Elevated Plasma Triglyceride Research Articles

The maternal and offsprings’ characteristics associated with HOMA-IR in young adults: a prospective cohort study

Diabetes is an important chronic disease. Many studies from Western countries found that both maternal environment during pregnancy and early offspring life’s factors can lead to diabetes and insulin resistance of offspring during adult life (Barker’s hypothesis). However, this data was limited in Asia. Therefore, this study was conducted to determine the predictor of diabetes in Thailand by using the surrogate markers: the homeostasis model assessment-estimated insulin resistance (HOMA-IR). The design was a prospective cohort study. First, pregnant women were recruited at first attendance at the antenatal care clinics (ANC) in our centers during 1989–1990. Various predictors were collected at subsequent ANC visits, during delivery, and 1 year after delivery. Then, in 2010, we followed up both mothers and offspring again. The characteristics of mothers and offspring which had p value < 0.2 in the univariate analysis were selected to be analyzed by multivariate analysis. There were 592 offsprings (272 males and 320 females). HOMA-IR is statistically found to be associated with the increasing of BMI, both of mother and offspring, as well as the elevated plasma triglyceride and the history of diabetes of the offspring. Interestingly, in contrast with Western reports, in-utero environment in this study in Thais did not have any significant association with HOMA-IR. Perhaps this association might be confounded by ethnic factors. Our novel finding implies that any offspring who have high BMI mother have a high chance to develop insulin resistance and perhaps diabetes in future, so they should be aware and prevent any modifiable risk factors.

Severe hypertriglyceridemia is primarily polygenic

Hypertriglyceridemia (HTG) is a complex trait defined by elevated plasma triglyceride levels. Genetic determinants of HTG have so far been examined in a piecemeal manner; understanding of its molecular basis, both monogenic and polygenic, is thus incomplete. The objective of this study was to characterize genetic profiles of patients with severe HTG, and quantify the genetic determinants and molecular contributors. We concurrently assessed rare and common variants in two independent cohorts of 251 and 312 Caucasian patients with severe HTG. DNA was subjected to targeted next-generation sequencing of 73 genes and 185 SNPs associated with dyslipidemia. LPL, APOC2, GPIHBP1, APOA5, and LMF1 genes were screened for rare variants, and a polygenic risk score was used to assess the accumulation of common variants. As there were no significant differences in the prevalence of genetic determinants between cohorts, data were combined for all 563 patients: 1.1% had biallelic (homozygous or compound heterozygous) rare variants, 14.4% had heterozygous rare variants, 32.0% had an extreme accumulation of common variants (ie, high polygenic risk), and 52.6% remained genetically undefined. Patients with HTG were 5.77 times (95% CI [4.26-7.82]; P<.0001) more likely to carry one of these types of genetic susceptibility compared with controls. We report the most in-depth, systematic evaluation of genetic determinants of severe HTG to date. The predominant feature was an extreme accumulation of common variants (high polygenic risk score), whereas a substantial proportion of patients also carried heterozygous rare variants. Overall, 46.3% of patients had polygenic HTG, whereas only 1.1% had biallelic or homozygous monogenic HTG.

Effect of Low Dose Docosahexaenoic Acid-Rich Fish Oil on Plasma Lipids and Lipoproteins in Pre-Menopausal Women: A Dose⁻Response Randomized Placebo-Controlled Trial.

Omega-3 long chain polyunsaturated fatty acid (n-3 LCPUFA) supplementation has been shown to improve plasma lipid profiles in men and post-menopausal women, however, data for pre-menopausal women are lacking. The benefits of intakes less than 1 g/day have not been well studied, and dose–response data is limited. The aim of this study was to determine the effect of low doses of docosahexaenoic acid (DHA)-rich tuna oil on plasma triglyceride (TG) lowering in pre-menopausal women, and investigate if low dose DHA-rich tuna oil supplementation would increase the low-density lipoprotein (LDL) and high-density lipoprotein (HDL) particle sizes. A randomized, double-blind, placebo-controlled trial was conducted, in which 53 healthy pre-menopausal women with mildly elevated plasma TG levels consumed 0, 0.35, 0.7, or 1 g/day n-3 LCPUFA as HiDHA™ tuna oil or placebo (Sunola oil) capsules for 8 weeks. Supplementation with 1 g/day n-3 LCPUFA, but not lower doses, reduced plasma TG by 23% in pre-menopausal women. This was reflected in a dose-dependent reduction in very-low-density lipoprotein (VLDL)-TG (R2 = 0.20, p = 0.003). A weak dose-dependent shift in HDL (but not LDL) particle size was identified (R2 = 0.05, p = 0.04). The results of this study indicate that DHA-rich n-3 LCPUFA supplementation at a dose of 1 g/day is an effective TG-lowering agent and increases HDL particle size in pre-menopausal women.

