Triglyceride-rich Lipoprotein Particles Research Articles

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.

Divergent pathways of liver fat accumulation, oxidation, and secretion in lipodystrophy versus obesity-associated NAFLD.

Fatty liver is common in obesity as well as in partial lipodystrophy (PL) syndromes, characterized by deficient adipose tissue. Insulin resistance is key to fatty liver pathogenesis in both entities. We aimed to compare the contributions of insulin resistance and adipose tissue to hepatic steatosis in PL and non-syndromic, obesity-associated non-alcoholic fatty liver disease (NS-NAFLD). In a cross-sectional comparison of people with NS-NAFLD (N = 73) and PL (N = 27), liver fat was measured by FibroScan® controlled attenuation parameter (CAP) and insulin resistance by HOMA-IR, Adipo-IR, and NMR-based LP-IR. Insulin resistance was greater in PL versus NS-NAFLD by HOMA-IR (p = 0.005), Adipo-IR (p = 0.01) and LP-IR (p = 0.05) while liver fat was comparable (304 vs. 324 dB/m, p = 0.12). Liver fat correlated with HOMA-IR in both groups, but CAP values were lower by 32 dB/m in PL compared with NS-NAFLD for any given HOMA-IR. In contrast, Adipo-IR and LP-IR correlated with CAP only in the NS-NAFLD group, suggesting different pathways for fat accumulation. Plasma free fatty acids, reflecting substrate input from the adipose tissue, were comparable between groups. However, the levels of β-hydroxybutyrate, a marker of β-oxidation, and large triglyceride-rich lipoprotein particles, a marker of VLDL secretion, were both higher in PL (p < 0.001 for both). Liver fat content was comparable in subjects with PL-associated NAFLD and NS-NAFLD, despite worse insulin resistance in partial lipodystrophy. Our data demonstrate higher triglyceride oxidation and export in PL, suggesting a compensatory shift of fat from liver storage into the circulation that does not occur in NS-NAFLD.

Large-scale metabolomic profiling and incident non-alcoholic fatty liver disease

Non-alcoholic fatty liver disease (NAFLD) is a highly prevalent disease with no specific drug therapy. High-throughput metabolomics present an unprecedented opportunity to identify biomarkers and potentially causal risk factors for NAFLD. Here, we determined the impact of 21 circulating metabolites, 17 lipids, and 132 lipoprotein particle characteristics on NAFLD combining prospective observational and two-sample Mendelian randomization (MR) analyses in 121,032UK Biobank participants. We identified several metabolic factors associated with NAFLD risk in observational and MR analyses including triglyceride-rich and high-density lipoprotein particles composition, as well as the ratio of polyunsaturated fatty acids to total fatty acids. This study, is one of the largest to investigate incident NAFLD, provides concordant observational and genetic evidence that therapies aimed at reducing circulating triglycerides and increasing large HDL particles, as well as interventions aimed at increasing polyunsaturated fattyacid content may warrant further investigation into NAFLD prevention and treatment.

Abstract P676: Association of Lipoprotein Subfractions With Atherosclerosis in the Baseline Sample of ELSA-Brasil Cohort Study - A Cross-Sectional Analysis

