Triglyceride-rich Lipoprotein Remnants Research Articles

A significant presence in atherosclerotic cardiovascular disease: Remnant cholesterol: A review.

The current first-line treatment for atherosclerotic cardiovascular disease (ASCVD) involves the reduction of a patient's low-density lipoprotein cholesterol (LDL-C) levels through the use of lipid-lowering drugs. However, even when other risk factors such as hypertension and diabetes are effectively managed, there remains a residual cardiovascular risk in these patients despite achieving target LDL-C levels with statins and new lipid-lowering medications. This risk was previously believed to be associated with lipid components other than LDL, such as triglycerides. However, recent studies have unveiled the crucial role of remnant cholesterol (RC) in atherosclerosis, not just triglycerides. The metabolized product of triglyceride-rich lipoproteins is referred to as triglyceride-rich remnant lipoprotein particles, and its cholesterol component is known as RC. Numerous pieces of evidence from epidemiological investigations and genetic studies demonstrate that RC plays a significant role in predicting the incidence of ASCVD. As a novel marker for atherosclerosis prediction, when LDL-C is appropriately controlled, RC should be prioritized for attention and intervention among individuals at high risk of ASCVD. Therefore, reducing RC levels through the use of various lipid-lowering drugs may yield long-term benefits. Nevertheless, routine testing of RC in clinical practice remains controversial, necessitating further research on the treatment of elevated RC levels to evaluate the advantages of reducing RC in patients at high risk of ASCVD.

Zodasiran, an RNAi Therapeutic Targeting ANGPTL3, for Mixed Hyperlipidemia

BackgroundAngiopoietin-like 3 (ANGPTL3) inhibits lipoprotein and endothelial lipases and hepatic uptake of triglyceride-rich lipoprotein remnants. ANGPTL3 loss-of-function carriers have lower levels of triglycerides, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, and non-HDL cholesterol and a lower risk of atherosclerotic cardiovascular disease than noncarriers. Zodasiran is an RNA interference (RNAi) therapy targeting expression of ANGPTL3 in the liver.MethodsWe conducted a double-blind, placebo-controlled, dose-ranging phase 2b trial to evaluate the safety and efficacy of zodasiran in adults with mixed hyperlipidemia (fasting triglyceride level of 150 to 499 mg per deciliter and either an LDL cholesterol level of ≥70 mg per deciliter or a non-HDL cholesterol level of ≥100 mg per deciliter). Eligible patients were randomly assigned in a 3:1 ratio to receive subcutaneous injections of zodasiran (50, 100, or 200 mg) or placebo on day 1 and week 12 and were followed through week 36. The primary end point was the percent change in the triglyceride level from baseline to week 24.ResultsA total of 204 patients underwent randomization. At week 24, substantial mean dose-dependent decreases from baseline in ANGPTL3 levels were observed with zodasiran (difference in change vs. placebo, −54 percentage points with 50 mg, −70 percentage points with 100 mg, and −74 percentage points with 200 mg), and significant dose-dependent decreases in triglyceride levels were observed (difference in change vs. placebo, −51 percentage points, −57 percentage points, and −63 percentage points, respectively) (P<0.001 for all comparisons). Other differences in change from baseline as compared with placebo included the following: for non-HDL cholesterol level, −29 percentage points with 50 mg, −29 percentage points with 100 mg, and −36 percentage points with 200 mg; for apolipoprotein B level, −19 percentage points, −15 percentage points, and −22 percentage points, respectively; and for LDL cholesterol level, −16 percentage points, −14 percentage points, and −20 percentage points, respectively. We observed a transient elevation in glycated hemoglobin levels in patients with preexisting diabetes who received the highest dose of zodasiran.ConclusionsIn patients with mixed hyperlipidemia, zodasiran was associated with significant decreases in triglyceride levels at 24 weeks. (Funded by Arrowhead Pharmaceuticals; ARCHES-2 ClinicalTrials.gov number, NCT04832971.)

