skin flush responses to niacin in patients with schizophrenia. Here we investigated whether these niacin responses might be associated with elevated plasma lipid and glucose concentrations in this patient group. We found that higher plasma triglyceride levels were associated with higher total volumetric niacin response (VNR) values and that the VNR accounted for ~14.2% of the variability in triglyceride levels. Triglyceride levels were significantly higher in patients with a positive niacin skin flush response compared to those with absent niacin skin flushing at the 5-minute interval with niacin concentrations of 0.1 and 0.01 M, and at the 10- and 15-minute intervals with a niacin concentration of 0.001 M.