Introduction: The association between lipoprotein subparticles and atherosclerosis is not consistent in literature. For example, it is still unclear whether low-density lipoprotein particles (LDLP), high-density lipoprotein particles (HDLP), and triglyceride-rich lipoprotein particles (TRLP) were associated with carotid artery plaque (CAP) in adult population. Objective: We analyzed the cross-sectional association of LDLP, HDLP, and TRLP subparticles with CAP at ELSA-Brasil baseline. Methods: Data from 3801 participants (median age of 50.0[44.0-57.0] years, 54.3% of women) with no previous cardiovascular (CV) disease and without using lipid-lowering medications were analyzed. CAP presence was assessed by ultrasound images, while LDLP (total, large, medium and small), HDLP (total, large, medium and small) and TRLP (total, very large, large, medium, small and very small) were analyzed by nuclear magnetic resonance spectroscopy. Logistic regression models included all lipoprotein subparticles simultaneously and were adjusted by sociodemographic (age, sex, ethnicity, education, private health insurance) and CV risk factors (body mass index, smoking, alcohol consumption, family history of CV disease, diabetes, hypertension), with odds ratios (OR) and respective 95% confidence interval according to 1 standard deviation increase in the predictor. Results: The prevalence of CAP was 33.9% (n=1287). Participants with CAP had higher age (median 55.0 vs. 47.0, p&lt;0.001), higher prevalence of males (55.7% vs. 40.6%, p&lt;0.001), of non-Whites (57.4% vs. 53.7%, p=0.028), and of lower education attainment (22.3% vs. 12.3%, p&lt;0.001), as well as greater burden of CV risk factors than participants without CAP (current smoking [22.1% vs. 14.1%], family history of CV disease [29.7% vs. 23.6%], diabetes [20.1% vs. 11.9%] and hypertension [38.7% vs. 21.8%], p&lt;0.001), LDL-Cholesterol [median 127.3 vs. 115.2, p&lt;0.001] and Triglycerides [median 112.4 vs. 100.5, p&lt;0.001]). Lipoprotein subparticles were majority correlated (p&lt;0.05). Among the lipoprotein classes (total TRLP, LDLP and HDLP), only total LDLP (OR: 1.89 [1.47; 2.44], p&lt;0.001) was associated with CAP. All the LDLP subparticles were associated with CAP: large (OR: 1.64 [1.27; 2.11], p&lt;0.001), medium (OR: 1.38 [1.08; 1.76], p=0.010) and small (OR: 1.58 [1.20; 2.07], p=0.001). The TRLP subparticles of small (OR: 1.42 [1.11; 1.82], p=0.006) and very small size (OR: 1.37 [1.05; 1.79], p=0.022) were also associated with CAP. Conclusion: The LDLP (large, medium and small) and TRLP (small and very small) were associated with CAP beyond sociodemographic and CV risk factors. This finding is in line with CV risk burden of large LDLP besides small LDLP and highlights a potential role of TRLP in atherosclerosis. However, further investigation between LDLP and TRLP with CAP progression is still needed.

Role of Altered Metabolism of Triglyceride-Rich Lipoprotein Particles in the Development of Vascular Dysfunction in Systemic Lupus Erythematosus

Impaired lipid metabolism contributes to accelerated inflammatory responses in addition to promoting the formation of atherosclerosis in systemic lupus erythematosus (SLE). We aimed to evaluate the lipid profile, inflammatory markers, and vascular diagnostic tests in active SLE patients to clarify the association between dyslipidemia and early vascular damage. 51 clinically active SLE patients and 41 age- and gender-matched control subjects were enrolled in the study. Lipoprotein subfractions were detected by Lipoprint. Brachial artery flow-mediated dilation and common carotid intima-media thickness were detected by ultrasonography. Arterial stiffness indicated by augmentation index (Aix) and pulse wave velocity was measured by arteriography. We found significantly higher Aix, higher VLDL ratio, plasma triglyceride, ApoB100, and small HDL, as well as lower HDL-C, large HDL, and ApoA1 in patients with SLE. There was a significant positive correlation of Aix with triglyceride, VLDL, IDL-C, IDL-B, and LDL1. A backward stepwise multiple regression analysis showed IDL-C subfraction to be the best predictor of Aix. Our results indicate that in young patients with SLE, triglyceride-rich lipoproteins influence vascular function detected by Aix. These parameters may be assessed and integrated into the management plan for screening cardiovascular risk in patients with SLE.

Lipoprotein subfraction patterns throughout gestation in The Gambia: changes in subfraction composition and their relationships with infant birth weights

BackgroundLipoprotein subfraction concentrations have been shown to change as gestation progresses in resource-rich settings. The objective of the current study was to evaluate the impact of pregnancy on different-sized lipoprotein particle concentrations and compositions in a resource-poor setting.MethodSamples were collected from pregnant women in rural Gambia at enrollment (8–20 weeks), 20 weeks, and 30 weeks of gestation. Concentrations of different-sized high-density, low-density, and triglyceride-rich lipoprotein particles (HDL, LDL, and TRL, respectively) were measured by nuclear magnetic resonance in 126 pooled plasma samples from a subset of women. HDL was isolated and the HDL proteome evaluated using mass spectroscopy. Subfraction concentrations from women in The Gambia were also compared to concentrations in women in the U.S. in mid gestation.ResultsTotal lipoprotein particles and all-sized TRL, LDL, and HDL particle concentrations increased during gestation, with the exception of medium-sized LDL and HDL particles which decreased. Subfraction concentrations were not associated with infant birth weights, though relationships were found between some lipoprotein subfraction concentrations in women with normal versus low birth weight infants (< 2500 kg). HDL’s proteome also changed during gestation, showing enrichment in proteins associated with metal ion binding, hemostasis, lipid metabolism, protease inhibitors, proteolysis, and complement activation. Compared to women in the U.S., Gambian women had lower large- and small-sized LDL and HDL concentrations, but similar medium-sized LDL and HDL concentrations.ConclusionsMost lipoprotein subfraction concentrations increase throughout pregnancy in Gambian women and are lower in Gambian vs U.S. women, the exception being medium-sized LDL and HDL particle concentrations which decrease during gestation and are similar in both cohorts of women. The proteomes of HDL also change in ways to support gestation. These changes warrant further study to determine how a lack of change or different changes could impact negative pregnancy outcomes.