Abstract 1005: Hypertriglyceridemia Promotes Aortic Aneurysm Formation And Rupture In Angiotensin Ii Infused Mice

Plasma total cholesterol (TC) and triglyceride (TG) are reported to be positively associated with the risk of abdominal aortic aneurysm (AAA). Our group discovered that hypercholesterolemia augments angiotensin II-induced AAA in mice. We also found that remnants of triglyceride-rich lipoproteins (TRLs) may be crucial for AngII-induced AAA. Recently, it was reported that hypertriglyceridemia (HTG) caused by inducible lipoprotein lipase deficiency (iLpl-/-) results in uptake and accumulation of TRL lipid in aortic endothelial cells in vivo. Based upon these findings, we hypothesized that HTG stimulates AAA formation. Methods: Adult male and female Lplf/f.beta-actin-Mer/Cre/Mer 1/0 and Lplf/f mice were administered 75 mg/kg/day tamoxifen for 5 consecutive days. Mice were fed either a standard diet (SD) throughout the study or a Western-type diet (WD) starting 1 wk after the completion of tamoxifen administration and continuing for a total of 5 wks. Mini osmotic pumps were implanted in mice 2 wks after completion of tamoxifen administration and delivered saline or AngII at 1,000 ng/kg/min for 4 wks. Results: AngII infused and SD fed iLpl-/- versus Lplf/f mice had elevated plasma TG and TC levels but similar abdominal aortic external diameter and AAA incidence. Since the SD was low in fat, a high fat WD was then fed to AngII-infused mice. Plasma TG and TC were increased in female iLpl-/- versus Lplf/f mice. However, plasma lipid concentrations could not be measured in male iLpl-/- because 10 of 11 animals had died from aortic rupture. In contrast, none of the male Lplf/f mice died and only 4 of 11 had abdominal aortic dilation. Female compared to male iLpl-/- mice were protected from AngII-induced aortic rupture (1/11 died) and only 1 of 9 females had abdominal aortic dilation. To eliminate the possibility that HTG alone caused aortic rupture in male mice, the study was repeated with the addition of saline infusion. In agreement with the first study, AngII plus WD lead to death by aortic rupture in all male iLpl-/- mice (9/9). In contrast, iLpl-/- male mice infused with saline had markedly greater survival (1/5 died of unknown cause). Conclusions: HTG causes aortic aneurysm development in AngII-infused male iLpl-/- mice. Thus, treating HTG could reduce AAA risk.

The Role of Triglycerides in Atherosclerosis: Recent Pathophysiologic Insights and Therapeutic Implications.

Triglycerides have long been recognized as a cardiovascular disease risk factor. However, their precise role in atherosclerosis and potential utility as a therapeutic target remains debated topics. This review aims to shed light on these aspects by exploring the complex relationship between triglycerides and atherosclerosis from pathophysiological and pharmacological perspectives. Triglycerides, primarily carried by chylomicrons and very low-density lipoproteins, play an essential role in energy storage and utilization. Dysregulation of triglyceride homeostasis and triglyceride- rich lipoproteins metabolism often leads to hypertriglyceridemia and subsequently increases atherosclerosis risk. Triglyceride-rich lipoproteins remnants interact with arterial wall endothelial cells, get retained in the subendothelial space, and elicit inflammatory responses, thereby accelerating atherogenesis. Despite the clear association between high triglyceride levels and increased cardiovascular disease risk, intervention trials targeting triglyceride reduction have produced mixed results. We discuss a range of triglyceride-lowering agents, from fibrates to omega-3 fatty acids, with a focus on their mechanism of action, efficacy, and major clinical trial outcomes. Notably, the role of newer agents, such as angiopoietin-like protein 3 and apolipoprotein C3 inhibitors, is also explored. We highlight the challenges and controversies, including the ongoing debate on the causal role of triglyceride in atherosclerosis and the discordant outcomes of recent clinical trials. The potential confounding effects of associated risk factors, such as elevated apolipoprotein B, insulin resistance, and metabolic syndrome, are considered. In conclusion, this review underscores the importance of a nuanced approach to understanding the role of triglycerides in atherosclerosis and their potential as a therapeutic target. Further research is needed to unravel the complex interplay between triglycerides, triglyceride-rich lipoproteins, and associated factors in atherosclerosis pathogenesis and refine triglyceride-targeted therapeutic strategies.

