Increased Plasma Triglyceride Research Articles

High fat intake aggravates hyperlipidemia and suppresses fatty liver symptoms induced by a high-sucrose diet in rats.

Overconsumption of sucrose or fat is widely acknowledged as a prominent feature of unhealthy dietary patterns. Both factors commonly co-occur and are recognized as hallmarks of the Western diet, which is an important contributor to non-communicative diseases. In this study, we investigated the hazards of high sucrose or fat intake, either alone or in combination. Wistar rats were divided into four groups and fed a control starch diet, high-sucrose diet, high-fat diet, or high-sucrose/fat diet for 30 days. High fat intake increased body weight and visceral and subcutaneous adipose tissue weights. Both high-sucrose and -fat diets were associated with increased plasma triglyceride and glucose levels, and high sucrose also elevated plasma cholesterol levels. The combination of high sucrose and fat synergistically elevated plasma triglyceride levels. The high-sucrose diet increased liver weight and hepatic total lipid and triglyceride levels, whereas this increase was suppressed by the high-fat diet. The high sucrose increased the mRNA levels of hepatic genes involved in fatty acid synthesis and transport (ACLY, ACACA, FAS, ELOVL6, SCD1, SREBP1, and CD36), whereas the high fat suppressed the high sucrose-induced expression of these genes. We observed that high sucrose and fat contents differently exerted their effects on hyperlipidemia and fatty liver. Furthermore, high fat aggravated hyperlipidemia and suppressed fatty liver induced by high sucrose.

Aerobic Exercise Training Protects Against Insulin Resistance, Despite Low-Sodium Diet-Induced Increased Inflammation and Visceral Adiposity.

Dietary sodium restriction increases plasma triglycerides (TG) and total cholesterol (TC) concentrations as well as causing insulin resistance and stimulation of the renin-angiotensin-aldosterone system (RAAS) and the sympathetic nervous system. Stimulation of the angiotensin II type-1 receptor (AT1) is associated with insulin resistance, inflammation, and the inhibition of adipogenesis. The current study investigated whether aerobic exercise training (AET) mitigates or inhibits the adverse effects of dietary sodium restriction on adiposity, inflammation, and insulin sensitivity in periepididymal adipose tissue. LDL receptor knockout mice were fed either a normal-sodium (NS; 1.27% NaCl) or a low-sodium (LS; 0.15% NaCl) diet and were either subjected to AET for 90 days or kept sedentary. Body mass, blood pressure (BP), hematocrit, plasma TC, TG, glucose and 24-hour urinary sodium (UNa) concentrations, insulin sensitivity, lipoprotein profile, histopathological analyses, and gene and protein expression were determined. The results were evaluated using two-way ANOVA. Differences were not observed in BP, hematocrit, diet consumption, and TC. The LS diet was found to enhance body mass, insulin resistance, plasma glucose, TG, LDL-C, and VLDL-TG and reduce UNa, HDL-C, and HDL-TG, showing a pro-atherogenic lipid profile. In periepididymal adipose tissue, the LS diet increased tissue mass, TG, TC, AT1 receptor, pro-inflammatory macro-phages contents, and the area of adipocytes; contrarily, the LS diet decreased anti-inflammatory macrophages, protein contents and the transcription of genes related to insulin sensitivity. The AET prevented insulin resistance, but did not protect against dyslipidemia, adipose tissue pro-inflammatory profile, increased tissue mass, AT1 receptor expression, TG, and TC induced by the LS diet.

Hypertriglyceridemia as a Key Contributor to Abdominal Aortic Aneurysm Development and Rupture: Insights from Genetic and Experimental Models.

Abdominal aortic aneurysm (AAA) is a life-threatening vascular disease without effective medications. This study integrated genetic, proteomic, and metabolomic data to identify causation between increased triglyceride (TG)-rich lipoproteins and AAA risk. Three hypertriglyceridemia mouse models were employed to test the hypothesis that increased plasma TG concentrations accelerate AAA development and rupture. In the angiotensin II-infusion AAA model, most Lpl -deficient mice with severely high plasma TG concentrations died of aortic rupture. Consistently, Apoa5 -deficient mice with moderately increased TG concentrations had accelerated AAA development, while human APOC3 transgenic mice with dramatically increased TG concentrations exhibited aortic dissection and rupture. Increased TG concentrations and palmitate inhibited lysyl oxidase maturation. Administration of antisense oligonucleotide targeting Angptl3 profoundly inhibited AAA progression in human APOC3 transgenic mice and Apoe -deficient mice. These results indicate that hypertriglyceridemia is a key contributor to AAA pathogenesis, highlighting the importance of triglyceride-rich lipoprotein management in treating AAA.

