Metabolism Of Triglyceride-rich Lipoproteins Research Articles

Biosynthesis and Metabolism of ApoB-Containing Lipoproteins.

Recent advances in human genetics, together with a substantial body of epidemiological, preclinical and clinical trial evidence, strongly support a causal relationship between triglyceride-rich lipoproteins (TRLs) and atherosclerotic cardiovascular disease. Consequently, the secretion and metabolism of TRLs have a significant impact on cardiovascular health. This knowledge underscores the importance of understanding the molecular mechanisms and regulation of very-low-density lipoprotein (VLDL) and chylomicron biogenesis. Fortunately, there has been a resurgence of interest in the intracellular assembly, trafficking, degradation, and secretion of VLDL, leading to many ground-breaking molecular insights. Furthermore, the identification of molecular control mechanisms related to triglyceride metabolism has greatly advanced our understanding of the complex metabolism of TRLs. In this review, we explore recent advances in the assembly, secretion, and metabolism of TRLs. We also discuss available treatment strategies for hypertriglyceridemia.

Reductions in remnant cholesterol and VLDL cholesterol through inhibition of ANGPTL3 protein synthesis: an analysis from the TRANSLATE-TIMI 70 trial.

Remnant cholesterol and very low-density lipoprotein cholesterol (VLDL-C) are increasingly recognized risk factors for atherosclerotic disease with few therapeutic options. Angiopoietin-like 3 (ANGPTL3), a key protein in the metabolism of triglyceride-rich lipoproteins, is a promising target. TRANSLATE-TIMI 70 was a double-blind, placebo-controlled randomized trial testing seven dose regimens of vupanorsen, an antisense oligonucleotide against ANGPTL3, in adults with non-HDL-C ≥ 100 mg/dL and triglycerides 150-500 mg/dL. The primary endpoint of this analysis was percentage change in remnant cholesterol (total cholesterol minus directly measured LDL-C minus HDL-C) and VLDL-C (directly measured) over 24 weeks. Two hundred eighty-six patients were enrolled, with a median age of 64 years and 44% female. Median baseline remnant cholesterol and VLDL-C were 42 and 31 mg/dL, respectively (reference: <30 mg/dL). Vupanorsen lowered remnant cholesterol by 42-59% at 24 weeks over placebo (P < 0.001), achieving a median level of 18 mg/dL at the highest dose. Over the same period, VLDL-C was reduced by 52-67% over placebo (P < 0.001), with a median achieved level of 2.5 mg/dL at the highest dose. The effect of vupanorsen on remnant cholesterol and VLDL-C reduction was dose-dependent and directly associated with the degree of ANGPTL3 inhibition: at 90% ANGPTL3 reduction, there was a 61% and 81% decrease in remnant cholesterol and VLDL-C, respectively. Inhibition of ANGPTL3 protein synthesis significantly lowered remnant cholesterol and VLDL-C in patients with hypertriglyceridaemia. The magnitude of reduction was associated with the degree of ANGPTL3 inhibition. These findings support ANGPTL3 inhibition as a promising target for lowering cholesterol on triglyceride-rich lipoproteins.

ANGPTL3 and ApoC-III inhibitors for treating hypertriglyceridemia in context: horses for courses?

Hypertriglyceridemia (HTG) is an independent and casual risk factor for atherosclerotic cardiovascular disease (ASCVD). There is an unmet need for more effective treatments for patients with HTG. Angiopoietin-like protein 3 (ANGPTL3) and apolipoprotein C-III (apoC-III) are key regulators of triglyceride-rich lipoprotein (TRL) metabolism. We review recent clinical trials targeting ANGPTL3 and apoC-III with monoclonal antibody and nucleic acid therapies, including antisense oligonucleotides and small interfering RNA. ANGPTL3 and apoC-III inhibitors are effective in lowering plasma triglycerides and TRLs, with possibly greater efficacy with the inhibition of apoC-III. By contrast to ANGPTL3 inhibition that has the advantage of greater lowering of plasma low-density lipoprotein (LDL)-cholesterol and apoB levels, apoC-III inhibition only has a modest or no effect in lowering plasma LDL-cholesterol and apoB concentrations. Therapeutic inhibition of ANGPTL3 and apoC-III can correct HTG possibly by reducing production and increasing catabolism of TRL particles, but this remains to be formally investigated in patients with HTG. Novel agents targeting ANGPTL3 and apoC-III can correct HTG and potentially lower risk of ASCVD in patients with HTG. The long-term safety and cost-effectiveness of these agents await confirmation in ongoing and future studies.