Triglyceride-rich lipoproteins and cardiovascular diseases.

The global prevalence of cardiovascular diseases (CVD) continues to rise steadily, making it a leading cause of mortality worldwide. Atherosclerosis (AS) serves as a primary driver of these conditions, commencing silently at an early age and culminating in adverse cardiovascular events that severely impact patients' quality of life or lead to fatality. Dyslipidemia, particularly elevated levels of low-density lipoprotein cholesterol (LDL-C), plays a pivotal role in AS pathogenesis as an independent risk factor. Research indicates that abnormal LDL-C accumulation within arterial walls acts as a crucial trigger for atherosclerotic plaque formation. As the disease progresses, plaque accumulation may rupture or dislodge, resulting in thrombus formation and complete blood supply obstruction, ultimately causing myocardial infarction, cerebral infarction, and other common adverse cardiovascular events. Despite adequate pharmacologic therapy targeting LDL-C reduction, patients with cardiometabolic abnormalities remain at high risk for disease recurrence, highlighting the importance of addressing lipid risk factors beyond LDL-C. Recent attention has focused on the causal relationship between triglycerides, triglyceride-rich lipoproteins (TRLs), and their remnants in AS risk. Genetic, epidemiologic, and clinical studies suggest a causal relationship between TRLs and their remnants and the increased risk of AS, and this dyslipidemia may be an independent risk factor for adverse cardiovascular events. Particularly in patients with obesity, metabolic syndrome, diabetes, and chronic kidney disease, disordered TRLs and its remnants levels significantly increase the risk of atherosclerosis and cardiovascular disease development. Accumulation of over-synthesized TRLs in plasma, impaired function of enzymes involved in TRLs lipolysis, and impaired hepatic clearance of cholesterol-rich TRLs remnants can lead to arterial deposition of TRLs and its remnants, promoting foam cell formation and arterial wall inflammation. Therefore, understanding the pathogenesis of TRLs-induced AS and targeting it therapeutically could slow or impede AS progression, thereby reducing cardiovascular disease morbidity and mortality, particularly coronary atherosclerotic heart disease.

Abstract 13940: Remnant Lipoprotein Particles and Cholesterol Contribute to Proatherogenic Phenotype and Subclinical Inflammation in Youth-Onset Type 2 Diabetes

Introduction: Youth-onset type 2 diabetes (YT2D) is a rapidly progressive disease characterized by severe insulin resistance (IR), elevated triglyceride concentrations, and low HDL-cholesterol (-C). However, the contribution of triglyceride-rich remnant lipoproteins (TRLp) and remnant-C to overall atherogenic risk in YT2D is unknown, especially in the absence of clinically relevant elevations in LDL-C. Hypothesis: We hypothesized that YT2D would have higher remnant TRLp, remnant-C, and greater subclinical inflammation and IR compared to healthy peers with obesity. Methods: We measured fasting lipoprotein particle size and number, GlycA (a composite marker of inflammation), and lipoprotein IR index (LPIR) using NMR LipoProfile® in 61 YT2D (age 17.2 ±2.9 y, mean±SD, BMI 39.1 ±8.4 kg/m2) and 25 healthy peers (age 17.9 ± 5.1 y, BMI 35.8 ±5.7 kg/m2). Remnant Lp (small TRLp plus very small TRLp) and remnant-C (total-C minus HDL-C minus LDL-C) were calculated and the relationship with GlycA and LPIR determined by spearman correlations. Results: YT2D had higher HemoglobinA1c (7.6 ± 2.0 vs 5.8 ± 0.8%), GlycA (427 [388, 474] vs 376 [332, 406] nmol/L, median[25th,75th]), LPIR (53.7 ± 23.6 vs 29.6 ± 16.5). YT2D had higher remnant TRLp and remnant-C (Figure 1) and a more proatherogenic lipid and lipoprotein profile: LDL-C: 89 ± 23 vs 74 ± 20 mg/dL; total LDLp: 1392 ±368 vs 1075 ±289 nmol/L; small LDLp: 890 ±450 vs 519 ±232 nmol/L, all P&lt;0.01. LPIR was associated with remnant-C (r=0.6, P&lt;0.001) but not with LDL-C (r=0.1, P=0.6). GlycA was associated with remnant-C, remnant TRLp, and small LDLp (all r≥0.3, P&lt;0.01). Conclusion: The proatherogenic profile in YT2D is characterized by higher small LDLp, remnant TRLp, and remnant-C and is related to IR and subclinical inflammation compared to healthy peers with obesity. Future research is needed to determine whether reducing all proatherogenic lipoproteins and inflammation will reduce ASCVD risk.

