Increased Plasma Triglyceride Research Articles

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.

Targeting Lung-Gut Axis for Regulating Pollution Particle-Mediated Inflammation and Metabolic Disorders.

Cigarette smoking (CS) or ambient particulate matter (PM) exposure is a risk factor for metabolic disorders, such as insulin resistance (IR), increased plasma triglycerides, hyperglycemia, and diabetes mellitus (DM); it can also cause gut microbiota dysbiosis. In smokers with metabolic disorders, CS cessation decreases the risks of serious pulmonary events, inflammation, and metabolic disorder. This review included recent studies examining the mechanisms underlying the effects of CS and PM on gut microbiota dysbiosis and metabolic disorder development; one of the potential mechanisms is the disruption of the lung-gut axis, leading to gut microbiota dysbiosis, intestinal dysfunction, systemic inflammation, and metabolic disease. Short-chain fatty acids (SCFAs) are the primary metabolites of gut bacteria, which are derived from the fermentation of dietary fibers. They activate G-protein-coupled receptor (GPCR) signaling, suppress histone deacetylase (HDAC) activity, and inhibit inflammation, facilitating the maintenance of gut health and biofunction. The aforementioned gut microbiota dysbiosis reduces SCFA levels. Treatment targeting SCFA/GPCR signaling may alleviate air pollution-associated inflammation and metabolic disorders, which involve lung-gut axis disruption.

The Triglyceride/High-Density Lipoprotein Cholesterol (TG/HDL-C) Ratio as a Risk Marker for Metabolic Syndrome and Cardiovascular Disease.

Atherosclerosis is an immunoinflammatory pathological procedure in which lipid plaques are formed in the vessel walls, partially or completely occluding the lumen, and is accountable for atherosclerotic cardiovascular disease (ASCVD). ACSVD consists of three components: coronary artery disease (CAD), peripheral vascular disease (PAD) and cerebrovascular disease (CCVD). A disturbed lipid metabolism and the subsequent dyslipidemia significantly contribute to the formation of plaques, with low-density lipoprotein cholesterol (LDL-C) being the main responsible factor. Nonetheless, even when LDL-C is well regulated, mainly with statin therapy, a residual risk for CVD still occurs, and it is attributable to the disturbances of other lipid components, namely triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C). Increased plasma TG and decreased HDL-C levels have been associated with metabolic syndrome (MetS) and CVD, and their ratio, TG/HDL-C, has been proposed as a novel biomarker for predicting the risk of both clinical entities. Under these terms, this review will present and discuss the current scientific and clinical data linking the TG/HDL-C ratio with the presence of MetS and CVD, including CAD, PAD and CCVD, in an effort to prove the value of the TG/HDL-C ratio as a valuable predictor for each aspect of CVD.

Palmitic Acid is Absorbed as sn-2 Monopalmitin from Milk and Formula with Rearranged Triacylglycerols and Results in Increased Plasma Triglyceride sn-2 and Cholesteryl Ester Palmitate in Piglets

Milk fatty acids contain 20–30% palmitic acid (16:0), with -70% of the 16:0 esterified to the sn-2 position of the milk triacylglycerol. Formulae containing vegetable and oleo oils contain different amounts of 16:0, but all have unsaturated fatty acids esterified to the triacylglycerol sn-2 position. Intraluminal triacylglycerol hydrolysis by endogenous lipases produces sn-2 monoacylglycerols and free fatty acids, which are absorbed and re-esterified in the enterocyte for secretion to plasma. The extent of absorption and re-esterification of sn-2 monoacylglycerols from milk or formula fats in infants is unknown. This was studied by feeding piglets sow milk or formulae containing similar total saturated fat, 18:1, 18:2(n-6) and 18:3(n-3) with unsaturated fatty acids at the sn-2 position or with rearranged triacylglycerols containing -30% 16:0, with 70% 16:0 in fatty acids at the sn-2 position. Feeding milk or 16:0 on the sn-2 position of formula with rearranged triacylglycerols resulted in higher 16:0 esterified to the plasma triacylglycerol sn-2 position and in cholesteryl esters than feeding formulae with 0.4 to 4.4% 16:0 in the sn-2 position fatty acids. The absorption of 16:0 as monopalmitin from milk and any metabolic importance in human infants has yet to be determined.