Exploring the link between T-regulatory cells and inflammatory cytokines in atherogenesis: findings from patients with stable angina pectoris.

Atherosclerosis, a chronic inflammatory disease impacting arteries, is closely linked to cardiovascular conditions. Dyslipidemia, marked by high low-density lipoprotein (LDL), low high-density lipoprotein (HDL), and increased plasma triglycerides, is a key risk factor. Atherogenesis begins when modified lipoproteins like oxidized LDL (ox-LDL) activate the immune system. This study explores the roles of T-regulatory cells (Tregs) and interleukins 10 (IL-10), 6 (IL-6), and 17 (IL-17) in atherogenesis. Samples were collected from the Hospital patients with stable angina pectoris (SAP). Peripheral blood mononuclear cells (PBMCs) were isolated using Ficoll density gradient and analyzed via flow cytometry. IL-10, IL-6, and IL-17 levels in cell culture supernatant were measured using ELISA. Data were expressed as mean ± SEM and analyzed with statistical software. Results indicate that only patients exhibited reduced Treg and IL-10 levels after high-dose ox-LDL treatment. Significant IL-6 reduction was observed in both NCA and SA groups after high-dose n-LDL and low/high ox-LDL treatments compared to untreated PBMCs. Future research will explore n-LDL and ox-LDL effects on Th17/Treg immune responses within a specific cytokine environment known for inducing inflammation, assessing their potential role in atherosclerosis progression.

Downregulation of adipose LPL by PAR2 contributes to the development of hypertriglyceridemia.

Lipoprotein lipase (LPL) hydrolyzes circulating triglycerides (TGs), releasing fatty acids (FA) and promoting lipid storage in white adipose tissue (WAT). However, the mechanisms regulating adipose LPL and its relationship with the development of hypertriglyceridemia are largely unknown. WAT from obese humans exhibited high PAR2 expression, which was inversely correlated with the LPL gene. Decreased LPL expression was also inversely correlated with elevated plasma TG levels, suggesting that adipose PAR2 might regulate hypertriglyceridemia by downregulating LPL. In mice, aging and high palmitic acid diet (PD) increased PAR2 expression in WAT, which was associated with a high level of macrophage migration inhibitory factor (MIF). MIF downregulated LPL expression and activity in adipocytes by binding with CXCR2/4 receptors and inhibiting Akt phosphorylation. In a MIF overexpression model, high-circulating MIF levels suppressed adipose LPL, and this suppression was associated with increased plasma TGs but not FA. Following PD feeding, adipose LPL expression and activity were significantly reduced, and this reduction was reversed in Par2-/- mice. Recombinant MIF infusion restored high plasma MIF levels in Par2-/- mice, and the levels decreased LPL and attenuated adipocyte lipid storage, leading to hypertriglyceridemia. These data collectively suggest that downregulation of adipose LPL by PAR2/MIF may contribute to the development of hypertriglyceridemia.

Impaired GK-GKRP interaction rather than direct GK activation worsens lipid profiles and contributes to long-term complications: a Mendelian randomization study

BackgroundGlucokinase (GK) plays a key role in glucose metabolism. In the liver, GK is regulated by GK regulatory protein (GKRP) with nuclear sequestration at low plasma glucose level. Some GK activators (GKAs) disrupt GK-GKRP interaction which increases hepatic cytoplasmic GK level. Excess hepatic GK activity may exceed the capacity of glycogen synthesis with excess triglyceride formation. It remains uncertain whether hypertriglyceridemia associated with some GKAs in previous clinical trials was due to direct GK activation or impaired GK-GKRP interaction.MethodsUsing publicly available genome-wide association study summary statistics, we selected independent genetic variants of GCKR and GCK associated with fasting plasma glucose (FPG) as instrumental variables, to mimic the effects of impaired GK-GKRP interaction and direct GK activation, respectively. We applied two-sample Mendelian Randomization (MR) framework to assess their causal associations with lipid-related traits, risks of metabolic dysfunction-associated steatotic liver disease (MASLD) and cardiovascular diseases. We verified these findings in one-sample MR analysis using individual-level statistics from the Hong Kong Diabetes Register (HKDR).ResultsGenetically-proxied impaired GK-GKRP interaction increased plasma triglycerides, low-density lipoprotein cholesterol and apolipoprotein B levels with increased odds ratio (OR) of 14.6 (95% CI 4.57–46.4) per 1 mmol/L lower FPG for MASLD and OR of 2.92 (95% CI 1.78–4.81) for coronary artery disease (CAD). Genetically-proxied GK activation was associated with decreased risk of CAD (OR 0.69, 95% CI 0.54–0.88) and not with dyslipidemia. One-sample MR validation in HKDR showed consistent results.ConclusionsImpaired GK-GKRP interaction, rather than direct GK activation, may worsen lipid profiles and increase risks of MASLD and CAD. Development of future GKAs should avoid interfering with GK-GKRP interaction.