Triglyceride-rich remnant lipoproteins are more atherogenic than LDL per particle: is this important?

Triglyceride-rich remnant lipoproteins are more atherogenic than LDL per particle: is this important?

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.

Triglyceride-rich lipoprotein remnants, low-density lipoproteins, and risk of coronary heart disease: a UK Biobank study.

The strength of the relationship of triglyceride-rich lipoproteins (TRL) with risk of coronary heart disease (CHD) compared with low-density lipoprotein (LDL) is yet to be resolved. Single-nucleotide polymorphisms (SNPs) associated with TRL/remnant cholesterol (TRL/remnant-C) and LDL cholesterol (LDL-C) were identified in the UK Biobank population. In a multivariable Mendelian randomization analysis, TRL/remnant-C was strongly and independently associated with CHD in a model adjusted for apolipoprotein B (apoB). Likewise, in a multivariable model, TRL/remnant-C and LDL-C also exhibited independent associations with CHD with odds ratios per 1 mmol/L higher cholesterol of 2.59 [95% confidence interval (CI): 1.99-3.36] and 1.37 [95% CI: 1.27-1.48], respectively. To examine the per-particle atherogenicity of TRL/remnants and LDL, SNPs were categorized into two clusters with differing effects on TRL/remnant-C and LDL-C. Cluster 1 contained SNPs in genes related to receptor-mediated lipoprotein removal that affected LDL-C more than TRL/remnant-C, whereas cluster 2 contained SNPs in genes related to lipolysis that had a much greater effect on TRL/remnant-C. The CHD odds ratio per standard deviation (Sd) higher apoB for cluster 2 (with the higher TRL/remnant to LDL ratio) was 1.76 (95% CI: 1.58-1.96), which was significantly greater than the CHD odds ratio per Sd higher apoB in cluster 1 [1.33 (95% CI: 1.26-1.40)]. A concordant result was obtained by using polygenic scores for each cluster to relate apoB to CHD risk. Distinct SNP clusters appear to impact differentially on remnant particles and LDL. Our findings are consistent with TRL/remnants having a substantially greater atherogenicity per particle than LDL.

Dietary choline increases brown adipose tissue activation markers and improves cholesterol metabolism in female APOE*3-Leiden.CETP mice.

Studies in mice have recently linked increased dietary choline consumption to increased incidence of obesity-related metabolic diseases, while several clinical trials have reported an anti-obesity effect of high dietary choline intake. Since the underlying mechanisms by which choline affects obesity are incompletely understood, the aim of the present study was to investigate the role of dietary choline supplementation in adiposity. Female APOE*3-Leiden.CETP mice, a well-established model for human-like lipoprotein metabolism and cardiometabolic diseases, were fed a Western-type diet supplemented with or without choline (1.2%, w/w) for up to 16 weeks. Dietary choline reduced body fat mass gain, prevented adipocyte enlargement, and attenuated adipose tissue inflammation. Besides, choline ameliorated liver steatosis and damage, associated with an upregulation of hepatic genes involved in fatty acid oxidation. Moreover, choline reduced plasma cholesterol, as explained by a reduction of plasma non-HDL cholesterol. Mechanistically, choline reduced hepatic VLDL-cholesterol secretion and enhanced the selective uptake of fatty acids from triglyceride-rich lipoprotein (TRL)-like particles by brown adipose tissue (BAT), consequently accelerating the clearance of the cholesterol-enriched TRL remnants by the liver. In APOE*3-Leiden.CETP mice, dietary choline reduces body fat by enhancing TRL-derived fatty acids by BAT, resulting in accelerated TRL turnover to improve hypercholesterolemia. These data provide a mechanistic basis for the observation in human intervention trials that high choline intake is linked with reduced body weight.