Understanding Hypertriglyceridemia: Integrating Genetic Insights.

Hypertriglyceridemia is an exceptionally complex metabolic disorder characterized by elevated plasma triglycerides associated with an increased risk of acute pancreatitis and cardiovascular diseases such as coronary artery disease. Its phenotype expression is widely heterogeneous and heavily influenced by conditions as obesity, alcohol consumption, or metabolic syndromes. Looking into the genetic underpinnings of hypertriglyceridemia, this review focuses on the genetic variants in LPL, APOA5, APOC2, GPIHBP1 and LMF1 triglyceride-regulating genes reportedly associated with abnormal genetic transcription and the translation of proteins participating in triglyceride-rich lipoprotein metabolism. Hypertriglyceridemia resulting from such genetic abnormalities can be categorized as monogenic or polygenic. Monogenic hypertriglyceridemia, also known as familial chylomicronemia syndrome, is caused by homozygous or compound heterozygous pathogenic variants in the five canonical genes. Polygenic hypertriglyceridemia, also known as multifactorial chylomicronemia syndrome in extreme cases of hypertriglyceridemia, is caused by heterozygous pathogenic genetic variants with variable penetrance affecting the canonical genes, and a set of common non-pathogenic genetic variants (polymorphisms, using the former nomenclature) with well-established association with elevated triglyceride levels. We further address recent progress in triglyceride-lowering treatments. Understanding the genetic basis of hypertriglyceridemia opens new translational opportunities in the scope of genetic screening and the development of novel therapies.

Apolipoprotein E isoforms and their Cys-thiol modifications impact LRP1-mediated metabolism of triglyceride-rich lipoproteins.

The low-density lipoprotein (LDL) receptor-related protein (LRP)1 participates in the metabolism of apolipoprotein (apo) E-containing lipoproteins (apoE-LP). We investigated the effects of modifications of cysteine (Cys)-thiol of apoE on LRP1-mediated metabolism. Among the three isoforms, apoE2-LP exhibited the lowest affinity for LRP1 but was significantly catabolized, whereas apoE4-LP was sufficiently bound to LRP1 but showed the lowest catabolic capability. The reduction enhanced the binding and suppressed the catabolism of apoE3-LP, but had no effect on apoE2-LP. The formation of disulfide-linked complexes with apoAII suppressed binding, but enhanced the catabolism of apoE2-LP. Redox modifications of apoE-Cys-thiol may modulate the LRP1-mediated metabolism of apoE2- or apoE3-LP, but not apoE4-LP. The failure of this function may be involved in the pathophysiology of dyslipidemia.

Lowering apolipoprotein C-III associates with regression of lipidic plaque materials in type 2 DM patients with coronary artery disease: the pre-specified analysis from the OPTIMAL trial