Deletion of Lymphangiogenic and Angiogenic Growth Factor VEGF-D Leads to Severe Hyperlipidemia and Delayed Clearance of Chylomicron Remnants.

Objective- Dyslipidemia is one of the key factors behind coronary heart disease. Blood and lymphatic vessels play pivotal roles in both lipoprotein metabolism and development of atherosclerotic plaques. Recent studies have linked members of VEGF (vascular endothelial growth factor) family to lipid metabolism, but the function of VEGF-D has remained unexplored. Here, we investigated how the deletion of VEGF-D affects lipid and lipoprotein metabolism in atherogenic LDLR-/- ApoB100/100 mice. Approach and Results- Deletion of VEGF-D (VEGF-D-/-LDLR-/-ApoB100/100) led to markedly elevated plasma cholesterol and triglyceride levels without an increase in atherogenesis. Size distribution and hepatic lipid uptake studies confirmed a delayed clearance of large chylomicron remnant particles that cannot easily penetrate through the vascular endothelium. Mechanistically, the inhibition of VEGF-D signaling significantly decreased the hepatic expression of SDC1 (syndecan 1), which is one of the main receptors for chylomicron remnant uptake when LDLR is absent. Immunohistochemical staining confirmed reduced expression of SDC1 in the sinusoidal surface of hepatocytes in VEGF-D deficient mice. Furthermore, hepatic RNA-sequencing revealed that VEGF-D is also an important regulator of genes related to lipid metabolism and inflammation. The lack of VEGF-D signaling via VEGFR3 (VEGF receptor 3) led to lowered expression of genes regulating triglyceride and cholesterol production, as well as downregulation of peroxisomal β-oxidation pathway. Conclusions- These results demonstrate that VEGF-D, a powerful lymphangiogenic and angiogenic growth factor, is also a major regulator of chylomicron metabolism in mice.

Prevalence of combined and noncombined dyslipidemia in an Iranian population.

Combination of dyslipidemic phenotypes, including elevated plasma levels of low-density lipoprotein cholesterol (LDL-C), elevated plasma triglycerides (TG), and decreased low-density lipoprotein cholesterol (HDL-C) concentrations, is important because of the association of individual phenotypes with increased risk of cardiovascular disease (CVD). We investigated the prevalence of combined dyslipidemias and their effects on CVD risk in an Iranian large population. A total of 9847 individuals were recruited as part of the Mashhad Stroke and Heart Atherosclerotic Disorders (MASHAD) cohort study. Anthropometric parameters and biochemical indices were measured in all of the subjects. Different types of combined dyslipidemias including high TG+low HDL-C, high TG+low HDL-C+high LDL-C, low HDL-C+high LDL-C, high TG+high LDL-C, and finally high TG+high LDL-C+low HDL-C were considered. Ten-year CVD risk was calculated using the QRISK2 risk algorithm and adjustments were made as suggested by the Joint British Societies' (JBS2). Logistic regression analyses were performed to determine the association between different combined dyslipidemias and categorical QRISK. A total of 3952 males and 5895 females were included in this current study. Among the included subjects, 83.4% had one form of dyslipidemia, and 16.6% subjects were not dyslipidemic. The mean age was 48.88±7.9 and 47.02±8.54years for dyslipidemic and nondyslipidemic groups, respectively. The results showed that the frequency of dyslipidemia was 98%, 87.1%, and 90% in subjects with metabolic syndrome, CVD, and diabetes, respectively. Our results suggested that around 15.7% of study population were at 10years CVD risk (high ≥20) and it was higher in men than women (P<.001). Moreover, risk of CVD was higher in TG↑ & HDL↓ & LDL↑ group than other groups. Prevalence of dyslipidemia was 83.4% among Iranian adults. The results showed that individuals with increased plasma TG and LDL-C, and low HDL-C levels had the highest 10years CVD risk compared to other combined dyslipidemic phenotypes.