Cargo-Specific Role for Retriever Subunit VPS26C in Hepatocyte Lipoprotein Receptor Recycling to Control Postprandial Triglyceride-Rich Lipoproteins.

The copper metabolism MURR1 domains/coiled-coil domain containing 22/coiled-coil domain containing 93 (CCC) complex is required for the transport of low-density lipoprotein receptor (LDLR) and LRP1 (LDLR-related protein 1) from endosomes to the cell surface of hepatocytes. Impaired functioning of hepatocytic CCC causes hypercholesterolemia in mice, dogs, and humans. Retriever, a protein complex consisting of subunits VPS26C, VPS35L, and VPS29, is associated with CCC, but its role in endosomal lipoprotein receptor transport is unclear. We here investigated the contribution of retriever to hepatocytic lipoprotein receptor recycling and plasma lipids regulation. Using somatic CRISPR/Cas9 gene editing, we generated liver-specific VPS35L or VPS26C-deficient mice. We determined total and surface levels of LDLR and LRP1 and plasma lipids. In addition, we studied the protein levels and composition of CCC and retriever. Hepatocyte VPS35L deficiency reduced VPS26C levels but had minimal impact on CCC composition. VPS35L deletion decreased hepatocytic surface expression of LDLR and LRP1, accompanied by a 21% increase in plasma cholesterol levels. Hepatic VPS26C ablation affected neither levels of VPS35L and CCC subunits, nor plasma lipid concentrations. However, VPS26C deficiency increased hepatic LDLR protein levels by 2-fold, probably compensating for reduced LRP1 functioning, as we showed in VPS26C-deficient hepatoma cells. Upon PCSK9 (proprotein convertase subtilisin/kexin type 9)-mediated LDLR elimination, VPS26C ablation delayed postprandial triglyceride clearance and increased plasma triglyceride levels by 26%. Our study suggests that VPS35L is shared between retriever and CCC to facilitate LDLR and LRP1 transport from endosomes to the cell surface. Conversely, retriever subunit VPS26C selectively transports LRP1, but not LDLR, and thereby may control hepatic uptake of postprandial triglyceride-rich lipoprotein remnants.

Role of thermogenic adipose tissue in lipid metabolism and atherosclerotic cardiovascular disease: lessons from studies in mice and humans.

Brown adipocytes within brown adipose tissue (BAT) and beige adipocytes within white adipose tissue dissipate nutritional energy as heat. Studies in mice have shown that activation of thermogenesis in brown and beige adipocytes enhances the lipolytic processing of triglyceride-rich lipoproteins (TRLs) in plasma to supply these adipocytes with fatty acids for oxidation. This process results in formation of TRL remnants that are removed from the circulation through binding of apolipoprotein E (ApoE) on their surface to the LDL receptor (LDLR) on hepatocytes, followed by internalization. Concomitantly, lipolytic processing of circulating TRLs leads to generation of excess surface phospholipids that are transferred to nascent HDLs, increasing their capacity for reverse cholesterol transport. Activation of thermogenic adipocytes thus lowers circulating triglycerides and non-HDL-cholesterol, while it increases HDL-cholesterol. The combined effect is protection from atherosclerosis development, which becomes evident in humanized mouse models with an intact ApoE-LDLR clearance pathway only, and is additive to the effects of classical lipid-lowering drugs including statins and proprotein convertase subtilisin/kexin type 9 inhibitors. A large recent study revealed that the presence of metabolically active BAT in humans is associated with lower triglycerides, higher HDL-cholesterol and lower risk of cardiovascular diseases. This narrative review aims to provide leads for further exploration of thermogenic adipose tissue as a therapeutic target. To this end, we describe the latest knowledge on the role of BAT in lipoprotein metabolism and address, for example, the discovery of the β2-adrenergic receptor as the dominant adrenergic receptor in human thermogenic adipocytes.