Association between coffee consumption with serum lipid profile in ELSA-Brasil study: a metabolomic approach.

This study evaluated the association between coffee consumption and serum lipid profile in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). This is a cross-sectional study on baseline data from participants of the cohort ELSA-Brasil. Only participants of São Paulo Research Center who underwent a nuclear magnetic resonance (NMR) spectroscopy examination of lipid profile were included (N = 4736). Coffee intake was categorized into four categories (cups/day, in reference cup size of 50mL, which is the household measure adopted in Brazil): never/almost never, ≤ 1, 1-3, and > 3. Serum lipid profile [i.e., Total Cholesterol (TC), Total Triglycerides (TG), Very Low-Density Lipoprotein-cholesterol (VLDL-c), Low-Density Lipoprotein-cholesterol (LDL-c), High-Density Lipoprotein-cholesterol (HDL-c), Triglyceride-rich Lipoprotein Particles (TRLP) and subfractions particles] was analyzed. To estimate the effect of coffee consumption on serum lipid profile, multivariate Generalized Linear Models were performed. Compared to participants who never or almost never drink coffee, individuals who consumed more than 3 cups/day showed an increase in concentrations of TC (β: 4.13; 95% CI 0.81, 7.45), TG (β: 9.53; 95% CI 1.65, 17.42), VLDL-c (β: 1.90; 95% CI 0.38, 3.42), TRLP (β: 8.42; 95% CI 1.24, 15.60), and Very Small-TRLP and Medium-TRLP subfractions (β: 7.36; 95% CI 0.21, 14.51; β: 2.53; 95% CI 0.89, 4.16, respectively), but not with HDL-c and LDL-c. Among individuals with low (≤ 1 cup/day) and moderate (1-3 cups/day) coffee consumption, no significant associations with lipids was observed. High coffee consumption (more than 3 cups per day) was associated with an increase in serum lipids, namely TC, TG, VLDL-c, and TRL particles, highlighting the importance of a moderate consumption of this beverage.

Calorie restriction improves lipid-related emerging cardiometabolic risk factors in healthy adults without obesity: Distinct influences of BMI and sex from CALERIE™ a multicentre, phase 2, randomised controlled trial.

SummaryBackgroundFor many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values within ranges considered normal for healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young (21–50 years), normal weight healthy population undergoing calorie restriction for two years.MethodsThe Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, multicenter, randomized controlled trial (May 2007-November 2012) in healthy, adults without obesity to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9 ± 7.2 years and body mass index (BMI) 25.1 ± 1.7 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy.FindingsAveraging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes—Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and low-density lipoprotein particles, a shift to larger high-density lipoprotein particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women.InterpretationIn normal to slightly overweight adults without overt risk factors or disease, 12 months of ∼12% CR improved newly identified risk markers for atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These markers suggest that CR improves risks by reducing inflammation and BCAAs and shifting lipoproteins from atherogenic to cholesterol transporting. Additionally, these improvements are greater for men and for those with greater BMIs indicating sex and BMI-influences merit attention in future investigations of lifestyle-mediated improvements in disease risk factors.FundingThe CALERIE™ trial design and implementation were supported by a National Institutes of Health (NIH) U-grant provided to four institutions, the three intervention sites and a coordinating center (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480). For this secondary analysis including sample acquisition and processing, data analysis and interpretation, additional funding was provided by the NIH to authors as follows: R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR).

