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ApoC-III ASO promotes tissue LPL activity in the absence of apoE-mediated TRL clearance.

ABSTRACT: Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased CVD risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDL receptor-mediated and LDL receptor-related protein 1-mediated hepatic TRL clearance and that apoC-III-enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe ^-/- Ndst1 ^f/f Alb-Cre ⁺). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe ^-/- Ndst1 ^f/f Alb-Cre ⁺ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe ^-/- Ndst1 ^f/f Alb-Cre ⁺ mice, which was associated with increased LPL activity in white adipose tissue in the fed state. Finally, clinical data confirmed that ASO-mediated lowering of APOC-III via volanesorsen can reduce plasma TG levels independent of the APOE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that, in the absence of functional apoE, apoC-III inhibits tissue LPL activity.

SUBMITTER: Ramms B

PROVIDER: S-EPMC6672034 | biostudies-literature | 2019 Aug

REPOSITORIES: biostudies-literature

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ApoC-III Glycoforms Are Differentially Cleared by Hepatic TRL (Triglyceride-Rich Lipoprotein) Receptors.

Project description:ObjectiveApoC-III (apolipoprotein C-III) glycosylation can predict cardiovascular disease risk. Higher abundance of disialylated (apoC-III2) over monosialylated (apoC-III1) glycoforms is associated with lower plasma triglyceride levels. Yet, it remains unclear whether apoC-III glycosylation impacts TRL (triglyceride-rich lipoprotein) clearance and whether apoC-III antisense therapy (volanesorsen) affects distribution of apoC-III glycoforms. Approach and Results: To measure the abundance of human apoC-III glycoforms in plasma over time, human TRLs were injected into wild-type mice and mice lacking hepatic TRL clearance receptors, namely HSPGs (heparan sulfate proteoglycans) or both LDLR (low-density lipoprotein receptor) and LRP1 (LDLR-related protein 1). ApoC-III was more rapidly cleared in the absence of HSPG (t1/2=25.4 minutes) than in wild-type animals (t1/2=55.1 minutes). In contrast, deficiency of LDLR and LRP1 (t1/2=56.1 minutes) did not affect clearance of apoC-III. After injection, a significant increase in the relative abundance of apoC-III2 was observed in HSPG-deficient mice, whereas the opposite was observed in mice lacking LDLR and LRP1. In patients, abundance of plasma apoC-III glycoforms was assessed after placebo or volanesorsen administration. Volanesorsen treatment correlated with a statistically significant 1.4-fold increase in the relative abundance of apoC-III2 and a 15% decrease in that of apoC-III1. The decrease in relative apoC-III1 abundance was strongly correlated with decreased plasma triglyceride levels in patients.ConclusionsOur results indicate that HSPGs preferentially clear apoC-III2. In contrast, apoC-III1 is more effectively cleared by LDLR/LRP1. Clinically, the increase in the apoC-III2/apoC-III1 ratio on antisense lowering of apoC-III might reflect faster clearance of apoC-III1 because this metabolic shift associates with improved triglyceride levels.

| S-EPMC6761044 | biostudies-literature

ApoE determines the metabolic fate of apoC-III

Project description:Hypertriglyceridemia results from accumulation of triglyceride (TG)-rich lipoproteins (TRLs) in the circulation and is associated with increased cardiovascular disease risk. ApoC-III is an apolipoprotein on TRLs and a prominent negative regulator of TG catabolism. We recently established that in vivo apoC-III predominantly inhibits LDLR and LRP1 mediated hepatic TRL clearance and that apoC-III enriched TRLs are preferentially cleared by syndecan-1 (SDC1). In this study, we determined the impact of apoE, a common ligand for all three receptors, on apoC-III metabolism using apoC-III antisense oligonucleotide (ASO) treatment in mice lacking apoE and functional SDC1 (Apoe(-/-) Ndst1(f/f) Alb-Cre+). ApoC-III ASO treatment significantly reduced plasma TG levels in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice without reducing hepatic VLDL production or improving hepatic TRL clearance. Further analysis revealed that apoC-III ASO treatment lowered plasma TGs in Apoe(-/-) Ndst1(f/f) Alb-Cre+ mice, which was associated with increased LPL activity in white adipose tissue (WAT) in the fed state. Finally, clinical data confirm that ASO-mediated lowering of apoC-III via volanesorsen can reduce plasma TG levels independent of the apoE isoform genotype. Our data indicate that apoE determines the metabolic impact of apoC-III as we establish that apoE is essential to mediate inhibition of TRL clearance by apoC-III and that in the absence of functional apoE apoC-III inhibits tissue LPL activity.