Abstract Introduction Apolipoprotein CIII (ApoC-III) is a circulating lipoprotein which affects triglyceride-rich lipoprotein metabolism and functionality of high-density lipoproteins. These properties indicate ApoC-III as a potential contributor to atherosclerosis. The OPTIMAL randomized controlled trial (jRCT1052180152) compared the efficacy of continuous glucose monitoring guided versus HbA1c-guided glycemic control on coronary atherosclerosis in Type 2 Diabetes (T2DM) patients by using serial near-infrared spectroscopy/intravascular ultrasound (NIRS/IVUS). Given that NIRS/IVUS imaging enables to quantitatively evaluate plaque burden and its lipidic component in vivo, the OPTIMAL study provides an opportunity to elucidate the association of ApoC-III with change in quantity and quality of coronary plaques. Purpose To elucidate whether serial change in ApoC-III affects the degree of atheroma progression and lipidic plaque materials on NIRS/IVUS imaging. Methods The OPTIMAL trial has serially monitored non-culprit lesions in 94 T2DM patients receiving PCI by NIRS/IVUS imaging. Of these, 46 patients (73 lesions) were included into the current analysis. Circulating ApoC-III levels were measured at both baseline and 48 weeks. The relationships of serial change in ApoC-III with NIRS/IVUS-derived measures [total atheroma volume (TAV) and maximum lipid core burden index in a 4-mm segment (maxLCBI4mm)] were analyzed. Results All of study subjects received a statin, and high-intensity statin was used in 65.2% of them. On-treatment LDL-C and HbA1c levels were 1.9±0.5mmol/L and 7.2±0.7%, respectively. On NIRS/IVUS analysis, any regression of TAV and maxLCBI4mm was observed in 71.2 and 38.4% of analyzed lesions, respectively (Table). There was no significant relationship between change in ApoC-III and TAV regression (r=0.02, p=0.89). However, a reduction of ApoC-III was significantly associated with a greater regression of maxLCBI4mm (r=0.26, p=0.03) (Figure). Furthermore, multivariate analysis adjusting for LDL-C and high-intensity statin use demonstrated lowering ApoC-III level as an independent predictor of maxLCBI4mm regression (OR=0.83, 95%CI=0.69-0.99, p=0.04) (Table). Even in patients receiving high-intensity statin, the relationship of change in ApoC-III with regression of maxLCBI4mm still existed (Figure). Conclusion Serial NIRS/IVUS imaging revealed that a reduction of circulating ApoC-III was associated with a greater regression of maxLCBI4mm. Our findings suggest ApoC-III as an important therapeutic target to modulate lipidic plaque materials in T2DM receiving a statin.Tables

Apolipoprotein-CIII O-Glycosylation, a Link between GALNT2 and Plasma Lipids.

Apolipoprotein-CIII (apo-CIII) is involved in triglyceride-rich lipoprotein metabolism and linked to beta-cell damage, insulin resistance, and cardiovascular disease. Apo-CIII exists in four main proteoforms: non-glycosylated (apo-CIII0a), and glycosylated apo-CIII with zero, one, or two sialic acids (apo-CIII0c, apo-CIII1 and apo-CIII2). Our objective is to determine how apo-CIII glycosylation affects lipid traits and type 2 diabetes prevalence, and to investigate the genetic basis of these relations with a genome-wide association study (GWAS) on apo-CIII glycosylation. We conducted GWAS on the four apo-CIII proteoforms in the DiaGene study in people with and without type 2 diabetes (n = 2318). We investigated the relations of the identified genetic loci and apo-CIII glycosylation with lipids and type 2 diabetes. The associations of the genetic variants with lipids were replicated in the Diabetes Care System (n = 5409). Rs4846913-A, in the GALNT2-gene, was associated with decreased apo-CIII0a. This variant was associated with increased high-density lipoprotein cholesterol and decreased triglycerides, while high apo-CIII0a was associated with raised high-density lipoprotein-cholesterol and triglycerides. Rs67086575-G, located in the IFT172-gene, was associated with decreased apo-CIII2 and with hypertriglyceridemia. In line, apo-CIII2 was associated with low triglycerides. On a genome-wide scale, we confirmed that the GALNT2-gene plays a major role i O-glycosylation of apolipoprotein-CIII, with subsequent associations with lipid parameters. We newly identified the IFT172/NRBP1 region, in the literature previously associated with hypertriglyceridemia, as involved in apolipoprotein-CIII sialylation and hypertriglyceridemia. These results link genomics, glycosylation, and lipid metabolism, and represent a key step towards unravelling the importance of O-glycosylation in health and disease.