Lack of liver steatosis in germ-free mice following hypercaloric diets.

Experimental liver steatosis induced by overfeeding is associated with enhanced gut permeability and endotoxin translocation to the liver. We examined the role of the gut microbiota for steatosis formation by performing the feeding experiments in mice raised under conventional and germ-free (GF) housing. Adult wild-type and GF mice were fed a Western-style diet (WSD) or a control diet (CD), the latter combined with liquid fructose supplementation (F) or not, for 8 weeks. Markers of liver steatosis and gut permeability were measured after intervention. Mice fed a WSD increased body weight compared to those fed a CD (p < 0.01) under conventional, but not under GF conditions. Increased liver weight, liver-to-body-weight ratio and hepatic triglycerides observed in both the WSD and the CD + F groups, when compared with the CD group, were not apparent under GF conditions, whereas elevated plasma triglycerides were visible (p < 0.05). Wild-type mice fed a WSD or a CD + F, respectively, had thinner adherent mucus layer compared to those fed a CD (p < 0.01), whereas GF mice had always a thin mucus layer independently of the diet. GF mice fed a CD showed increased plasma levels of FITC-dextran 4000 (1.9-fold, p < 0.05) and intestinal fatty acid-binding protein-2 (2.4-fold, p < 0.05) compared with wild-type mice. GF housing results in an impaired weight gain and a lack of steatosis following a WSD. Also the fructose-induced steatosis, which is unrelated to body weight changes, is absent in GF mice. Thus, diet-induced experimental liver steatosis depends in multiple ways on intestinal bacteria.

Apolipoprotein C-III in triglyceride-rich lipoprotein metabolism.

Apolipoprotein (apo) C-III is a key player in triglyceride-rich lipoprotein metabolism and strongly associated with elevated plasma triglyceride levels. Several new studies added important insights on apoC-III and its physiological function confirming its promise as a valid therapeutic target. APOC3 is expressed in liver and intestine and regulates triglyceride-rich lipoprotein (TRL) catabolism and anabolism. The transcriptional regulation in both organs requires different regulatory elements. Clinical and preclinical studies established that apoC-III raises plasma triglyceride levels predominantly by inhibiting hepatic TRL clearance. Mechanistic insights into missense variants indicate accelerated renal clearance of apoC-III variants resulting in enhanced TRL catabolism. In contrast, an APOC3 gain-of-function variant enhances de novo lipogenesis and hepatic TRL production. Multiple studies confirmed the correlation between increased apoC-III levels and cardiovascular disease. This has opened up new therapeutic avenues allowing targeting of specific apoC-III properties in triglyceride metabolism. Novel in vivo models and APOC3 missense variants revealed unique mechanisms by which apoC-III inhibits TRL catabolism. Clinical trials with Volanesorsen, an APOC3 antisense oligonucleotide, report very promising lipid-lowering outcomes. However, future studies will need to address if acute apoC-III lowering will have the same clinical benefits as a life-long reduction.

Discovery of peroxisome proliferator–activated receptor α (PPARα) activators with a ligand-screening system using a human PPARα-expressing cell line

Peroxisome proliferator-activated receptor α (PPARα) is a ligand-activated transcription factor that belongs to the superfamily of nuclear hormone receptors. PPARα is mainly expressed in the liver, where it activates fatty acid oxidation and lipoprotein metabolism and improves plasma lipid profiles. Therefore, PPARα activators are often used to treat patients with dyslipidemia. To discover additional PPARα activators as potential compounds for use in hypolipidemic drugs, here we established human hepatoblastoma cell lines with luciferase reporter expression from the promoters containing peroxisome proliferator-responsive elements (PPREs) and tetracycline-regulated expression of full-length human PPARα to quantify the effects of chemical ligands on PPARα activity. Using the established cell-based PPARα-activator screening system to screen a library of >12,000 chemical compounds, we identified several hit compounds with basic chemical skeletons different from those of known PPARα agonists. One of the hit compounds, a 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivative we termed compound 3, selectively up-regulated PPARα transcriptional activity, leading to PPARα target gene expression both in vitro and in vivo Of note, the half-maximal effective concentrations of the hit compounds were lower than that of the known PPARα ligand fenofibrate. Finally, fenofibrate or compound 3 treatment of high fructose-fed rats having elevated plasma triglyceride levels for 14 days indicated that compound 3 reduces plasma triglyceride levels with similar efficiency as fenofibrate. These observations raise the possibility that 1H-pyrazolo[3,4-b]pyridine-4-carboxylic acid derivatives might be effective drug candidates for selective targeting of PPARα to manage dyslipidemia.