2019-05-24 | GSE131284 | GEO

ApoC-III inhibits clearance of triglyceride-rich lipoproteins through LDL family receptors.

Project description:Hypertriglyceridemia is an independent risk factor for cardiovascular disease, and plasma triglycerides (TGs) correlate strongly with plasma apolipoprotein C-III (ApoC-III) levels. Antisense oligonucleotides (ASOs) for ApoC-III reduce plasma TGs in primates and mice, but the underlying mechanism of action remains controversial. We determined that a murine-specific ApoC-III-targeting ASO reduces fasting TG levels through a mechanism that is dependent on low-density lipoprotein receptors (LDLRs) and LDLR-related protein 1 (LRP1). ApoC-III ASO treatment lowered plasma TGs in mice lacking lipoprotein lipase (LPL), hepatic heparan sulfate proteoglycan (HSPG) receptors, LDLR, or LRP1 and in animals with combined deletion of the genes encoding HSPG receptors and LDLRs or LRP1. However, the ApoC-III ASO did not lower TG levels in mice lacking both LDLR and LRP1. LDLR and LRP1 were also required for ApoC-III ASO-induced reduction of plasma TGs in mice fed a high-fat diet, in postprandial clearance studies, and when ApoC-III-rich or ApoC-III-depleted lipoproteins were injected into mice. ASO reduction of ApoC-III had no effect on VLDL secretion, heparin-induced TG reduction, or uptake of lipids into heart and skeletal muscle. Our data indicate that ApoC-III inhibits turnover of TG-rich lipoproteins primarily through a hepatic clearance mechanism mediated by the LDLR/LRP1 axis.

| S-EPMC4966320 | biostudies-literature

ApoE determines the metabolic fate of apoC-III

Project description:ApoE determines the metabolic fate of apoC-III

| PRJNA543116 | ENA

A human APOC3 missense variant and monoclonal antibody accelerate apoC-III clearance and lower triglyceride-rich lipoprotein levels.

Project description:Recent large-scale genetic sequencing efforts have identified rare coding variants in genes in the triglyceride-rich lipoprotein (TRL) clearance pathway that are protective against coronary heart disease (CHD), independently of LDL cholesterol (LDL-C) levels. Insight into the mechanisms of protection of these variants may facilitate the development of new therapies for lowering TRL levels. The gene APOC3 encodes apoC-III, a critical inhibitor of triglyceride (TG) lipolysis and remnant TRL clearance. Here we report a detailed interrogation of the mechanism of TRL lowering by the APOC3 Ala43Thr (A43T) variant, the only missense (rather than protein-truncating) variant in APOC3 reported to be TG lowering and protective against CHD. We found that both human APOC3 A43T heterozygotes and mice expressing human APOC3 A43T display markedly reduced circulating apoC-III levels. In mice, this reduction is due to impaired binding of A43T apoC-III to lipoproteins and accelerated renal catabolism of free apoC-III. Moreover, the reduced content of apoC-III in TRLs resulted in accelerated clearance of circulating TRLs. On the basis of this protective mechanism, we developed a monoclonal antibody targeting lipoprotein-bound human apoC-III that promotes circulating apoC-III clearance in mice expressing human APOC3 and enhances TRL catabolism in vivo. These data reveal the molecular mechanism by which a missense variant in APOC3 causes reduced circulating TG levels and, hence, protects from CHD. This protective mechanism has the potential to be exploited as a new therapeutic approach to reduce apoC-III levels and circulating TRL burden.

| S-EPMC5669375 | biostudies-literature

LPL gene variants affect apoC-III response to combination therapy of statins and fenofibric acid in a randomized clinical trial of individuals with mixed dyslipidemia.