Sugar and Dyslipidemia: A Double-Hit, Perfect Storm.

The availability of sugar has expanded over the past 50 years, due to improved industrial processes and corn subsidies, particularly in the form of sweetened beverages. This correlates with a surge in the prevalence of cardiometabolic disorders, which has brought this issue back into the spotlight for public health. In this narrative review, we focus on the role of fructose in the genesis of cardiometabolic dyslipidemia (an increase in serum triglyceride-rich lipoproteins (TRL): VLDL, chylomicrons (CM), and their remnants) bringing together the most recent data on humans, which demonstrates the crucial interaction between glucose and fructose, increasing the synthesis while decreasing the catabolism of these particles in a synergistic downward spiral. After reviewing TRL metabolism, we discuss the fundamental principles governing the metabolism of fructose in the intestine and liver and the effects of dysregulated fructolysis, in conjunction with the activation of carbohydrate-responsive element-binding protein (ChREBP) by glucose and the resulting crosstalk. The first byproduct of fructose catabolism, fructose-1-P, is highlighted for its function as a signaling molecule that promotes fat synthesis. We emphasize the role of fructose/glucose interaction in the liver, which enhances de novo lipogenesis, triglyceride (TG) synthesis, and VLDL production. In addition, we draw attention to current research that demonstrates how fructose affects the activity of lipoprotein lipase by increasing the concentration of inhibitors such as apolipoprotein CIII (apoCIII) and angiopoietin-like protein 3 (ANGPTL3), which reduce the catabolism of VLDL and chylomicrons and cause the building up of their atherogenic remnants. The end outcome is a dual, synergistic, and harmful action that encourages atherogenesis. Thus, considering the growing concerns regarding the connection between sugar consumption and cardiometabolic disease, current research strongly supports the actions of public health organizations aimed at reducing sugar intake, including dietary guidance addressing "safe" limits for sugar consumption.

Apolipoprotein A2 reduces the levels of circulating triglyceride-rich lipoproteins, an effect blocked by apolipoprotein E

Apolipoprotein A2 (APOA2), the second in quantity apolipoprotein of high density lipoprotein (HDL) is synthesized by the liver and much less by the intestine. Studies in humans, failed to establish a clear role for APOA2 in coronary heart disease and overall human physiology. Even though we know that APOA2 plays a key role in the biogenesis and functionality of HDL particles and can interact physically with other apolipoproteins such as apolipoprotein E (APOE), forming dimers, our knowledge on its role in triglyceride-rich lipoprotein (TRL) metabolism remains limited. Here, we investigated how functional interactions between APOA2 and APOE may affect plasma lipoprotein metabolism in the absence of apolipoprotein A1 (APOA1). For this purpose, APOA1 deficient and APOA1xAPOE double deficient mice were fed high fat diet for two weeks and were subsequently infected with either an adenovirus expressing the human APOA2 (AdAPOA2) or a control adenovirus AdGFP. Five days post-infection blood was collected, and plasma and lipoprotein fractions were isolated. After confirmation of human APOA2 expression in vivo by western blot we measured plasma and lipoprotein total cholesterol and triglyceride levels. APOA2 expression increased total cholesterol and triglyceride levels in APOA1 deficient mice. To the contrary, when APOA2 was expressed in APOA1xAPOE double deficient mice, which lack functional APOE a significant reduction in both plasma cholesterol and triglyceride levels associated with a notable reduction in TRL was observed. Overall, our data support that a significant functional interaction between APOA2 and APOE impacts plasma TRL metabolism.

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux

The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as “remnants”, is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.