Enterocyte-specific FATP4 deficiency elevates blood lipids via a shift from polar to neutral lipids in distal intestine.

Fatty acid transport protein (FATP)4 was thought to mediate intestinal lipid absorption, which was disputed by a study using keratinocyte-Fatp4-rescued Fatp4-/- mice. These knockouts when fed with a Western diet showed elevated intestinal triglyceride (TG) and fatty acid levels. To investigate a possible role of FATP4 on intestinal lipid processing, ent-Fatp4 (KO) mice were generated by Villin-Cre-specific inactivation of the Fatp4 gene. We aimed to measure circulating and intestinal lipids in control and KO mice after acute or chronic fat intake or during aging. Remarkably, ent-Fatp4 mice displayed an approximately 30% decrease in ileal behenic, lignoceric, and nervonic acids, ceramides containing these FA, as well as, ileal sphingomyelin, phosphatidylcholine, and phosphatidylinositol levels. Such decreases were concomitant with an increase in jejunal cholesterol ester. After a 2-wk recovery from high lipid overload by tyloxapol and oral-lipid treatment, ent-Fatp4 mice showed an increase in plasma TG and chylomicrons. Upon overnight fasting followed by an oral fat meal, ent-Fatp4 mice showed an increase in plasma TG-rich lipoproteins and the particle number of chylomicrons and very low-density lipoproteins. During aging or after feeding with a high-fat high-cholesterol (HFHC) diet, ent-Fatp4 mice showed an increase in plasma TG, fatty acids, glycerol, and lipoproteins as well as intestinal lipids. HFHC-fed KO mice displayed an increase in body weight, the number of lipid droplets with larger sizes in the ileum, concomitant with a decrease in ileal ceramides and phosphatidylcholine. Thus, enterocyte FATP4 deficiency led to a metabolic shift from polar to neutral lipids in distal intestine rendering an increase in plasma lipids and lipoproteins.NEW & NOTEWORTHY Enterocyte-specific Fatp4 deficiency in mice increased intestinal lipid absorption with elevation of blood lipids during fasting and aging, as well as after an acute oral fat-loading or chronic HFHC feeding. Lipidomics revealed that knockout mice displayed a shift from very long-chain to long-chain fatty acids, and from polar to neutral lipids, predominantly in the ileum. Thus, FATP4 may have a physiological function in the control of blood lipids via metabolic shifts in distal intestine.

The proteomic profile is altered but not repaired after bariatric surgery in type 2 diabetes pigs

To reveal the sources of obesity and type 2 diabetes (T2D) in humans, animal models, mainly rodents, have been used. Here, we propose a pig model of T2D. Weaned piglets were fed high fat/high sugar diet suppling 150% of metabolizable energy. Measurements of weight gain, blood morphology, glucose plasma levels, cholesterol, and triglycerides, as well as glucose tolerance (oral glucose tolerance test, OGTT) were employed to observe T2D development. The histology and mass spectrometry analyses were made post mortem. Within 6 months, the high fat-high sugar (HFHS) fed pigs showed gradual and significant increase in plasma triglycerides and glucose levels in comparison to the controls. Using OGTT test, we found stable glucose intolerance in 10 out of 14 HFHS pigs. Mass spectrometry analysis indicated significant changes in 330 proteins in the intestine, liver, and pancreas of the HFHS pigs. These pigs showed also an increase in DNA base modifications and elevated level of the ALKBH proteins in the tissues. Six diabetic HFHS pigs underwent Scopinaro bariatric surgery restoring glycaemia one month after surgery. In conclusion, a high energy diet applied to piglets resulted in the development of hyperlipidaemia, hyperglycaemia, and type 2 diabetes being reversed by a bariatric procedure, excluding the proteomic profile utill one month after the surgery.