Cardiorespiratory Fitness Is Inversely Associated With Clustering of Metabolic Syndrome Risk Factors: The Ball State Adult Fitness Program Longitudinal Lifestyle Study.

ObjectiveThe focus of this study was the association between the metabolic syndrome (MetSyn) and cardiorespiratory fitness (CRF) defined as maximal oxygen uptake (VO2max). Although previous research has shown a relationship between MetSyn and CRF, most studies are based on less objective measures of CRF and different cardiometabolic risk factor thresholds from earlier guidelines.Participants and MethodsThe metabolic markers included in the present study were central obesity, elevated plasma triglycerides, elevated fasting high-density lipoprotein cholesterol, impaired fasting plasma glucose, hypertension, or pharmacologic treatment for diagnosed hypertension, hypertriglyceridemia, low high-density lipoprotein cholesterol, or diabetes. A cohort of 3636 adults (1629 women, 2007 men; mean ± SD age, 44.7±12.3 years) completed CRF and metabolic risk factor assessment between January 1, 1971, and November 1, 2016. The CRF was defined as a measured VO2max from a cardiopulmonary exercise test on a treadmill, with a respiratory exchange ratio value of 1.0 or more.ResultsPrevalence of MetSyn (≥3 factors) was 26% (n=953) in the cohort, with men having a greater likelihood for MetSyn compared with women (P<.001). The difference in VO2max between those individuals with MetSyn and those without was approximately 2.3 (2.0-2.5) metabolic equivalents. Logistic regression analyses showed a significant inverse and graded association between quartiles of CRF and MetSyn for the group overall (P<.001), with odds ratios (95% CI) using the lowest fitness group as the referent group of 0.67 (0.55-0.81), 0.41 (0.34-0.51), and 0.10 (0.07-0.14) for VO2max (P<.001). The sex-specific odds ratios were 0.25 (0.18-0.34), 0.05 (0.02-0.10), and 0.02 (0.01-0.09) for women and 0.43 (0.31-0.59), 0.19 (0.14-0.27), and 0.03 (0.02-0.05) for men (P<.001).ConclusionThese results with current risk factor thresholds and a large number of women demonstrate that low VO2max is associated with MetSyn.

Abstract 390: A New Humanized Mouse Model to Study Lipid Abnormalities and HDL Function in Poorly Controlled Type 1 Diabetes Mellitus

Elevated plasma triglycerides (TG) and VLDL are often present in poorly controlled type 1 diabetes mellitus (T1DM). Furthermore, T1DM patients exhibit an increased risk of cardiovascular disease (CVD) despite normal or high HDL-cholesterol. There is a need for new mouse models to study T1DM lipid abnormalities because mice do not express cholesteryl ester transfer protein (CETP), which transfers cholesteryl ester (CE) from HDL to VLDL and other lipoproteins in exchange for TG, and because mice do not exhibit human-like HDL populations. To develop a physiologically relevant model, we crossed a virally-induced mouse model of T1DM ( Ldlr -/- ;Gp Tg ) deficient in the LDL receptor with human apolipoprotein A-I ( APOA1 ) transgenic mice. These mice (n=8-10) were injected with a liver-specific adeno-associated virus driving expression of human CETP, mimicking the human CETP activity/apoA-I ratio, and the 3 major human HDL subpopulations. Using this model ( APOA1 Tg ;Ldlr -/- ;Gp Tg ), we examined the impact of diabetes on dyslipidemia, HDL particle concentration (HDL-P), and serum HDL function. Induction of diabetes increased plasma TG and cholesterol, primarily due to an increase in VLDL, as compared with non-diabetic (ND) littermates. The dyslipidemia was associated with increases in hepatic TG content and hepatic TG production rate (2-fold over ND). Moreover, resident peritoneal macrophages from diabetic mice exhibited a 5-fold increase in CE loading, increased lipid raft content (20%), and increased Tnfa (3-fold) and Il1b mRNA (4-fold), as compared with ND littermates. In addition, T1DM mice had increased small, medium and large HDL-P (2-fold) concentrations compared with ND controls. Serum HDL from T1DM mice showed a significant increase in its cholesterol efflux capacity through both ABCA1 and ABCG1. Thus, in this humanized mouse model, poorly controlled T1DM leads to elevated plasma TG and VLDL due in part to increased hepatic TG production. This dyslipidemia is associated with higher HDL-P and an increase in serum HDL’s cholesterol efflux capacity, likely due to the increased plasma HDL-P. We have found similar changes in HDL concentration and function in humans with T1DM, suggesting that our mouse model might provide insights into CVD risk in T1DM patients.