Lysosomal acid lipase promotes endothelial proliferation in cold-activated adipose tissue

ABSTRACT Oxidative tissues such as brown adipose tissue and muscle internalize large amounts of circulating lipids and glucose as energy source. Endothelial cells (ECs) provide a platform for regulated transport and processing of blood-borne nutrients. Next to this role, it has become recognized that intercellular crosstalk between ECs and underlying parenchymal cells is indispensable for maintenance of tissue homoeostasis. Here, we comment on our recent observation that capillary ECs in thermogenic adipose tissues take up and metabolize entire triglyceride-rich lipoprotein (TRL) particles in response to cold exposure. This process is dependent on CD36, lipoprotein lipase (LPL) and lysosomal acid lipase (LAL). Remarkably, loss of LAL specifically in endothelial cells results in impaired endothelial proliferation and diminished thermogenic adaptation. Mechanistically, cell culture experiments indicate that LAL-mediated TRL processing leads to the generation of reactive oxygen species, which in turn activate hypoxia-induced factor (HIF)-mediated proliferative responses. In the current manuscript, we provide in vivo evidence that LAL-deficiency impairs proliferation of endothelial cells in thermogenic adipose tissue. In addition, we show uptake of nanoparticle-labelled TRL and LAL expression in cardiac endothelial cells, suggesting a physiological function of endothelial lipoprotein processing not only in thermogenic adipose tissue but also in cardiac muscle.

Transcriptomic therapy for dyslipidemias utilizing nucleic acids targeted at ANGPTL3.

Angiopoietin-like protein 3 (ANGPTL3) is a key physiological regulator of plasma lipid and lipoproteinmetabolism that involves the control of enzymes, lipoprotein and endothelial lipases. Inhibition of ANGPTL3 offers a new approach for correcting the health risks of dyslipidemia, including familial hypercholesterolemia, mixed hyperlipidemia, metabolic syndromeand/or severe hypertriglyceridemia. ANGPTL3 inhibition with nucleic acid-based antisense oligonucleotide and siRNA can correct dyslipidemia chiefly by reducing production and increasing catabolism of triglyceride-rich lipoprotein and LDL particles. Early clinical trials have demonstrated that these agents can safely and effectively lower plasma triglyceride and LDL-cholesterol levels by up to 70and 50%, respectively. However, the long-term safety and cost-effectiveness of these agents await to be confirmed in anongoing and future clinical trials.

Volanesorsen for treatment of familial chylomicronemia syndrome

ABSTRACT Introduction Familial chylomicronemia syndrome (FCS) is a rare subtype of severe hypertriglyceridemia that affects ~1 in 100, 000 to 1,000,000 individuals. The major risk to health is acute pancreatitis. FCS is defined by biallelic loss-of-function mutations in one of five canonical genes that encode proteins critical to lipolysis of large triglyceride-rich lipoprotein particles. Unlike the vast majority of patients with severe hypertriglyceridemia, FCS patients lack any lipolytic capacity and are thus resistant to standard medications. Areas covered This review focuses on a mechanism that effectively reduces elevated triglyceride levels in FCS, namely interference of synthesis of apolipoprotein (apo) C-III. Volanesorsen is an antisense RNA drug administered subcutaneously that knocks down apo C-III, resulting in dramatic reductions in triglyceride levels both in FCS patients and in the wider population of subjects with severe hypertriglyceridemia. Expert opinion Volanesorsen is a highly effective treatment to reduce elevated triglycerides in FCS patients, providing proof-of-concept of the validity of targeting apo C-III. However, off target effects of volanesorsen, including thrombocytopenia, may ultimately limit its use. Nonetheless, building on the knowledge derived from the volanesorsen experience, there is intensified interest in promising newer agents that also target apo C-III but have technical modifications that limit potential off target adverse effects.

Calorie Restriction Improves Lipid-Related Emerging Cardiometabolic Risk Factors in Healthy Non-Obese Adults: Distinct Influences of BMI and Sex From CALERIE™ - A Multicentre, Phase 2, Randomised Controlled Trial