Apolipoprotein F is reduced in humans with steatosis and controls plasma triglyceride-rich lipoprotein metabolism.

NAFLD affects nearly 25% of the global population. Cardiovascular disease (CVD) is the most common cause of death among patients with NAFLD, in line with highly prevalent dyslipidemia in this population. Increased plasma triglyceride (TG)-rich lipoprotein (TRL) concentrations, an important risk factor for CVD, are closely linked with hepatic TG content. Therefore, it is of great interest to identify regulatory mechanisms of hepatic TRL production and remnant uptake in the setting of hepatic steatosis. To identify liver-regulated pathways linking intrahepatic and plasma TG metabolism, we performed transcriptomic analysis of liver biopsies from two independent cohorts of obese patients. Hepatic encoding apolipoprotein F ( APOF ) expression showed the fourth-strongest negatively correlation with hepatic steatosis and the strongest negative correlation with plasma TG levels. The effects of adenoviral-mediated human ApoF (hApoF) overexpression on plasma and hepatic TG were assessed in C57BL6/J mice. Surprisingly, hApoF overexpression increased both hepatic very low density lipoprotein (VLDL)-TG secretion and hepatic lipoprotein remnant clearance, associated a ~25% reduction in plasma TG levels. Conversely, reducing endogenous ApoF expression reduced VLDL secretion in vivo , and reduced hepatocyte VLDL uptake by ~15% in vitro . Transcriptomic analysis of APOF -overexpressing mouse livers revealed a gene signature related to enhanced ApoB-lipoprotein clearance, including increased expression of Ldlr and Lrp1 , among others. These data reveal a previously undescribed role for ApoF in the control of plasma and hepatic lipoprotein metabolism by favoring VLDL-TG secretion and hepatic lipoprotein remnant particle clearance.

Palmar Striated Xanthomas in Clinical Practice.

Context Palmar striated xanthomas (PSX) are macular subcutaneous lesions conferring a yellow-to-orange coloration of palmar and finger creases that characterize dysbetalipoproteinemia, a disease associated with sustained plasma accumulation of triglyceride-rich lipoprotein remnants. Although remnants accumulation may occur in any condition interfering with triglyceride-rich lipoprotein hydrolysis or clearance, the presence of PSX has not been systematically assessed across the spectrum of lipid disorders potentially associated with sustained or recurrent remnants accumulation.ObjectiveThe aim of this study was to assess the occurrence of (PSX) in a wide spectrum of lipid disorders ranging from very severe hypercholesterolemia (homozygous familial hypercholesterolemia) to very severe hypertriglyceridemia (chylomicronemia).MethodsThis study involved 3382 dyslipidemic White adult patients (1856 men and 1526 women) seen at the Chicoutimi Hospital Lipid Clinic (Quebec, Canada), covering a wide range of lipid disorders, from severe hypertriglyceridemia to severe hypercholesterolemia. Categorical variables were compared using the Pearson χ 2 statistic, whereas univariate analysis of variance or nonparametric Kruskal-Wallis was used for continuous variables.ResultsA total of 5.1% (173/3382) of the studied patients presented PSX, a majority of them (67.1%) being women. PSX were observed in 18.8% of patients with dysbetalipoproteinemia and also among 14.1% of hypertriglyceridemic patients with partial lipoprotein lipase deficiency, 3.7% of patients with chylomicronemia, and in all those with homozygous familial hypercholesterolemia. Overall, 10.7% of patients with PSX did not meet dysbetalipoproteinemia diagnosis criteria.ConclusionAccording to our study, the PSX prevalence estimate among patients without dysbetalipoproteinemia would be around 10% and they could be observed in a wide spectrum of lipid disorders associated with recurrent or sustained remnant lipoprotein accumulation.