Effects of subcutaneous vs. oral nanoparticle-mediated insulin delivery on hemostasis disorders in type 1 diabetes: A rat model study

Complications associated with Type 1 diabetes (T1D) have complex origins that revolve around chronic hyperglycemia; these complications involve hemostasis disorders, coagulopathies, and vascular damage. Our study aims to develop innovative approaches to minimize these complications and to compare the outcomes of the new approach with those of traditional methods. To achieve our objective, we designed novel nanoparticles comprising covalent organic frameworks (nCOF) loaded with insulin, termed nCOF/Insulin, and compared it to subcutaneous insulin to elucidate the influence of insulin delivery methods on various parameters, including bleeding time, coagulation factors, platelet counts, cortisol plasma levels, lipid profiles, and oxidative stress parameters. Traditional subcutaneous insulin injections exacerbated hemostasis disorder and vascular injuries in streptozotocin (STZ)-induced diabetic rats through increasing plasma triglycerides and lipid peroxidation. Conversely, oral delivery of nCOF/Insulin ameliorated hemostatic disorders and restored the endothelial oxidant/antioxidant balance by reducing lipid peroxidation and enhancing the lipid profile. Our study pioneers the understanding of how STZ-induced diabetes disrupts bleeding time, induces a hypercoagulable state, and causes vascular damage through lipid peroxidation. Additionally, it provides the first evidence for the involvement of subcutaneous insulin treatment in exacerbating vascular and hemostasis disorders in type 1 diabetes (T1D). Introducing an innovative oral insulin delivery via the nCOF approach represents a potential paradigm shift in diabetes management and patient care and promises to improve treatment strategies for type 1 Diabetes.

Carboxyl-terminal sequences in APOA5 are important for suppressing ANGPTL3/8 activity

Apolipoprotein AV (APOA5) lowers plasma triglyceride (TG) levels by binding to the angiopoietin-like protein 3/8 complex (ANGPTL3/8) and suppressing its capacity to inhibit lipoprotein lipase (LPL) catalytic activity and its ability to detach LPL from binding sites within capillaries. However, the sequences in APOA5 that are required for suppressing ANGPTL3/8 activity have never been defined. A clue to the identity of those sequences was the presence of severe hypertriglyceridemia in two patients harboring an APOA5 mutation that truncates APOA5 by 35 residues ("APOA5Δ35"). We found that wild-type (WT) human APOA5, but not APOA5Δ35, suppressed ANGPTL3/8's ability to inhibit LPL catalytic activity. To pursue that finding, we prepared a mutant mouse APOA5 protein lacking 40 C-terminal amino acids ("APOA5Δ40"). Mouse WT-APOA5, but not APOA5Δ40, suppressed ANGPTL3/8's capacity to inhibit LPL catalytic activity and sharply reduced plasma TG levels in mice. WT-APOA5, but not APOA5Δ40, increased intracapillary LPL levels and reduced plasma TG levels in Apoa5-/- mice (where TG levels are high and intravascular LPL levels are low). Also, WT-APOA5, but not APOA5Δ40, blocked the ability of ANGPTL3/8 to detach LPL from cultured cells. Finally, an antibody against a synthetic peptide corresponding to the last 26 amino acids of mouse APOA5 reduced intracapillary LPL levels and increased plasma TG levels in WT mice. We conclude that C-terminal sequences in APOA5 are crucial for suppressing ANGPTL3/8 activity in vitro and for regulating intracapillary LPL levels and plasma TG levels in vivo.

An Increase in Food Insecurity Correlated with an Increase in Plasma Triglycerides among Latinx Children