Project description:ApoC-III is a proatherogenic protein associated with elevated triglycerides; its deficiency is associated with reduced atherosclerosis. Mixed dyslipidemia, characterized by elevated triglyceride and apoC-III levels and low HDL cholesterol level, with or without elevated LDL cholesterol, increases cardiovascular disease risk and is commonly treated with combined statin and fibrate therapy. We sought to identify single nucleotide polymorphisms (SNPs) associated with apoC-III level response to combination therapy with statins and fenofibric acid (FA) in individuals with mixed dyslipidemia. Participants (n = 1,250) in a multicenter, randomized, double-blind, active-controlled study examining response to FA alone and in combination with statin were genotyped for candidate SNPs. Multivariate linear regression and two-way ANOVA for percent change in apoC-III level were performed. SNPs in the lipoprotein lipase (LPL) gene region, rs1801177 (P = 4.7 × 10(-8)), rs7016529 (P = 1.2 × 10(-6)), and rs249 (P = 4.1 × 10(-5)), were associated with apoC-III response to combination therapy. A haplotype composed of the minor alleles of these SNPs, with 2% population frequency, was associated with an unexpected apoC-III increase in response to statins and FA. This is the first report to show that genetic variation within the LPL gene region can affect the response of apoC-III levels to combined statin and FA therapy.

| S-EPMC3276479 | biostudies-literature

APOC-III: a Gatekeeper in Controlling Triglyceride Metabolism.

Project description:Purpose of reviewApolipoprotein C-III (ApoC-III) is a widely known player in triglyceride metabolism, and it has been recently recognized as a polyhedric factor which may regulate several pathways beyond lipid metabolism by influencing cardiovascular, metabolic, and neurological disease risk. This review summarizes the different functions of ApoC-III and underlines the recent findings related to its multifaceted pathophysiological role.Recent findingsThe role of ApoC-III has been implicated in HDL metabolism and in the development of atherosclerosis, inflammation, and ER stress in endothelial cells. ApoC-III has been recently considered an important player in insulin resistance mechanisms, lipodystrophy, diabetic dyslipidemia, and postprandial hypertriglyceridemia (PPT). The emerging evidence of the involvement of ApoC-III in the in the pathogenesis of Alzheimer's disease open the way to further study if modification of ApoC-III level slows disease progression. Furthermore, ApoC-III is clearly linked to cardiovascular disease (CVD) risk, and progression of coronary artery disease (CAD) as well as the calcification of aortic valve and recent clinical trials has pointed out the inhibition of ApoC-III as a promising approach to manage hypertriglyceridemia and prevent CVD. Several evidences highlight the role of ApoC-III not only in triglyceride metabolism but also in several cardio-metabolic pathways. Results from recent clinical trials underline that the inhibition of ApoC-III is a promising therapeutical strategy for the management of severe hypertriglyceridemia and in CVD prevention.

| S-EPMC9947064 | biostudies-literature

ApoC-III and visceral adipose tissue contribute to paradoxically normal triglyceride levels in insulin-resistant African-American women.

Project description:BackgroundAfrican-Americans are more insulin-resistant than whites but have lower triglyceride (TG) concentrations. The metabolic basis for this is unknown. Our goal was to determine in a cross-sectional study the effect of insulin resistance, visceral adipose tissue (VAT) and the apolipoproteins, B, C-III and E, on race differences in TG content of very low density lipoproteins (VLDL).MethodsThe participants were 31 women (16 African-American, 15 white) of similar age (37 ± 9 vs. 38 ± 11y (mean ± SD), P = 0.72) and BMI (32.4 ± 7.2 vs. 29.3 ± 6.0 kg/m2, P = 0.21). A standard diet (33% fat, 52% carbohydrate, 15% protein) was given for 7 days followed by a test meal (40% fat, 40% carbohydrate, 20% protein) on Day 8. Insulin sensitivity index (SI) was calculated from the minimal model. VAT was measured at L2-3. The influence of race, SI, VAT and apolipoproteins on the TG content of VLDL was determined by random effects models (REM).ResultsAfrican-Americans were more insulin-resistant (SI: 3.6 ± 1.3 vs. 5.6 ± 2.6 mU/L-1.min-1, P < 0.01) with less VAT (75 ± 59 vs. 102 ± 71 cm2, P < 0.01). TG, apoB and apoC-III content of light and dense VLDL were lower in African-Americans (all P < 0.05 except for apoC-III in light VLDL, P = 0.11). ApoE content did not vary by race. In REM, VAT but not SI influenced the TG concentration of VLDL. In models with race, SI, VAT and all apolipoproteins entered, race was not significant but apoC-III and VAT remained significant determinants of TG concentration in light and dense VLDL.ConclusionsLow concentrations of apoC-III and VAT in African-Americans contribute to race differences in TG concentrations.Trial registrationClinicalTrials.gov Identifier: NCT00484861.