Background: For many cardiovascular risk factors there is no lower limit to which further reduction will result in decreased disease risk; this includes values extending ranges of normal healthy adults. This seems to be true for new emerging metabolic risk factors identified by innovative technological advances. Further, there seems to be ever evolving evidence of differential responses to lifestyle interventions by sex and body compositions in the normal range. In this secondary analysis, we had the opportunity to test these principles for newly identified molecular biomarkers of cardiometabolic risk in a young, normal weight healthy population undergoing calorie restriction for two years. Methods: The Comprehensive Assessment of Long-term Effects of Reducing Intake of Energy (CALERIE™) was a 24-month, randomized controlled trial in healthy, non-obese adults to evaluate the potential for calorie restriction (CR) to promote anti-aging adaptations, including those associated with disease risk. 218 participants (age 37.9±7.19 years and BMI 25.1±1.73 kg/m2, mean±SD) were randomized 2:1 to 24 months of CR (prescribed as 25% reduction from baseline calorie intake) versus ad libitum (AL). Fasting plasma from baseline, 12, and 24 months was used for assessments of lipoproteins, metabolites, and inflammatory markers using nuclear magnetic resonance spectroscopy.­­­­­­­­­ Results: Averaging 11.9% CR, the CR group had reductions at 12 and 24 months in the cardiovascular disease risk markers, apolipoprotein B and GlycA, and risks for insulin resistance and type 2 diabetes—Lipoprotein Insulin Resistance Index and Diabetes Risk Index (all PCRvsAL ≤0.0009). Insulin resistance and diabetes risk improvements resulted from CR-induced alterations in lipoproteins, specifically reductions in triglyceride-rich lipoprotein particles and LDL particles, a shift to larger HDL particles (more effective cholesterol transporters), and reductions in branched chain amino acids (BCAAs) (all PCRvsAL ≤0.004). These CR responses were more pronounced in overweight than normal weight participants and greater in men than women. Conclusions: In normal to slightly overweight adults without overt risk factors or disease, 12 months of ~12% CR improved risks of atherosclerotic cardiovascular disease, insulin resistance and type 2 diabetes. These CR-mediated benefits accrued via reduced inflammation and branched chain amino acids, and a shift from atherogenic to cholesterol transporting lipoproteins. Additionally, CR benefits were influenced by sex and BMI, factors meriting close attention in future investigations of lifestyle-mediated improvements in disease risk factors. Clinical Trial Registration Details: NCT00427193. Funding Information: CALERIETM was conducted as a National Institutes of Health (NIH) U-grant (U01 AG022132, U01 AG020478, U01 AG020487 U01 AG020480 ). As defined by this mechanism, the study design and conduct was a collaborative effort between internal NIH and external study investigators. Additional project funding was provided by NIH R01 AG054840 (MO, VBK); R33 AG070455 (KMH, DCP, MB, SBR, CKM, LMR, SKD, CFP, CJR, WEK); P30 DK072476 (CKM, LMR); and U54 GM104940 (CKM, LMR) and without any additional scientific contribution or other role in this report. Declaration of Interests: MAC, IS, and JDO are employees of Labcorp. All other authors have no conflicts interests. Ethics Approval Statement: The study protocol (NCT00427193) was approved by the institutional review boards at all participating clinical centers (Washington University School of Medicine, St Louis, MO; Pennington Biomedical Research Center, Baton Rouge, LA; Tufts University, Boston, MA), and the coordinating center (Duke University, Durham, NC). All study participants provided written informed consent and study oversight was provided by a Data and Safety Monitoring Board.

Unfavorable Triglyceride-rich Particle Profile in Subclinical Thyroid Disease: A Cross-sectional Analysis of ELSA-Brasil.

Subclinical thyroid disorders have been associated with atherosclerosis and increased cardiovascular risk. As triglyceride-rich lipoprotein particles (TRLPs) have recently emerged as a casual factor for atherogenesis, the aim of this study was to evaluate the relationship between subclinical hypo- and hyperthyroidism and TRLP subfractions. We selected 5066 participants from the ELSA-Brasil cohort with available data of thyroid function and lipid profile measured by nuclear magnetic resonance (NMR) spectroscopy. Individuals were divided into 3 groups by baseline thyroid function (subclinical hypothyroidism, euthyroidism, and subclinical hyperthyroidism). Triglyceride-rich lipoprotein particle subfractions were analyzed through NMR spectroscopy. To examine the association between TRLP subfractions and thyroid function, we conducted univariate and multivariate linear regression models adjusted for demographic characteristics, body mass index, diabetes, smoking status, and alcohol use. Of 3304 individuals, 54% were women, with a mean age of 50.6 ± 8.7 years, 51% white, and 53% with at least a college education. Of these individuals, 92% were euthyroid, whereas 6.8% had subclinical hypothyroidism and 1.2% had subclinical hyperthyroidism. The univariate linear regression showed that very small TRLPs (P = 0.026) and very large TRLPs (P = 0.008) were statistically increased in subclinical hypothyroidism when compared with euthyroidism. In subclinical hyperthyroidism, there was a reduction in total TRLPs (P = 0.003), seemingly driven by reduced very small TRLPs (P = 0.067). The findings were confirmed when adjusted for demographic characteristics, as well as comorbidities. This study suggests that subclinical hypothyroidism is associated with very small and very large TRLPs, which are related to an unfavorable atherogenic profile. Subclinical hyperthyroidism is associated to lower very small TRLPs.