Effect of omega-3 fatty acid ethyl esters on postprandial arterial elasticity in patients with familial hypercholesterolemia

Impaired arterial elasticity reflects increased risk of atherosclerotic cardiovascular disease in patients with familial hypercholesterolemia (FH). Treatment with omega-3 fatty acid ethyl esters (ω-3FAEEs) in FH patients has been shown to improve postprandial triglyceride-rich lipoprotein (TRL) metabolism, including TRL-apolipoprotein(a) [TRL-apo(a)]. Whether ω-3FAEE intervention also improves postprandial arterial elasticity in FH has not been demonstrated. We carried out an 8-week open-label, randomized, crossover trial to test the effect of ω-3FAEEs (4g/day) on postprandial arterial elasticity in 20FH subjects following ingestion of an oral fat load. Fasting and postprandial large (C1) and small (C2) artery elasticity at 4 and 6h were measured by pulse contour analysis of the radial artery. The area under-the-curves (AUCs) (0-6h) for C1, C2, plasma triglycerides and TRL-apo(a) were determined using the trapezium rule. Compared with no treatment, ω-3FAEEs significantly increased fasting (+9%, P<0.05) and postprandial C1 at 4h (+13%, P<0.05) and at 6h (+10%, P<0.05), with improvement in the postprandial C1 AUC (+10%, P<0.01). ω-3FAEEs also decreased postprandial triglyceride and TRL-apo(a) AUCs (-17% and-19%, respectively, P<0.05). ω-3FAEEs had no significant effect on fasting and postprandial C2. The change in C1 AUC was inversely associated with the changes in the AUC of triglycerides (r=-0.609, P<0.01) and TRL-apo(a) (r=-0.490, P<0.05). High-dose ω-3FAEEs improves postprandial large artery elasticity in adults with FH. Reduction in postprandial TRL-apo(a) with ω-3FAEEs may contribute to the improvement in large artery elasticity. However, our findings need to be confirmed in a larger population. https://www. com/NCT01577056.

Impact of triglyceride-rich lipoproteins on early in-stent neoatherosclerosis formation in patients undergoing statin treatment

Neoatherosclerosis (NA), which refers to neointimal atherosclerosis within a stent, is considered one of the underlying causes of late-phase stent failure following a newer generation drug-eluting stent (DES) placement procedure. Even contemporary guideline-directed medical therapy may be insufficient to prevent NA. This study aimed to investigate how intricately lipid markers are associated with NA formation in the early phase of treatment with well-maintained low-density lipoprotein cholesterol (LDL-C) levels. We enrolled 114 consecutive patients undergoing statin treatment and percutaneous coronary intervention (PCI) with current-generation DES for coronary artery disease. At a median 12 months after PCI, optical coherence tomography (OCT) was performed. Various lipid markers, including LDL-C, triglyceride (TG), triglyceride-rich lipoprotein cholesterol (TRL-C), non-high-density lipoprotein cholesterol (non-HDL-C), malondialdehyde-modified LDL (MDA-LDL), and several apolipoproteins, were also evaluated. NA was observed in 17 (14.9%) patients. The LDL-C level was equivalent in patients with or without NA (77.2 vs. 69.8 mg/dL; p=0.15). However, the levels of TG, apolipoprotein C3 (apoC3), TRL-C, non-HDL-C, and apolipoprotein B (apoB), and MDA-LDL were significantly higher in the patients with NA. Furthermore, multivariate logistic regression adjusting for HbA1c and stent duration revealed apoC3, TRL-C, non-HDL-C, apoB, and MDA-LDL levels as risk factors for NA. However, when apoB was included as a covariate, other factors became nonsignificant. Abnormal triglyceride-rich lipoprotein metabolism and high atherogenic apoB-containing lipoprotein particle numbers are associated with the formation of NA in patients undergoing statin treatment at a median 12 months post-PCI.

New Therapeutic Approaches to the Treatment of Dyslipidemia 1: ApoC-III and ANGPTL3.