BackgroundFood insecurity and metabolic diseases both disproportionately affect Hispanic children. Cross-sectional studies have linked food insecurity with adverse cardiometabolic markers, including elevated plasma triglycerides and glucose concentrations. However, the association between changes in food insecurity and changes in cardiometabolic markers in children remains to be explored. Furthermore, few studies have assessed the impact of school-based nutrition interventions on household food insecurity. ObjectiveThe objectives of this study are to assess the effect of the TX Sprouts intervention on household food insecurity and to examine the association between changes in household food insecurity and changes in cardiometabolic markers over 1 academic year. MethodsThis secondary analysis used data from TX Sprouts, a cluster-randomized school-based gardening, cooking, and nutrition trial. The study enrolled 3rd–5th-grade students from 16 schools that served primarily (>50%) Hispanic families with low income in Austin, TX. Participants (n = 619) provided household food insecurity data and fasting lipid panels at both baseline and postintervention, ∼9 mo following. ResultsThere was no intervention effect on household food insecurity. Independent of the intervention, a 1-point increase in food insecurity, indicative of becoming more food insecure, was associated with a 2.61 mg/dL increase in triglycerides (P = 0.001; 95% CI: 1.04, 4.19) at follow-up. Children who were food insecure at baseline and became food secure at follow-up had a mean 5.05 mg/dL decrease in triglycerides compared with a 7.50 mg/dL increase in triglycerides in children who remained food insecure throughout (95% CI: −23.40, −1.71, P = 0.023). There were no other associations between changes in food insecurity and cardiometabolic markers. ConclusionAlthough the intervention did not improve food insecurity, reductions in food insecurity over 9 mo were associated with improved cardiometabolic markers in high-risk children, emphasizing the need for interventions targeting food insecurity.The study is registered at clinicaltrials.gov under NCT02668744 (https://classic.clinicaltrials.gov/ct2/show/NCT02668744).

SAT403 Long-term Metabolic Effects Of Gonadotropin Releasing Hormone Agonist (GnRH) Therapy In Transgender Women Veterans

Abstract Disclosure: G. Le: None. S. Pinkson: None. J. Trejo: None. L. Gondin Hernandez: None. M. Mok: None. A. endoza: None. D. Tripathy: None. There is controversy regarding the effects of long-term GnRH agonist therapy on cardiovascular risk factors in older men with prostate cancer. GnRH agonists are used for gender affirming hormone therapy in adolescents and in adults who fail to suppress testosterone adequately. We examined the cardiometabolic effects of long-term GnRH agonist therapy in transwomen veterans. A retrospective chart review was performed on 74 transwomen veterans who were followed at the ALM VA Endocrinology clinic for at least 12 months and had detailed clinical, hormonal and biochemical profile (testosterone, estradiol, HbA1c, lipid profile) measured. Thirtytwo transwomen on GnRH agonist therapy (age 48 ± 2 yrs, BMI 28 ± 1 kg.m2) followed for 45 ± 5 months were compared with 22 transwomen (age 44 ± 3 yrs, BMI 28 ± 2 kg.m2) followed for 41 ± 7 months not on GnRH therapy. In the GnRH group, 14 were on oral E2, 12 on E2 patch and 6 were on E2 Injection. Similarly, in the non-GnRH group, the number of subjects on oral E2, E2 patch or E2 Injection were 17, 1, and 4 respectively. The average oral estrogen dose in both groups was 4 ± 0.4 mg. In the GnRH group, serum testosterone declined from 420 ± 36 ng/dl to 40 ± 5 ng/dL and serum estradiol before and after therapy was 39 ± 9 vs 89 ± 12 pg/mL. GnRH therapy led to increase in BMI (28 ± 1 vs 31 ± 2 kg.m2, p=0.006), though no difference was observed in SBP (126 ± 2 vs 120 ± 2 mmHg, p=ns), total Cholesterol (170 ± 7 vs 171 ± 8 mg/dL), HDL Cholesterol (45 ± 2 vs. 46 ± 2 mg/dL), LDL Cholesterol (98 ± 7 vs 99 ± 5 mg/dL) before and after treatment. There was no change in BMI (28 ± 2 vs 29 ± 1 kg.m2), SBP (121 ± 3 vs 125 ± 3, p=ns), total cholesterol (173 ± 5 vs. 170 ± 9 mg/dL), HDL chol (46 ± 2 vs. 49 ± 2 mg/dL), or LDL chol (97 ± 6 vs. 95 ± 7 mg/dL) in the control group. Plasma triglycerides increased in both the GnRH (134 ± 10 vs 168 ± 16 mg/dL, p<0.05) as well as in the control group (154 ± 30 vs 167 ± 20 mg/dL, p<0.05) after treatment. In conclusion, long-term estrogen therapy in transwomen increased plasma triglyceride. Concomitant GnRH agonist therapy was associated with greater weight gain, but did not affect other cardiovascular risk factors. Presentation: Saturday, June 17, 2023

Acetate mitigates cardiac mitochondrial dysfunction in experimental model of polycystic ovarian syndrome by modulating GPCR41/43 and PROKR1