The dual glucose-dependent insulinotropic peptide and glucagon-like peptide-1 receptor agonist, tirzepatide, improves lipoprotein biomarkers associated with insulin resistance and cardiovascular risk in patients with type 2 diabetes.

AimTo better understand the marked decrease in serum triglycerides observed with tirzepatide in patients with type 2 diabetes, additional lipoprotein‐related biomarkers were measured post hoc in available samples from the same study.Materials and MethodsPatients were randomized to receive once‐weekly subcutaneous tirzepatide (1, 5, 10 or 15 mg), dulaglutide (1.5 mg) or placebo. Serum lipoprotein profile, apolipoprotein (apo) A‐I, B and C‐III and preheparin lipoprotein lipase (LPL) were measured at baseline and at 4, 12 and 26 weeks. Lipoprotein particle profile by nuclear magnetic resonance was assessed at baseline and 26 weeks. The lipoprotein insulin resistance (LPIR) score was calculated.ResultsAt 26 weeks, tirzepatide dose‐dependently decreased apoB and apoC‐III levels, and increased serum preheparin LPL compared with placebo. Tirzepatide 10 and 15 mg decreased large triglyceride‐rich lipoprotein particles (TRLP), small low‐density lipoprotein particles (LDLP) and LPIR score compared with both placebo and dulaglutide. Treatment with dulaglutide also reduced apoB and apoC‐III levels but had no effect on either serum LPL or large TRLP, small LDLP and LPIR score. The number of total LDLP was also decreased with tirzepatide 10 and 15 mg compared with placebo. A greater reduction in apoC‐III with tirzepatide was observed in patients with high compared with normal baseline triglycerides. At 26 weeks, change in apoC‐III, but not body weight, was the best predictor of changes in triglycerides with tirzepatide, explaining up to 22.9% of their variability.ConclusionsTirzepatide treatment dose‐dependently decreased levels of apoC‐III and apoB and the number of large TRLP and small LDLP, suggesting a net improvement in atherogenic lipoprotein profile.

Reduced Reverse Cholesterol Transport Efficacy in Healthy Men with Undesirable Postprandial Triglyceride Response.

Elevation of nonfasting triglyceride (TG) levels above 1.8 g/L (2 mmol/L) is associated with increased risk of cardiovascular diseases. Exacerbated postprandial hypertriglyceridemia (PP–HTG) and metabolic context both modulate the overall efficacy of the reverse cholesterol transport (RCT) pathway, but the specific contribution of exaggerated PP–HTG on RCT efficacy remains indeterminate. Healthy male volunteers (n = 78) exhibiting no clinical features of metabolic disorders underwent a postprandial exploration following consumption of a typical Western meal providing 1200 kcal. Subjects were stratified according to maximal nonfasting TG levels reached after ingestion of the test meal into subjects with a desirable PP–TG response (GLow, TG < 1.8 g/L, n = 47) and subjects with an undesirable PP–TG response (GHigh, TG > 1.8 g/L, n = 31). The impact of the degree of PP–TG response on major steps of RCT pathway, including cholesterol efflux from human macrophages, cholesteryl ester transfer protein (CETP) activity, and hepatic high-density lipoprotein (HDL)-cholesteryl ester (CE) selective uptake, was evaluated. Cholesterol efflux from human macrophages was not significantly affected by the degree of the PP–TG response. Postprandial increase in CETP-mediated CE transfer from HDL to triglyceride-rich lipoprotein particles, and more specifically to chylomicrons, was enhanced in GHigh vs. GLow. The hepatic HDL-CE delivery was reduced in subjects from GHigh in comparison with those from GLow. Undesirable PP–TG response induces an overall reduction in RCT efficacy that contributes to the onset elevation of both fasting and nonfasting TG levels and to the development of cardiometabolic diseases.