Low-density lipoprotein cholesterol (LDL-C)-lowering therapy that increases LDL receptor expression in several ways robustly reduces the risk of atherosclerotic cardiovascular disease (CVD). However, a substantial risk of CVD still remains after intensive LDL-C reduction, which requires new treatment modalities for dyslipidemia and cardiovascular risk management. Triglycerides (TGs) and triglyceride-rich lipoproteins (TRLs) have received attention as indicators of residual cardiovascular risk and as direct causal factors for atherosclerosis and CVDs. Advances in understanding TG and TRL metabolism and their association with clinically evident CVDs have led to the development of novel therapeutic targets, including apolipoprotein C-III (apoC-III) and angiopoietin-like protein 3 (ANGPTL3). Genetic association studies have indicated that both apoC-III and ANGPTL3 play a causal role in the development of atherosclerotic CVD. Both molecules contribute to lipid dysregulation and atherosclerosis primarily by inhibiting lipoprotein lipase; however, recent evidence has shown that novel pathways exist in relation to their lipid-modifying activities. Notably, recent progress in therapeutic approaches, such as monoclonal antibodies or antisense oligonucleotides, has led to several novel therapeutics targeting apoC-III and ANGPTL3. This review summarized the recent updates and discussions related to apoC-III and ANGPTL3 expression.

Abstract 11601: Association Between Remnant Cholesterol and Coronary Plaque Features: The Miami Heart Study at Baptist Health South Florida

Introduction: Remnant particles, the product of partial metabolism of triglyceride-rich lipoproteins, have been associated with atherosclerotic cardiovascular diseases (ASCVD), independent of low-density lipoprotein cholesterol (LDL-C). This study aims to further examine the role of remnant cholesterol (RC) in atherogenesis by assessing its association with plaque characteristics. Methods: After excluding individuals on statin therapy (n=527), we included 1,832 statin-naïve participants from the Miami Heart Study, a prospective cohort of clinical ASCVD-free individuals in Miami (2015-2018) evaluated using coronary computed tomography angiography (CTA). RC was estimated as non-high density lipoprotein cholesterol minus LDL-C. Multivariable logistic regression models were used to estimate the association between low/high RC/LDL-C groups (defined by &lt; or ≥ medians) and plaque features. Results: Mean age of participants was 52.5±6.7 years, 54% women, 49.5% Hispanic. Median LDL-C and RC were 129.1 and 21.6 mg/dL, respectively. For each SD increase in RC levels, the odds of having non-calcified coronary plaque increased (OR 1.19 [95% CI 1.07-1.33]) and so did the segmental involvement score (OR 1.05 [95% CI 1.01-1.09]) independent of traditional risk factors including LDL-C. The prevalence of coronary plaque features per RC/LDL-C group are shown in Table. Among those with low LDL-C, having high RC conferred a significantly higher risk of non-calcified plaque (OR 1.61 [95% CI 1.11-2.32]) compared to having low RC, although associations were not statistically significant with other plaque features (Table). Conclusions: In asymptomatic individuals with low LDL-C, elevated RC was independently associated with non-calcified plaque.

Recent Updates in Hypertriglyceridemia Management for Cardiovascular Disease Prevention.

Mounting evidence continues to support the causal role of triglyceride-rich lipoproteins (TRL) in the development of atherosclerotic cardiovascular disease (ASCVD). Substantial residual ASCVD risk remains among high-risk patients who have elevated triglycerides despite reduction in low-density lipoprotein cholesterol (LDL-C) with statin therapy. Ongoing research efforts have focused on evaluating triglyceride-lowering therapies among patients with hypertriglyceridemia. The REDUCE-IT trial showed that the addition of icosapent ethyl, a highly purified form of eicosapentaenoic acid (EPA), can reduce vascular events among statin-treated individuals with elevated triglycerides who have either clinical ASCVD or diabetes plus another risk factor. Although additional evidence for EPA has emerged from other trials, conflicting results have been reported by subsequent trials that tested different omega-3 fatty acid formulations. Randomized clinical trials have not demonstrated incremental ASCVD benefit of fibrates on background of statin therapy, but fibrates are used to help prevent pancreatitis in patients with severe hypertriglyceridemia. Selective inhibitors of apolipoprotein C-III (apoC3) and angiopoietin-like protein 3 (ANGPTL3), proteins that are involved in metabolism of TRLs by regulating lipoprotein lipase, have been tested in selected patient populations and showed significant reduction in triglyceride and LDL-C levels. Statin therapy continues to be the cornerstone of pharmacologic reduction of cardiovascular risk. High-dose EPA in the form of icosapent ethyl has been demonstrated to have cardiovascular benefit on top of statins in persons with elevated triglycerides at high ASCVD risk. Ongoing clinical trials are evaluating novel selective therapies such as apoC3 and ANGPTL3 inhibitors.