Regulation of angiopoietin-like 4 and lipoprotein lipase in human adipose tissue

Elevated plasma triglycerides are increasingly viewed as a causal risk factor for coronary artery disease. One protein that raises plasma triglyceride levels and that has emerged as a modulator of coronary artery disease risk is angiopoietin-like 4 (ANGPTL4). ANGPTL4 raises plasma triglyceride levels by inhibiting lipoprotein lipase (LPL), the enzyme that catalyzes the hydrolysis of circulating triglycerides on the capillary endothelium. The objective of the present study was to assess the association between ANGPTL4 and LPL in human adipose tissue, and to examine the influence of nutritional status on ANGPTL4 expression. We determined ANGPTL4 and LPL mRNA and protein levels in different adipose tissue depots in a large number of severely obese patients who underwent bariatric surgery. Furthermore, in 72 abdominally obese subjects, we measured ANGPTL4 and LPL mRNA levels in subcutaneous adipose tissue in the fasted and postprandial state. ANGPTL4 mRNA levels were highest in subcutaneous adipose tissue, whereas LPL mRNA levels were highest in mesenteric adipose tissue. ANGPTL4 and LPL mRNA levels were strongly positively correlated in the omental and subcutaneous adipose tissue depots. In contrast, ANGPTL4 and LPL protein levels were negatively correlated in subcutaneous adipose tissue, suggesting a suppressive effect of ANGPTL4 on LPL protein abundance in subcutaneous adipose tissue. ANGPTL4 mRNA levels were 38% higher in the fasted compared to the postprandial state. Our data provide valuable insights into the relationship between ANGPTL4 and LPL in human adipose tissue, as well as the physiological function and regulation of ANGPTL4 in humans.

CARDIOPROTECTIVE EFFECTS OF CURCUMIN AGAINST DIABETES AND NICOTINE-COMBINED OXIDATIVE STRESS

Background: Diabetic cardiomyopathy (DCM) develop through oxidative stress-induced myocardial cell apoptosis that cause cardiac tissue damage resulting in hemodynamics disturbance while Cigarette Smoking (CS) is associated with a significant increase in the risk of recurrent ventricular tachyarrhythmia in ischemic and non-ischemic cardiomyopathy patients caused by oxidative stress. Curcuma longa extract (curcumin) is known to protect against hyperglycemia-induced oxidative stress. This brought in mind to investigate the probability of the crcumin ability to ameliorate the combined diabetes and smoking induced oxidative stress caused DCM&#x0D; Materials and Methods: Diabetic rats were administered nicotine to investigate the effect of the combined oxidative stress of diabetes and nicotine. Moreover, curcumin was administered to examine its protective effect on possible oxidative stress induced diabetes and nicotine.&#x0D; Results: Nicotine administration in a dose of 1.5 mg/kg to diabetic rats increased the oxidative stress. This occurs through elevation of plasma nitric oxide (NO) and upregulation of cardiac tissue inducible nitric oxide synthase (iNOS) and Endothelin-1 mRNA expressions, in addition to elevation of plasma triglycerides (TG), and LDL and reduction of HDL levels. Nicotine administration also reduced the cardiac tissue protective mechanism through reduction of plasma superoxide dismutase (SOD), cardiac tissue Erythropoietin (EPO), vascular endothelial growth factor (VEGF) isoforms and VEGF receptor mRNA expressions. These combined oxidative stresses were manifested by elevation of the plasma cardiac markers troponin I and creatine kinase (CK-MB). Supplementation of curcumin prevented the diabetic and nicotine-induced oxidative stress through reduction of plasma NO and iNOS and Endothelin-1 mRNA expressions to their control levels and elevation of plasma SOD and upregulation of cardiac tissue Erythropoietin (EPO), vascular endothelial growth factor (VEGF) isoforms and VEGF receptor mRNA expressions. This curcumin protective effect of the cardiac tissue was manifested by normalization of the plasma cardiac marker troponin I and CK-MB.&#x0D; Conclusion: These results strongly confirmed that curcumin protected cardiac tissues from the combined oxidative stress induced by diabetes and nicotine.