| S-EPMC3878037 | biostudies-literature

ApoC-III is a novel inducer of calcification in human aortic valves.

Project description:Calcific aortic valve disease (CAVD) occurs when subpopulations of valve cells undergo specific differentiation pathways, promoting tissue fibrosis and calcification. Lipoprotein particles carry oxidized lipids that promote valvular disease, but low-density lipoprotein-lowering therapies have failed in clinical trials, and there are currently no pharmacological interventions available for this disease. Apolipoproteins are known promoters of atherosclerosis, but whether they possess pathogenic properties in CAVD is less clear. To search for a possible link, we assessed 12 apolipoproteins in nonfibrotic/noncalcific and fibrotic/calcific aortic valve tissues by proteomics and immunohistochemistry to understand if they were enriched in calcified areas. Eight apolipoproteins (apoA-I, apoA-II, apoA-IV, apoB, apoC-III, apoD, apoL-I, and apoM) were enriched in the calcific versus nonfibrotic/noncalcific tissues. Apo(a), apoB, apoC-III, apoE, and apoJ localized within the disease-prone fibrosa and colocalized with calcific regions as detected by immunohistochemistry. Circulating apoC-III on lipoprotein(a) is a potential biomarker of aortic stenosis incidence and progression, but whether apoC-III also induces aortic valve calcification is unknown. We found that apoC-III was increased in fibrotic and calcific tissues and observed within the calcification-prone fibrosa layer as well as around calcification. In addition, we showed that apoC-III induced calcification in primary human valvular cell cultures via a mitochondrial dysfunction/inflammation-mediated pathway. This study provides a first assessment of a broad array of apolipoproteins in CAVD tissues, demonstrates that specific apolipoproteins associate with valvular calcification, and implicates apoC-III as an active and modifiable driver of CAVD beyond its potential role as a biomarker.

| S-EPMC7948477 | biostudies-literature

Apolipoprotein C-III inhibits triglyceride hydrolysis by GPIHBP1-bound LPL.

Project description:apoC-III is often assumed to retard the intravascular processing of triglyceride-rich lipoproteins (TRLs) by inhibiting LPL, but that view is based largely on studies of free LPL. We now recognize that intravascular LPL is neither free nor loosely bound, but instead is tightly bound to glycosylphosphatidylinositol-anchored HDL-binding protein 1 (GPIHBP1) on endothelial cells. Here, we revisited the effects of apoC-III on LPL, focusing on apoC-III's capacity to affect the activity of GPIHBP1-bound LPL. We found that TRLs from APOC3 transgenic mice bound normally to GPIHBP1-bound LPL on cultured cells in vitro and to heart capillaries in vivo. However, the triglycerides in apoC-III-enriched TRLs were hydrolyzed more slowly by free LPL, and the inhibitory effect of apoC-III on triglyceride lipolysis was exaggerated when LPL was bound to GPIHBP1 on the surface of agarose beads. Also, recombinant apoC-III reduced triglyceride hydrolysis by free LPL only modestly, but the inhibitory effect was greater when the LPL was bound to GPIHBP1. A mutant apoC-III associated with low plasma triglyceride levels (p.A23T) displayed a reduced capacity to inhibit free and GPIHBP1-bound LPL. Our results show that apoC-III potently inhibits triglyceride hydrolysis when LPL is bound to GPIHBP1.

| S-EPMC5580902 | biostudies-other

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