Hypertriglyceridemia, a causal risk factor for atherosclerosis, and its laboratory assessment.

Epidemiological and clinical studies show a causal association between serum triglyceride (TG) level, the number of triglyceride-rich lipoproteins (TRLs) and their remnants, and the increased risk of atherosclerosis and cardiovascular disease (CVD) development. In light of current guidelines for dyslipidemia management, the laboratory parameters reflecting TRL content are recommended as part of the routine lipid analysis process and used for CVD risk assessment, especially in people with hypertriglyceridemia (HTG), diabetes mellitus, obesity and low levels of low-density lipoprotein cholesterol (LDL-C), in which high residual CVD risk is observed. The basic routinely available laboratory parameters related with TRL are serum TG and non-high-density lipoprotein cholesterol (non-HDL-C) levels, but there are also other biomarkers related to TRL metabolism, the determination of which can be helpful in identifying the basis of HTG development or assessing CVD risk or can be the target of pharmacological intervention. In this review, we present the currently available laboratory parameters related to HTG. We summarise their link with TRL metabolism and HTG development, the determination methods as well as their clinical significance, the target values and interpretation of the results in relation to the current dyslipidemia guidelines.

Platycodi Radix Beverage Improves Postprandial Lipemic Response Associated With Plasma Bacteria-Derived Extracellular Vesicles in Healthy Adults With an Oral Fat Load

ObjectivesThis study aimed to examine the responsiveness of postprandial triglyceride-rich lipoprotein (TRL) metabolism to Platycodi radix beverage (PR) is associated with the alterations in plasma bacteria-derived extracellular vesicles (EVs) composition.MethodsNinety-six healthy and normolipidemic adults were randomly divided into two groups and consumed PR or placebo for 8 weeks. An oral fat tolerance test was performed before and after the 8-week intervention to access the postprandial lipid response. Plasma TG, chylomicron TG (CM-TG), and lipoprotein lipase (LPL) mass levels were measured at fasting, 3, and 6 hours during the oral fat tolerance test and summarized by computing the area under the curve (AUC). EVs isolated from fasting plasma samples were identified using 16S rRNA sequencing. A linear mixed-effect model was used to analyze the difference between the two groups. TLR clearance responder to PR consumption was defined by QUalitative INteraction Trees (QUINT). Lasso regularized generalized linear model (GLM) was used to find genera associated with the responsiveness.ResultsPR consumption for 8 weeks noticeably decreased AUC (0–3h) values for TG and CM-TG compared to the placebo group. Responders for TRL clearance were defined as subjects having higher LPL mass (150.6 ng/mL) and dietary fat intake (38.5 g/day) at baseline. Responders showed remarkable reductions in AUC (0–6h) values for TG and CM-TG in the PR group compared to the placebo group. Furthermore, GLM analysis demonstrated that the responsiveness of postprandial TRL clearance was accurately predicted by the model consisting of changes in the relative abundance of 16 genera, suggesting the close association between them.ConclusionsThese findings suggest that PR consumption modulates postprandial TRL clearance by altering plasma EV composition in normolipidemic adults with habitually higher fat intake over 38.5 g/day.Funding SourcesThis work was supported by the BK21 FOUR (Fostering Outstanding Universities for Research) funded by the Ministry of Education (MOE, Korea) and National Research Foundation of Korea (NRF), and the Bio & Medical Technology Development Program of the National Research Foundation (NRF), funded by the Ministry of Science & ICT (2012M3A9C4048761).