Hepatocyte mARC1 promotes fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) has a prevalence of ∼25% worldwide, with significant public health consequences yet few effective treatments. Human genetics can help elucidate novel biology and identify targets for new therapeutics. Genetic variants in mitochondrial amidoxime-reducing component 1 (MTARC1) have been associated with NAFLD and liver-related mortality; however, its pathophysiological role and the cell type(s) mediating these effects remain unclear. We aimed to investigate how MTARC1 exerts its effects on NAFLD by integrating human genetics with invitro and invivo studies of mARC1 knockdown. Analyses including multi-trait colocalisation and Mendelian randomisation were used to assess the genetic associations of MTARC1. In addition, we established an invitro long-term primary human hepatocyte model with metabolic readouts and used the Gubra Amylin NASH (GAN)-diet non-alcoholic steatohepatitis mouse model treated with hepatocyte-specific N-acetylgalactosamine (GalNAc)-siRNA to understand the invivo impacts of MTARC1. We showed that genetic variants within the MTARC1 locus are associated with liver enzymes, liver fat, plasma lipids, and body composition, and these associations are attributable to the same causal variant (p.A165T, rs2642438G>A), suggesting a shared mechanism. We demonstrated that increased MTARC1 mRNA had an adverse effect on these traits using Mendelian randomisation, implying therapeutic inhibition of mARC1 could be beneficial. Invitro mARC1 knockdown decreased lipid accumulation and increased triglyceride secretion, and invivo GalNAc-siRNA-mediated knockdown of mARC1 lowered hepatic but increased plasma triglycerides. We found alterations in pathways regulating lipid metabolism and decreased secretion of 3-hydroxybutyrate upon mARC1 knockdown invitro and invivo. Collectively, our findings from human genetics, and invitro and invivo hepatocyte-specific mARC1 knockdown support the potential efficacy of hepatocyte-specific targeting of mARC1 for treatment of NAFLD. We report that genetically predicted increases in MTARC1 mRNA associate with poor liver health. Furthermore, knockdown of mARC1 reduces hepatic steatosis in primary human hepatocytes and a murine NASH model. Together, these findings further underscore the therapeutic potential of targeting hepatocyte MTARC1 forNAFLD.

Acetyl-CoA carboxylase inhibitor increases LDL-apoB production rate in NASH with cirrhosis: prevention by fenofibrate

Treatment with acetyl-CoA carboxylase inhibitors (ACCi) in nonalcoholic steatohepatitis (NASH) may increase plasma triglycerides (TGs), with variable changes in apoB concentrations. ACC is rate limiting in de novo lipogenesis and regulates fatty acid oxidation, making it an attractive therapeutic target in NASH. Our objectives were to determine the effects of the ACCi, firsocostat, on production rates of plasma LDL-apoB in NASH and the effects of combined therapy with fenofibrate. Metabolic labeling with heavy water and tandem mass spectrometric analysis of LDL-apoB enrichments was performed in 16 NASH patients treated with firsocostat for 12 weeks and in 29 NASH subjects treated with firsocostat and fenofibrate for 12 weeks. In NASH on firsocostat, plasma TG increased significantly by 17% from baseline to week 12 (P = 0.0056). Significant increases were also observed in LDL-apoB fractional replacement rate (baseline to week 12: 31 ± 20.2 to 46 ± 22.6%/day, P = 0.03) and absolute synthesis rate (ASR) (30.4–45.2 mg/dl/day, P = 0.016) but not plasma apoB concentrations. The effect of firsocostat on LDL-apoB ASR was restricted to patients with cirrhosis (21.0 ± 9.6 at baseline and 44.2 ± 17 mg/dl/day at week 12, P = 0.002, N = 8); noncirrhotic patients did not change (39.8 ± 20.8 and 46.3 ± 14.8 mg/dl/day, respectively, P = 0.51, N = 8). Combination treatment with fenofibrate and firsocostat prevented increases in plasma TG, LDL-apoB fractional replacement rate, and ASR. In summary, in NASH with cirrhosis, ACCi treatment increases LDL-apoB100 production rate and this effect can be prevented by concurrent fenofibrate therapy.