Skeletal Muscle Acute and Chronic Metabolic Response to Essential Amino Acid Supplementation in Hypertriglyceridemic Older Adults

BackgroundSupplementation with essential amino acids (EAAs) + arginine is a promising nutritional approach to decrease plasma triglyceride (TG) concentrations, which are an independent risk factor for ischemic heart disease. ObjectiveThe objective of this study was to examine the effects of 8 wk of EAA supplementation on skeletal muscle basal metabolite concentrations and changes in metabolic response to acute EAA intake, with an emphasis on mitochondrial metabolism, in adults with elevated TGs to better understand the mechanisms of lowering plasma TGs. MethodsOlder adults with elevated plasma TG concentrations were given 22 g EAAs to ingest acutely before and after an 8-wk EAA supplementation period. Skeletal muscle biopsy samples were collected before and after acute EAA intake, both pre- and postsupplementation (4 biopsy samples), and targeted metabolomic analyses of organic acids and acylcarnitines were conducted on the specimens. ResultsAcute EAA intake resulted in increased skeletal muscle acylcarnitine concentrations associated with oxidative catabolism of the supplement components, with the largest increases found in acylcarnitines of branched-chain amino acid oxidative catabolism, including isovaleryl-carnitine (2200%) and 2-methylbutyryl-carnitine (2400%). The chronic EAA supplementation resulted in a 19% decrease in plasma TGs along with accumulation of long-chain acylcarnitines myristoyl- (90%) and stearoyl- (120%) carnitine in skeletal muscle and increases in succinyl-carnitine (250%) and the late-stage tricarboxylic acid cycle intermediates fumarate (44%) and malate (110%). ConclusionsSupplementation with EAAs shows promise as an approach for moderate reduction in plasma TGs. Changes in skeletal muscle metabolites suggest incomplete fatty acid oxidation and increased anaplerosis, which suggests a potential bottleneck in fatty acid metabolism.

Metabolic parameters in psoriatic patients treated with interleukin-12/23 blockade (ustekinumab).

The associations between psoriasis, metabolic syndrome and cardiovascular events are increasingly recognized. Studies have shown decreased cardiovascular events with the treatment of methotrexate and anti-tumor necrosis factor, however, effects of interleukin (IL)-12/23 blockade remain debatable. Our study investigated the effect of IL-12/23 blockade on the metabolic parameters in patients with psoriasis. We performed a retrospective cohort study to assess 93 consecutive patients with moderate to severe plaque type psoriasis who received IL-12/23 blockade (ustekinumab) for 24 weeks between January 2012 and May 2016. Metabolic parameters and disease activity (Psoriasis Area and Severity Index [PASI] score) at baseline and 24 weeks of treatment were collected. At week 24, the disease activity improved significantly (P < 0.0001), with a significant reduction of erythrocyte sedimentation rate. Conversely, body mass index was significantly elevated in PASI-75 responders at week 24 of treatment and was independent of disease severity. Fasting sugar and triglyceride levels were also elevated at week 24 in both PASI-75 responders and PASI-75 non-responders. Cholesterol, low-density lipoprotein (LDL) and high-density lipoprotein (HDL) remained unchanged. These metabolic parameters were not correlated with the improvement in disease severity after ustekinumab treatment. Nonetheless, the atherogenic index, LDL/HDL ratio and cholesterol/HDL ratio remained unchanged. Male sex and cigarette smoking are predictors of elevated plasma triglyceride levels. Our results suggest that despite tremendous improvement in disease activity after ustekinumab treatment, obesity, fasting sugar and hypertriglyceridemia still present in these patients. Regular screening of lipid profile, obesity control and smoking cessation are advised during the treatment of ustekinumab especially in male psoriatic patients with predisposing cardiovascular risks.