Triglyceride and Triglyceride-Rich Lipoproteins in Atherosclerosis.

Cardiovascular disease (CVD) is still the leading cause of death globally, and atherosclerosis is the main pathological basis of CVDs. Low-density lipoprotein cholesterol (LDL-C) is a strong causal factor of atherosclerosis. However, the first-line lipid-lowering drugs, statins, only reduce approximately 30% of the CVD risk. Of note, atherosclerotic CVD (ASCVD) cannot be eliminated in a great number of patients even their LDL-C levels meet the recommended clinical goals. Previously, whether the elevated plasma level of triglyceride is causally associated with ASCVD has been controversial. Recent genetic and epidemiological studies have demonstrated that triglyceride and triglyceride-rich lipoprotein (TGRL) are the main causal risk factors of the residual ASCVD. TGRLs and their metabolites can promote atherosclerosis via modulating inflammation, oxidative stress, and formation of foam cells. In this article, we will make a short review of TG and TGRL metabolism, display evidence of association between TG and ASCVD, summarize the atherogenic factors of TGRLs and their metabolites, and discuss the current findings and advances in TG-lowering therapies. This review provides information useful for the researchers in the field of CVD as well as for pharmacologists and clinicians.

Abstract 118: Cholesteryl Ester Transfer Protein Overrides The Protective Effect Of APOA1 On Arterial APOB Lipoprotein Trapping And Atherosclerosis Progression In A Mouse Model Of Type 1 Diabetes

Despite the benefits of LDL-cholesterol-reducing medications, patients with type 1 diabetes (T1D) continue to have an increased risk of incident CVD. Preclinical and clinical observations indicate that triglyceride-rich lipoproteins (TRLs) and their remnants may contribute significantly to CVD risk in T1D. Recently, we have shown that diabetes increases levels of atherogenic TRL remnants and that improvement of remnant clearance halts atherosclerosis in a mouse model of T1D. Cholesteryl ester transfer protein (CETP), which is normally absent in mice, links metabolism of TRLs to that of HDL by mediating the transfer of cholesteryl ester from HDL to VLDL and other APOB-containing lipoproteins in exchange for triglycerides. We hypothesized that CETP impairs the atheroprotective effects of APOA1 by altering TRL and HDL metabolism in diabetes. To test this hypothesis, we developed a virally-induced T1D mouse model expressing the human APOA1 transgene ( APOA1 Tg , Ldlr –/– ). Cohorts of these mice were injected with a liver-targeted adeno-associated virus to express human CETP, and the effects on lipoproteins, plasma apolipoproteins, HDL particle concentrations (HDL-P), and atherosclerosis in the presence and absence of diabetes were determined. This mouse model exhibits an HDL profile similar to humans, with small, medium and large HDL-P, whereas wildtype ( Ldlr -/- ) littermates have only one sized HDL-P. Expression of the APOA1 transgene significantly suppressed diabetes-accelerated necrotic core expansion and accumulation of APOB and APOE in the aortic sinus (compared to wildtype Ldlr -/- mice), while CETP impaired the protective effect of APOA1 on these parameters in diabetic APOA1 Tg , Ldlr –/– mice (n= 22-30, p &lt; 0.05). Further characterization of plasma lipoproteins and apolipoproteins by targeted mass spectrometry, FPLC and differential ion mobility analysis indicated that CETP leads to smaller TRL remnant particles, increases triglyceride content in HDL, lower levels of plasma APOA1 and reduction in large HDL-P under diabetic conditions (n= 8-10, p &lt; 0.05). Our results are consistent with the proposal that inhibition of CETP might be cardioprotective in the setting of T1D and highlight the close links between TRL and HDL metabolism in diabetes.

HDL, heart disease, and the lung

HDL, heart disease, and the lung