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.

Inflammatory Links Between Hypertriglyceridemia and Atherogenesis.

Recent studies indicate an association between hypertriglyceridemia (HTG) and atherosclerotic cardiovascular disease (ASCVD). The purpose of this review is to discuss the potential mechanism connecting HTG and ASCVD risk and the potential efficacy of HTG-targeting therapies in ASCVD prevention. HTG, with elevations in triglyceride-rich lipoproteins (TGRL) and their remnants, are causal ASCVD risk factors. The mechanisms whereby HTG increases ASCVD risk are not well understood but may include multiple factors. Inflammation plays a crucial role in atherosclerosis. TGRL compared to low-density lipoproteins (LDL) correlate better with inflammation. TGRL remnants can penetrate endothelium and interact with macrophages leading to foam cell formation and inflammation in arterial walls, thereby contributing to atherogenesis. In addition, circulating monocytes can take up TGRL and become lipid-laden foamy monocytes, which infiltrate the arterial wall and may also contribute to atherogenesis. Novel therapies targeting HTG or inflammation are in development and have potential of reducing residual ASCVD risk associated with HTG. Clinical and preclinical studies show a causal role of HTG in promoting ASCVD, in which inflammation plays a vital role. Novel therapies targeting HTG or inflammation have potential of reducing residual ASCVD risk.

Hypertriglyceridemia Induced Acute Pancreatitis Caused by a Novel LIPC Gene Variant in a Pediatric Patient

Hypertriglyceridemia induced acute pancreatitis is a rare cause of pancreatitis in children. Hepatic lipase deficiency is an extremely rare cause of hypertriglyceridemia, reported in only a few families to date. Hepatic lipase is the enzyme involved in the hydrolysis of triglycerides and phospholipids in remnants of triglyceride-rich lipoproteins that have a role in the conversion of very low density lipoprotein remnants to low density lipoproteins. Hepatic lipase deficiency is inherited in an autosomal recessive pattern. Detection of heterozygous carriers of hepatic lipase mutations remains accidental at the population level, as affected persons with a heterozygous state of hepatic lipase mutation do not display specific lipoprotein abnormalities and also patients with complete hepatic lipase deficiency have inconstant phenotype. The proximal promoter of the LIPC gene consists of four polymorphic sites in complete linkage disequilibrium. Five missense mutations in encoding exons have been described and proved to be responsible for hepatic lipase deficiency to date: S267F, T383M, L334F, A174T, and R186H, affecting the activity and secretion of hepatic lipase. We identified a primary disorder of the lipid metabolism as the cause of the acute episode of pancreatitis in a four years old patient, consisting of hepatic lipase deficiency caused by a novel genetic variant of the LIPC gene, a gross deletion of the genomic region encompassing exon 1. This variant was not previously described in the literature in persons with LIPC-related disorders and its significance is currently uncertain, but in the presented clinical and paraclinical context, it has the characteristics of a pathological variant inducing a hepatic lipase deficiency phenotype.

Addressing dyslipidemic risk beyond LDL-cholesterol.