The role of short chain fatty acid, acetate in cardiac mitochondrial dysfunction especially in PCOS individuals is unknown. Therefore, the present study investigated the modulatory role of GPCRs (41 and 43) by acetate on cardiac mitochondrial status in PCOS rat model. Eight-week-old female Wistar rats were randomly allotted into four groups (n = 5). Polycystic ovarian syndrome was induced by administering letrozole (1 mg/kg p.o.) once daily for 21 days, thereafter the animals were treated with 200 mg/kg (oral gavage) of acetate for six weeks. Letrozole-induced PCOS rats showed elevated circulating testosterone and anti-mullerian hormone, with multiple ovarian cysts. In addition, these rats also manifested insulin resistance, hyperinsulinemia, and increased plasma triglyceride (TG), TG/HDLc and decreased HDLc, as well as elevated level of cardiac TG, glycogen, glycogen synthase, and plasma/cardiac NF-kB, TNF-α, and SDF-1. Cardiac MDA and caspase-6 increased, while plasma/cardiac NrF2 decreased in PCOS animals. A decrease in mitochondrial ATP synthase, ATP/AMP ratio, CPT2 and SDH, and increased HDAC2 were observed in PCOS rats with decreased level of GPCR 41 and 43 when compared with control. Immunohistochemical evaluation of cardiac tissue also showed decrease expression of PROKR1 in PCOS rats compared with control rats. However, treatment with acetate reversed these systemic, cardiac and mitochondrial anomalies. The present results suggest the therapeutic benefit of acetate, an HDAC2i against cardiac mitochondrial dysfunction in PCOS rat model, by attenuating cardiac inflammation, oxidative stress and apoptosis and these effects are accompanied by modulation of GPCR41 and 43 as well as increased expression of PROKR1.

The effect of N-arachidonoylethanolamide administration on energy and fat metabolism of early lactating dairy cows

The aim of the study was to investigate the effect of N-arachidonoylethanolamide (AEA), an endocannabinoid with orexigenic characteristics, on plasma endocannabinoid concentrations, feed intake, energy balance, lipomobilisation, and hepatic lipid metabolism of early-lactating dairy cows. The experiment involved 10 pairs of Holstein half-sibling cows (end of 2nd–3rd pregnancy). Half-sibs of each pair were randomly assigned to either AEA (n = 10) or control (CON) group (n = 10). From day 1 to 30 postpartum, the AEA group received 5 intraperitoneal injections per week of 3 µg/kg body weight AEA and the CON group 0.9% NaCl. In week 1–3 postpartum, AEA administration had no effect on dry matter intake, body weight, or lipomobilisation, but increased plasma triglyceride concentration on d 21 p.p. and mRNA abundances of genes related to hepatic triglyceride synthesis. In week 4 postpartum, the AEA group showed reduced feed intake and whole-body carbohydrate oxidation, but increased whole-body fat oxidation and hepatic lipid accumulation, likely as a result of a counter-regulatory leptin increase. In conclusion, the present study shows a tissue-specific AEA insensitivity and may point to a leptin-controlled regulation of the ECS in early-lactation.

6-OR: PAR2 Downregulates Adipose LPL through MIF—A Novel Adipose Mechanism Contributing to the Development of Hypertriglyceridemia

Lipoprotein lipase (LPL) is a key enzyme that hydrolyzes circulating triglycerides to release fatty acid (FA). In adipose tissue, LPL is required for lipid storage. However, it is currently unknown whether alteration of LPL in white adipose tissue (WAT) contributes to the development of hypertriglyceridemia. Our present study indicated that WAT isolated from human obese patients have increased expression of PAR2 which is negatively associated with LPL gene. The reduced LPL expression is also negatively correlated with increased plasma TG levels, suggesting that adipose PAR2 may modulate hyperlipidemia through downregulating LPL. In mice, aging and high palmitic oil diet significantly increased PAR2 expression in adipose tissue which was associated with high plasma MIF levels. PAR2 deficiency attenuates the rise of MIF, suggesting a key role of PAR2 in regulating adipose MIF release. MIF reduced LPL expression and activity in adipocytes. In a MIF overexpressed animal model (Mif lung Tg), high circulating MIF levels inhibited adipose LPL which was associated with increased plasma triglyceride but not fatty acid. Following high palmitic oil diet feeding, adipose LPL expression and activity were also reduced, and this reduction was reversed in PAR2 knockout mice. Interestingly, PAR2 mediated LPL in adipose tissue regulates hypertriglyceridemia through controlling adipocyte lipid storage. In Par2-/- mice, recombinant MIF perfusion recovered high plasma MIF levels, which decreased LPL and attenuated adipocyte lipid storage leading to hypertriglyceridemia. These data together suggest that the downregulation of adipose LPL by PAR2/MIF is an important mechanism for the development of hypertriglyceridemia. Disclosure Y.Huang: None. L.Li: None. L.Chen: None. X.Chen: None. P.Gao: None. Y.Qi: None. D.Qi: None. Funding Canadian Institutes of Health Research (PJT156116)