OR08-05 Sex and Ethnic Differences in Advanced Lipoprotein Profiles in South Asians, African-Americans, and Caucasians

Background: African-Americans (AA) and South Asians (SA) are known to have higher risk for T2D and cardiovascular disease (CVD) compared to Caucasians (CA). Advanced analysis of lipoprotein particles with nuclear magnetic resonance (NMR) spectroscopy can offer insights into CVD risk and lipid metabolism beyond a standard lipid panel. Insulin resistance (IR) is known to be associated with atherogenic lipoprotein profile. Objective: To characterize the lipoprotein profile in AA, CA, and SA men and women. Design: A cross-sectional study of 182 healthy, non-diabetic SA, AA and CA patients was conducted at NIH. Subjects underwent an intravenous glucose tolerance test from which insulin sensitivity (Si) was derived using the Minimal Model. Lipoprotein profiles were measured by NMR with the LP4 deconvolution algorithm, which reports triglyceride-rich lipoprotein particles (TRLPs), high-density lipoprotein particles (HDLPs), and low-density lipoprotein particles (LDLPs). For group comparisons, Si was adjusted for age and fat free mass. Lipoprotein parameters were adjusted for age and body fat %. Results: Fifty-nine non-diabetic SA (33 males, 26 females), 49 AA (26 males, 23 females), and 74 CA (29 males, 45 females) were included in the study. Ethnic differences in Si were observed in men (p=0.002) but not in women (p=0.43). SA men had a significantly lower Si than both AA and CA men (p=0.02). TG concentrations and TRL particle number were significantly higher in CA men and women when compared with AA. TRLP size was not different between the ethnic groups in either sex. LDL particle number and ApoB concentration was significantly higher in SA men and women compared to AA and CA. There were no ethnic or sex differences in LDL size. HDL concentration, HDL particle number, and ApoA-I levels were not different between the groups in both sexes. However, in SA, large HDL particle number and HDL particle size was significantly lower than CA. Cholesteryl ester transfer protein (CETP) activity was significantly higher in SA men, but not women, when compared with AA and CA. Ethnic differences in LDLP and L-HDLP number remained even after adjusting for Si. Conclusions: In SA men and women, the lipoprotein phenotype (higher LDLP and lower L-HDLP) is independent of insulin sensitivity. Increased CETP activity may contribute to the lower large HDL particle number in this group. In AA, TG and TRLP number were lower as previously reported. Further investigation is needed to determine the factors mediating the atherogenic profile in SA.

Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease

BackgroundElevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. ObjectivesThe purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). MethodsIn a prospective case-cohort study within the Women’s Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. ResultsThe risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HRQ4: 2.58 [95% CI: 1.18 to 5.63]; ptrend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71 [95% CI: 1.59 to 8.63]; ptrend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl). ConclusionsTRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women’s Health Study; NCT00000479)

Lipoprotein insulin resistance score and branched-chain amino acids increase after adrenalectomy for unilateral aldosterone-producing adenoma: a preliminary study

Background and aimsPrimary aldosteronism (PA) due to unilateral aldosterone-producing adenoma (APA) is preferentially treated by unilateral adrenalectomy (ADX), but little is known about the changes in lipid and glucose metabolism that may occur after ADX.MethodsWe studied 19 non-diabetic patients who did not use lipid-lowering drugs with PA due to APA before and 6 months after unilateral ADX. Fasting plasma lipids, lipoprotein subfractions, branched-chain amino acids (BCAA), and GlycA, a pro-inflammatory glycoprotein biomarker, were measured by nuclear magnetic resonance (NMR) spectroscopy. The Lipoprotein Insulin Resistance (LP-IR) score, which is based on six lipoprotein variables, was calculated.ResultsIn all patients, hyperaldosteronism was resolved after ADX. Body mass index and fasting plasma glucose were unchanged, but HbA1c increased (p = 0.002). Plasma triglycerides, large triglyceride-rich lipoprotein (TRL) cholesterol, and large TRL particles were increased (p < 0.01), resulting in an increase in TRL size (p = 0.027). High-density lipoprotein size was decreased (p = 0.015). LP-IR scores (p = 0.001) and total BCAA (p = 0.017) were increased, but GlycA remained unaltered.ConclusionsBased on increases in LP-IR scores and BCAA, which each have been shown to predict new onset type 2 diabetes mellitus independent of conventional risk factors in the general population, this preliminary study suggests that diabetes risk is not improved but may even be increased after ADX for APA despite remission of PA.