Despite the success of LDL-lowering drugs in reducing cardiovascular disease (CVD), there remains a large burden of residual disease due in part to persistent dyslipidemia characterized by elevated levels of triglyceride-rich lipoproteins (TRLs) and reduced levels of HDL. This form of dyslipidemia is increasing globally as a result of the rising prevalence of obesity and metabolic syndrome. Accumulating evidence suggests that impaired hepatic clearance of cholesterol-rich TRL remnants leads to their accumulation in arteries, promoting foam cell formation and inflammation. Low levels of HDL may associate with reduced cholesterol efflux from foam cells, aggravating atherosclerosis. While fibrates and fish oils reduce TRL, they have not been uniformly successful in reducing CVD, and there is a large unmet need for new approaches to reduce remnants and CVD. Rare genetic variants that lower triglyceride levels via activation of lipolysis and associate with reduced CVD suggest new approaches to treating dyslipidemia. Apolipoprotein C3 (APOC3) and angiopoietin-like 3 (ANGPTL3) have emerged as targets for inhibition by antibody, antisense, or RNAi approaches. Inhibition of either molecule lowers TRL but respectively raises or lowers HDL levels. Large clinical trials of such agents in patients with high CVD risk and elevated levels of TRL will be required to demonstrate efficacy of these approaches.

CREBH normalizes dyslipidemia and halts atherosclerosis in diabetes by decreasing circulating remnant lipoproteins.

Loss-of-function mutations in the transcription factor CREB3L3 (CREBH) associate with severe hypertriglyceridemia in humans. CREBH is believed to lower plasma triglycerides by augmenting the activity of lipoprotein lipase (LPL). However, by using a mouse model of type 1 diabetes mellitus (T1DM), we found that greater liver expression of active CREBH normalized both elevated plasma triglycerides and cholesterol. Residual triglyceride-rich lipoprotein (TRL) remnants were enriched in apolipoprotein E (APOE) and impoverished in APOC3, an apolipoprotein composition indicative of increased hepatic clearance. The underlying mechanism was independent of LPL, as CREBH reduced both triglycerides and cholesterol in LPL-deficient mice. Instead, APOE was critical for CREBH's ability to lower circulating remnant lipoproteins because it failed to reduce TRL cholesterol in Apoe-/- mice. Importantly, individuals with CREB3L3 loss-of-function mutations exhibited increased levels of remnant lipoproteins that were deprived of APOE. Recent evidence suggests that impaired clearance of TRL remnants promotes cardiovascular disease in patients with T1DM. Consistently, we found that hepatic expression of CREBH prevented the progression of diabetes-accelerated atherosclerosis. Our results support the proposal that CREBH acts through an APOE-dependent pathway to increase hepatic clearance of remnant lipoproteins. They also implicate elevated levels of remnants in the pathogenesis of atherosclerosis in T1DM.

Menopause Per se Is Associated with Coronary Artery Calcium Score: Results from the ELSA-Brasil.

Background: Menopause and aging deteriorate the metabolic profile, but little is known about how they independently contribute to structural changes in coronary arteries. We compared a broad cardiometabolic risk profile of women according to their menopausal status and investigated if menopause per se is associated with presence of coronary artery calcium (CAC) in the ELSA-Brasil. Materials and Methods: All participants, except perimenopausal women, who had menopause <40 years or from non-natural causes or reported use of hormone therapy were included. Sample was stratified according to menopause and age categories (premenopause ≤45 years, premenopause >45 years, and postmenopause); their clinical profile and computed tomography-determined CAC were compared using Kruskal-Wallis and chi squared test for frequencies. Associations of CAC (binary variable) with menopause categories adjusted for traditional and nontraditional covariables were tested using logistic regression. Results: From 2,047 participants 51 ± 9 years of age, 1,175 were premenopausal (702 ≤ 45 years) and 872 were postmenopausal women. Mean values of anthropometric variables, blood pressure, lipid and glucose parameters, branched-chain amino acids (BCAA), and homeosthasis model assessment (HOMA-IR), as well as frequencies of morbidities, were more favorable in premenopausal, particularly in younger ones. In crude analyses, CAC >0 was associated with triglyceride-rich lipoprotein remnants, dense low-density lipoprotein, BCAA, and other variables, but not with HOMA-IR. Menopause was independently associated with CAC >0 (odds ratios 2.37 [95% confidence interval 1.17-4.81]) when compared to the younger premenopausal group. Conclusion: Associations of menopause with CAC, independent of traditional and nontraditional cardiovascular risk factors, suggest that hormonal decline per se may contribute to calcium deposition in coronary arteries.