Resveratrol supplementation improves lipid and glucose metabolism in high-fat diet-fed blunt snout bream.

Here, we aimed to investigate whether resveratrol (RSV) can ameliorate high-fat diet (HFD)-induced metabolic disorder in fish. Blunt snout bream (Megalobrama amblycephala) with average weight 27.99±0.56g were fed a normal fat diet (NFD, 5% fat, w/w), a HFD (11% fat), or a HFD supplemented with 0.04, 0.36, or 1.08% RSV for 10weeks. As expected, fish fed a HFD developed hepatic steatosis, as shown by elevated hepatic and plasma triglycerides, raised whole body fat, intraperitoneal fat ratio and hepatosomatic index, and increased plasma alanine aminotransferase (ALT) and aspartate aminotransferase (AST). RSV supplementation lessened increases in body mass, whole body fat, and intraperitoneal fat, and alleviated development of hepatic steatosis, elevations of plasma triglyceride and glucose, and abnormalities of ALT and AST in HFD-fed fish. RSV supplementation increased SIRT1 messenger RNA (mRNA) expression and consequently hepatic mRNA expression of adipose triglyceride lipase (ATGL), carnitine palmitoyltransferase (CPT1a), and microsomal triglyceride transfer protein (MTTP), implying upregulation of lipolysis, β-oxidation, and lipid transport, respectively, in the liver. Conversely, hepatic lipoprotein lipase (LPL), sterol regulatory element-binding protein 1 (SREBP-1c), peroxisome proliferator-activated receptor γ (PPARγ), and ATP citrate lyase (ACLY) mRNA expression were decreased, implying suppression of fatty acid uptake, lipogenesis, and fatty acid synthesis. Additionally, RSV downregulated glucokinase (GCK) and sodium-dependent glucose cotransporter 1 (SGLT1) and upregulated glucose transporter 2 (GLUT2) mRNA expression, thus restoring normal glucose fluxes. Thus, RSV improves lipid and glucose metabolisms in blunt snout bream, which are potentially mediated by activation of SIRT1.

Artesunate prevents rats from the clozapine-induced hepatic steatosis and elevation in plasma triglycerides

Clozapine is an atypical antipsychotic with therapeutic efficacy in treatment-resistant schizophrenia patients and low incidence of extrapyramidal side effects. However, the use of clozapine has been limited by its adverse effects on metabolism. Artesunate is a semisynthetic derivative of artemisinin and was shown to decrease the plasma cholesterol and triglyceride in rabbits and rats in recent studies. The aim of this study was to examine possible effects of artesunate on the clozapine-induced metabolic alterations in rats given saline, clozapine, artesunate, or clozapine plus artesunate for 6 weeks. The clozapine group showed significantly high plasma levels of triglyceride, hepatic steatosis, and fibrosis along with high levels of C-reactive protein, alanine aminotransferase, and aspartate aminotransferase compared to the saline group. But the treatment had no effect on weight gain and caused no hyperglycemia, hyperinsulinemia, and behavioral changes in the rats. More significantly, these clozapine-induced changes were not seen in rats coadministered with clozapine plus artesunate. These results added evidence supporting psychiatrists to try add-on treatment of artesunate in schizophrenia patients to ameliorate clozapine-induced adverse metabolic effects.

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OBJECTIVES/SPECIFIC AIMS: This study will assess the effect of essential amino acid (EAA) supplementation on plasma triglyceride (TG) in elderly adults. We will also explore the mechanisms mediating EAA mediated changes in fat metabolism and to suggest promising routes to refine therapy of hypertriglyceridemia. METHODS/STUDY POPULATION: In total, 7 nondiabetic male and female subjects ages 50–75 years with elevated plasma TG levels (130–500 mg/dL) were recruited to participate in an acute (5 h) and long-term (8 wk) EAA supplementation study. We measured changes in regional and whole body fat metabolism, including changes in body composition, plasma TG levels, whole body fat metabolic rates, tissue mitochondrial respiratory capacity, and metabolomic profiles before and after supplementation. RESULTS/ANTICIPATED RESULTS: Long-term EAA supplementation decreased fasted plasma TG levels by 19% (p&lt;0.01). Metabolomics of skeletal muscle found acute EAA supplementation resulted in increased EAA metabolic products while long-term supplementation resulted in increased anaplerosis [flux into the tricarboxylic acid cycle (TCA) intermediate pool] and anaplerotic substrates [propionyl (p&lt;0.01) and succinyl (p&lt;0.01) carnitine] and intermediates of long-chain fatty acid metabolism [stearoyl (p&lt;0.01) and myristoyl (p&lt;0.05) carnitine]. However, tissue level respiratory capacity appeared to be unaffected by EAA supplementation. DISCUSSION/SIGNIFICANCE OF IMPACT: EAA supplementation has potential to improve lipid metabolism and plasma TG levels in non-diabetic older adults. Mitochondrial metabolomics suggest that insufficient TCA pool size may limit tissue fatty acid oxidation and may provide an additional route for nutritional therapy.