LOSS OF EPITHELIAL DUOX2 SIGNALING IS ACCOMPANIED BY A REDUCTION IN AKKERMANSIACEAE AND PROMOTES THE DEVELOPMENT OF METABOLIC SYNDROME IN A MICROBIOME-DEPENDENT MANNER

Abstract BACKGROUND Dysbiosis, an imbalance in microbial composition or function, is a key player in the development of conditions associated with chronic inflammation. The gut epithelium regulates host-microbiome dynamics through a variety of mechanisms, including the release of reactive oxygen species by NADPH oxidases. Dual oxidase 2 (DUOX2) is an antimicrobial NADPH oxidase expressed in the thyroid gland and gut epithelium and its activity is associated with dysbiosis. Loss of function mutations in DUOX2 are linked to the development of metabolic and inflammatory conditions such as congenital hypothyroidism and inflammatory bowel disease. Metabolic syndrome (MetS) is a cluster of conditions characterized by dysbiosis, inflammation, obesity, glucose intolerance, and hepatic steatosis. Dysbiosis in MetS is associated with a reduction in Bacteroidaceae and Akkermansiaceae. Despite this association, the mechanism by which dysbiosis leads to chronic inflammation and MetS is poorly defined. Here, we investigate the relationship between impaired epithelial barrier function and the development of MetS by focusing for the first time on intestinal specific DUOX2 deficiency as a mechanistic link. METHODS Mice carrying an intestinal epithelial-specific deletion of DUOX2 (DA IEC-KO), and wild-type (WT) littermates were fed a standard diet and euthanized at 24 weeks. DUOX2 activity was determined by Amplex Red. Metabolic alterations were determined by glucose tolerance tests and body, adipose tissue, and liver weight measurements and histological and gene expression assessments. Intestinal permeability was determined by FITC-dextran and microbial translocation assessments. The role of the microbiome was assessed by RNA-sequencing of stool and in antibiotic-treated mice. RESULTS DA IEC-KO mice produced less epithelial H2O2 and exhibited increased body, liver, and adipose tissue weights that were accompanied by glucose intolerance and increased plasma triglycerides, lipid deposition in the liver, and lipid droplet size in adipocytes. Expression of macrophage and thermogenesis markers, F4/80, CD68, and UCP1 were altered in the liver and adipose tissue of these mice. DA IEC-KO mice showed altered gut permeability and increased bacterial translocation to the liver and adipocytes. Microbial sequencing revealed that loss of intestinal epithelial DUOX2 activity led to significant differences in alpha and beta diversity, and a marked reduction in the family Akkermansiaceae. Antibiotic depletion of the microbiota abrogated all MetS phenotypes observed. CONCLUSION Our findings suggest that loss of intestinal epithelial DUOX2 activity leads to increased intestinal permeability and MetS in a microbiome dependent manner. These findings are significant in that they elucidate a novel role for epithelial DUOX2 at the host-microbial interface with distant systemic effects.

Effect of various dietary fructose concentrations on the gallstone formation process in mice.

Background: little information is availaible on the effect of fructose on bile lipids. The first stage in the formation of gallstones corresponds to biliary cholesterol crystallization, derived from the vesicular transporters. The aim of this study was to investigate the influence of consuming diets with different fructose concentrations on serum lipids and their implications on gallstones formation. Methods: BALB/c mice divided into a control group as well as groups were treated with different fructose concentrations (10 %, 30 %, 50 % or 70 %) for different periods (1, 2 or 5 months). Blood, liver and bile samples were obtained. In bile samples, cholesterol and phospholipids levels were analyzed, and cholesterol transporters (vesicles and micelles) were separated by gel filtration chromatography. Results: treated animals showed: 1) increases in body weight similar to the control group; 2) a significant increase in plasma triglycerides only at very high fructose concentrations; 3) a significant increase in total serum cholesterol in the treatment for 1 month; 4) no variations in HDL-cholesterol; 5) a significant increase in serum glucose only at very high fructose concentrations in the second month of treatment; 6) no differences in the plasma alanine-aminotransferase activity; 7) a significant increase in liver triglyceride levels only at very high fructose concentrations; 8) no change in biliary lipid concentrations or in micellar and vesicular phospholipids. Conclusion: changes in plasma, liver and bile lipids were only observed at very high fructose concentrations diets. We conclude that fructose apparently does not alter the gallstone formation process in our experimental model.