Pleiotropic effects of Salacia reticulata and Simvastatin on oxidative stress and insulin resistance in a rat model

BackgroundThe present study investigated the effects of Salacia reticulata and simvastatin on oxidative stress and insulin resistance in Sprague-Dawley (SD) rats. We compared the protective effect of a methanolic extract of Salacia reticulata (SR) with simvastatin (SVS) in rats fed a high-fat diet (HFD). Methods and resultsMale Sprague-Dawley rats were divided into the following five different groups: control (C), C+SR, HFD, HFD+SR, and HFD+SVS. High-fat diet fed rats showed hyperglycemia, hyperinsulinemia, hyperleptinemia, dyslipidemia, and hypoadiponectinemia after 90 days. Treatment of high-fat diet fed rats with SR/SVS significantly (p < 0.05) reduced high-fat diet induced increases in plasma triglycerides, total cholesterol, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL) and decreased high- density lipoprotein (HDL) accompanied by an increase in lipid peroxidation (LPO) and protein oxidation. In addition, a significant decrease in the activities of antioxidant enzymes and enzymes of the polyol pathway was observed in rats fed high-fat diet. SR was found to be more effective than SVS. Moreover, infiltration of inflammatory cells and fibrosis in the liver of high-fat diet fed rats by SR/SVS were also prevented. ConclusionsThe present study confirms that SR/SVS may be a new and promising remedial approach because of its beneficial effects on the pathophysiological processes of obesity and related metabolic disorders.

Neuronal ApoE4 in Alzheimer's disease and potential therapeutic targets.

The most prevalent genetic risk factor for Alzheimer's disease (AD) is Apolipoprotein E (ApoE), a gene located on chromosome 19 that encodes three alleles (e2, e3, and e4) that give rise to the ApoE subtypes E2, E3, and E4, respectively. E2 and E4 have been linked to increased plasma triglyceride concentrations and are known to play a critical role in lipoprotein metabolism. The prominent pathological features of AD mainly include senile plaques formed by amyloid β (Aβ42) aggregation and neuronal fibrous tangles (NFTs), and the deposited plaques are mainly composed of Aβ hyperphosphorylation and truncated head. In the central nervous system, the ApoE protein is primarily derived from astrocytes, but ApoE is also produced when neurons are stressed or affected by certain stress, injury, and aging conditions. ApoE4 in neurons induces Aβ and tau protein pathologies, leading to neuroinflammation and neuronal damage, impairing learning and memory functions. However, how neuronal ApoE4 mediates AD pathology remains unclear. Recent studies have shown that neuronal ApoE4 may lead to greater neurotoxicity, which increases the risk of AD development. This review focuses on the pathophysiology of neuronal ApoE4 and explains how neuronal ApoE4 mediates Aβ deposition, pathological mechanisms of tau protein hyperphosphorylation, and potential therapeutic targets.

Longitudinal Gut Microbiota Dysbiosis Underlies Olanzapine-Induced Weight Gain.