Abstract P490: Subclinical Thyroid Disorders and Triglyceride-rich Lipoprotein Particles Concentration. ELSA-Brasil Cohort

Background: Subclinical thyroid disorders have been associated with atherosclerosis and increased cardiovascular risk. Subclinical hypothyroidism is associated with higher levels of total cholesterol and Low-density lipoprotein cholesterol as well as high levels of triglycerides and low levels of high-density lipoprotein cholesterol. Triglyceride-rich Lipoprotein Particles concentration (TRLP) have recently emerged as a causal factor for atherogenesis. Aim: To evaluate the relationship between Subclinical Hypothyroidism and Subclinical Hyperthyroidism and Triglyceride-rich Lipoprotein Particles. Methods: Participants from the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil) were classified according to the baseline thyroid function as Subclinical Hypothyroidism, Euthyroidism, and Subclinical Hyperthyroidism. Conventional lipid concentrations (total, HDL cholesterol, and triglycerides were determined by a nonprecipitated colorimetric method. The TRLP subfractions were analyzed through Nuclear Magnetic Resonance spectroscopy. To examine the association between TRLP subfractions and thyroid function, we conducted a multivariate linear regression model adjusted for demographic characteristics (race, gender, and educational level), body-mass index, diabetes, smoking status, and alcoholic beverages intake. Results: Of 3,550 individuals free of cardiovascular or thyroid diseases (54%, women; median age 51 years; 51% White, and 53% with at least college education) 92%of them were euthyroid, 6.8% had subclinical hypothyroidism, and 1.2% had subclinical hyperthyroidism. No differences were observed concern the levels of total, HDL, and LDL-cholesterol, but triglycerides were higher for people with Subclinical Hypothyroidism. After adjustment by the covariates described above and using subjects with normal thyroid function as the reference group, for people with Subclinical hypothyroidism a difference of means ( and 95% Confidence Interval) for Total TRLP levels (in ng/L) obtained was 0.06 (-0.00 to 0.13), and for the TRLP subfractions elevated for Very-Small [0.16 (0.02 to 0.28)] and Very-Large [0.21 (0.05 to 0.36)], and similar values for Small [-0.01 (-0.13 to 0.12)]; Medium [0.05 (-0.08 to 0.17)] and Large [0.16 (-0.06 to 0.38)] subfractions. In Subclinical Hyperthyroidism, there was a reduction in Total TRLP (-0.24 (-0.40 - -0.08)), seemingly driven by reduced Very Small-TRLP (0.23 (-0.11 - 0.57). Conclusion: This study suggests that subclinical hypothyroidism is associated with high levels of Very-Small and Very-Large TRLP, which are related to an unfavorable atherogenic profile. Subclinical Hyperthyroidism is associated with low concentrations of Very-Small TRLP.

Postprandial dyslipidemia in insulin resistant states in adolescent populations.

Obesity and the metabolic syndrome are becoming increasingly prevalent not only in adults, but also in adolescents. The metabolic syndrome, a complex cluster of metabolic abnormalities, increases one's risk of developing type 2 diabetes and cardiovascular disease (CVD). Dyslipidemia, a key component of the metabolic syndrome, is highly associated with insulin resistance and contributes to increased CVD risk. Dyslipidemia has traditionally been assessed using a fasting lipid profile [i.e. fasting triglycerides, total cholesterol, low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein cholesterol (HDL-C)]. However, the postprandial state predominates over the course of a day and non-fasting triglycerides independently predict CVD risk. In insulin resistant states, the intestine overproduces triglyceride-rich lipoprotein (TRL) particles, termed chylomicrons (CMs), following ingestion of a fat-containing meal, as well as in the fasting state. Along with elevated hepatic TRLs (i.e. very-low density lipoproteins), CMs contribute to remnant lipoprotein accumulation, small dense LDL particles, and reduced HDL-C, which collectively increase CVD risk. Given the early genesis of atherosclerosis and physiological metabolic changes during adolescence, studying postprandial dyslipidemia in the adolescent population is an important area of study. Postprandial dyslipidemia in the pediatric population poses a significant public health concern, warranting a better understanding of its pathogenesis and association with insulin resistance and CVD. This review discusses the metabolic syndrome, focusing on the link between insulin resistance, postprandial dyslipidemia, and CVD risk. Furthermore, the clinical significance and functional assessment of postprandial dyslipidemia, specifically in the adolescent population, is discussed in more detail.