A Mendelian Randomization Study of Metabolite Profiles, Fasting Glucose, and Type 2 Diabetes.

Mendelian randomization (MR) provides us the opportunity to investigate the causal paths of metabolites in type 2 diabetes and glucose homeostasis. We developed and tested an MR approach based on genetic risk scoring for plasma metabolite levels, utilizing a pathway-based sensitivity analysis to control for nonspecific effects. We focused on 124 circulating metabolites that correlate with fasting glucose in the Erasmus Rucphen Family (ERF) study (n = 2,564) and tested the possible causal effect of each metabolite with glucose and type 2 diabetes and vice versa. We detected 14 paths with potential causal effects by MR, following pathway-based sensitivity analysis. Our results suggest that elevated plasma triglycerides might be partially responsible for increased glucose levels and type 2 diabetes risk, which is consistent with previous reports. Additionally, elevated HDL components, i.e., small HDL triglycerides, might have a causal role of elevating glucose levels. In contrast, large (L) and extra large (XL) HDL lipid components, i.e., XL-HDL cholesterol, XL-HDL-free cholesterol, XL-HDL phospholipids, L-HDL cholesterol, and L-HDL-free cholesterol, as well as HDL cholesterol seem to be protective against increasing fasting glucose but not against type 2 diabetes. Finally, we demonstrate that genetic predisposition to type 2 diabetes associates with increased levels of alanine and decreased levels of phosphatidylcholine alkyl-acyl C42:5 and phosphatidylcholine alkyl-acyl C44:4. Our MR results provide novel insight into promising causal paths to and from glucose and type 2 diabetes and underline the value of additional information from high-resolution metabolomics over classic biochemistry.

Acetyl CoA Carboxylase Inhibition Reduces Hepatic Steatosis but Elevates Plasma Triglycerides in Mice and Humans: A Bedside to Bench Investigation

Inhibiting lipogenesis prevents hepatic steatosis in rodents with insulin resistance. To determine if reducing lipogenesis functions similarly in humans, we developed MK-4074, a liver-specific inhibitor of acetyl-CoA carboxylase (ACC1) and (ACC2), enzymes that produce malonyl-CoA for fatty acid synthesis. MK-4074 administered to subjects with hepatic steatosis for 1month lowered lipogenesis, increased ketones, and reduced liver triglycerides by 36%. Unexpectedly, MK-4074 increased plasma triglycerides by 200%. To further investigate, mice that lack ACC1 and ACC2 in hepatocytes (ACC dLKO) were generated. Deletion of ACCs decreased polyunsaturated fatty acid (PUFA) concentrations in liver due to reduced malonyl-CoA, which is required for elongation of essential fatty acids. PUFA deficiency induced SREBP-1c, which increased GPAT1 expression and VLDL secretion. PUFA supplementation or siRNA-mediated knockdown of GPAT1 normalized plasma triglycerides. Thus, inhibiting lipogenesis in humans reduced hepatic steatosis, but inhibiting ACC resulted in hypertriglyceridemia due to activation of SREBP-1c and increased VLDL secretion.

Triglyceride Metabolism under Attack

Hydrolysis of circulating triglycerides is carried out by the enzyme lipoprotein lipase, which is transported and anchored to the capillary wall by the protein GPIHBP1. Recent evidence indicates that certain individuals develop autoantibodies against GPIHBP1, impairing lipoprotein lipase function and leading to markedly elevated plasma triglyceride levels (Beigneux etal., 2017).