Olanzapine is one of the most effective medicines available for stabilizing schizophrenia spectrum disorders. However, it has been reported to show the greatest propensity for inducing body weight gain and producing metabolic side effects, which cause a great burden in patients with psychiatric disorders. Since the gut microbiota has a profound impact on the initiation and development of metabolic diseases, we conducted a longitudinal study to explore its role in olanzapine-induced obesity and metabolic abnormalities. Female Sprague-Dawley rats were treated with different doses of olanzapine, and metabolic and inflammatory markers were measured. Olanzapine significantly induced body weight gain (up to a 2.1-fold change), which was accompanied by hepatic inflammation and increased plasma triglyceride levels (up to a 2.9-fold change), as well as gut microbiota dysbiosis. Subsequently, fuzzy c-means clustering was used to characterize three clusters of longitudinal trajectories for microbial fluctuations: (i) genera continuing to increase, (ii) genera continuing to decrease, and (iii) genera temporarily changing. Among them, Enterorhabdus (r = 0.38), Parasutterella (r = 0.43), and Prevotellaceae UCG-001 (r = 0.52) positively correlated with body weight gain. In addition, two MetaCyc metabolic pathways were identified as associated with olanzapine-induced body weight gain, including the superpathway of glucose and xylose degradation and the superpathway of l-threonine biosynthesis. In conclusion, we demonstrate that olanzapine can directly alter the gut microbiota and rapidly induce dysbiosis, which is significantly associated with body weight gain. This may suggest gut microbiota targets in future studies on metabolic abnormalities caused by olanzapine. IMPORTANCE Olanzapine is one of the most effective second-generation antipsychotics for stabilizing schizophrenia spectrum disorders. However, olanzapine has multiple drug-induced metabolic side effects, including weight gain. This study provides insight to the gut microbiota target in olanzapine-induced obesity. Specifically, we explored the longitudinal gut microbiota trajectories of female Sprague-Dawley rats undergoing olanzapine treatment. We showed that olanzapine treatment causes a dynamic alteration of gut microbiota diversity. Additionally, we identified three genera, Parasutterella, Enterorhabdus, and Prevotellaceae UCG-001, that may play an important role in olanzapine-induced obesity. In this case, the supply or removal of specific elements of the gut microbiota may represent a promising avenue for treatment of olanzapine-related metabolic side effects.

A novel homozygous nonsense variant of LMF1 in pregnancy-induced hypertriglyceridemia with acute pancreatitis

Hypertriglyceridemia (HTG)-induced pancreatitis during pregnancy could lead to maternal and fetal death. However, its genetic bases are not fully understood, and its treatment strategies are yet to be established.Here we report a case with a novel homozygous nonsense variant of LMF1 in pregnancy-associated HTG with acute pancreatitis.Our patient had childhood-onset severe HTG that had been well-controlled by dietary management in the non-pregnant period with plasma triglyceride (TG) levels at around 200 mg/dL. Milky plasma was noted at the first-trimester pregnancy checkup, followed by a severe increase in plasma TG (10,500 mg/dL) that resulted in pancreatitis in the last trimester. The implementation of strict dietary fat restriction (less than 4 grams per day) reduced plasma TG levels and led to successful delivery. Exome sequencing revealed a novel homozygous nonsense variant in LMF1 (c.697C>T, p.Arg233Ter). The activities of lipoprotein lipase (LPL) and hepatic lipase in post-heparin plasma were not abolished but reduced. The use of pemafibrate decreased plasma TG levels with a concomitant increase in LPL activity.HTG in childhood or early pregnancy is commonly assumed to be polygenic in origin but should be regarded as a feature suggestive of monogenic hyperchylomicronemia. Adequate TG monitoring and dietary fat restriction should be implemented to prevent potentially lethal events of pancreatitis.

Volanesorsen and triglyceride levels in familial chylomicronemia syndrome: Long-term efficacy and safety data from patients in an open-label extension trial

Familial chylomicronemia syndrome (FCS) is a rare, autosomal recessive genetic disorder characterized by a marked increase in plasma triglyceride (TG) levels and recurrent episodes of pancreatitis. The response to conventional TG-lowering therapies is suboptimal. Volanesorsen, an antisense oligonucleotide that targets hepatic apoC-III mRNA, has been shown to significantly reduce TGs in patients with FCS. To further evaluate the safety and efficacy of extended treatment with volanesorsen in patients with FCS. This phase 3 open-label extension study evaluated the efficacy and safety of extended treatment with volanesorsen in three groups of patients with FCS: Those who had previously received volanesorsen or placebo in the APPROACH and COMPASS studies, and treatment-naive patients not participating in either study. Key endpoints included change in fasting TG and other lipid measurements, and safety over 52 weeks. Volanesorsen treatment resulted in sustained reductions in plasma TG levels in previously treated patients from the APPROACH and COMPASS studies. Volanesorsen-treated patients from the three populations studied had mean decreases in fasting plasma TGs from index study baseline to months 3, 6, 12 and 24 as follows: decreases of 48%, 55%, 50%, and 50%, respectively (APPROACH); decreases of 65%, 43%, 42%, and 66%, respectively (COMPASS); and decreases of 60%, 51%, 47%, and 46%, respectively (treatment-naive). Common adverse events were injection site reactions and platelet count decrease, consistent with previous studies. Extended open-label treatment with volanesorsen in patients with FCS resulted in sustained reductions of plasma TG levels and safety consistent with the index studies.