Very Low Density Lipoprotein Size Research Articles

Abstract 743: Association between physical activity and lipid profile among breast cancer survivors

Abstract Backgrounds/Aims: Unfavorable lipid profiles may be associated with prognosis among breast cancer survivors. We aimed to examine the association between physical activity levels and subclasses of lipoprotein among breast cancer survivors. Methods: We included a total of 378 women diagnosed with primary breast cancer and survived for ≥6 months since the surgery. Physical activity levels were presented as the metabolic equivalent of task (MET) hours/week from a structured questionnaire. High-throughput proton nuclear magnetic resonance (NMR) metabolomics platform was used to quantify plasma levels of specific lipid biomarkers and particle sizes. The multivariable adjusted least-square means (LS-means) and 95% confidence intervals (CIs) of lipid profile markers across physical activity (quartile) were estimated by using generalized linear models. Results: We observed inverse associations of physical activity levels with circulating levels of total triglycerides (TG), TG in very low-density lipoprotein (VLDL), and TG in high-density lipoprotein (HDL) among breast cancer survivors. LS-means (95% CIs) for 1st and 4th quartiles of physical activity were 1.07 (0.99-1.17) and 0.96 (0.88-1.04; p for trend=0.048) for total TG (nmol/L), 0.68 (0.62-0.74) and 0.60 (0.54-0.66; p for trend=0.045) for TG in VLDL (nmol/L), and 0.14 (0.13-0.15) and 0.12 (0.11-0.13; p for trend=0.045) for TG in HDL (nmol/L). These associations were limited to breast cancer survivors with stage II or III. We also found a smaller VLDL size with high physical activity among those with stage II or III. Among participants with a BMI of ≥25 kg/m2, we found that high physical activity was associated with decreased levels of TG in VLDL and small VLDL size; according to subsequent quartiles of physical activity, LS-means (95% CIs) were 0.73 (0.62-0.87), 0.88 (0.72-1.08), 0.74 (0.61-0.89), and 0.56 (0.44-0.71) for TG in VLDL (nmol/L), respectively (p for trend=0.047); and 38.67 (38.34-39.00), 38.75 (38.36-39.15), 38.65 (38.28-39.01), and 37.98 (37.52-38.45) for VLDL size (nm), respectively (p for trend=0.024). Conclusions: We found that high physical activity was associated with lower circulating levels of subclasses of TG and smaller VLDL size among breast cancer survivors with stage II or III or those with a BMI of ≥25 kg/m2. Further prospective or randomized controlled studies are warranted to confirm the significance of physical activity associated with favorable lipid profiles among breast cancer survivors. Funding Information: This research was supported by the National Research Foundation of Korea (NRF) grant funded by the Korea government (Ministry of Science and ICT, MSIT) (No. 2014R1A2A2A01007794, 2019R1F1A1061017, and 2021R1F1A1062476) and K-BIO KIURI Center program (NRF2020M3H1A107330413). Citation Format: Hyun Jeong Cho, Minji Kang, Zisun Kim, Hyun Jo Youn, Jihyoung Cho, Jun Won Min, Yoo Seok Kim, Jung Eun Lee. Association between physical activity and lipid profile among breast cancer survivors [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 743.

Triglyceride Metabolism Modifies Lipoprotein(a) Plasma Concentration.

Lipoprotein(a) (Lp(a)) is a significant cardiovascular risk factor. Knowing the mechanisms that regulate its concentration can facilitate the development of Lp(a)-lowering drugs. This study analyzes the relationship between triglycerides (TGs) and Lp(a) concentrations, cross-sectionally and longitudinally, and the influence of the number and composition of TG-rich lipoproteins, and the APOE genotype. Data from Aragon Workers Health Study (AWHS) (n = 5467), National Health and Nutrition Examination Survey III phase 2 (n = 3860), and Hospital Universitario Miguel Servet (HUMS) (n = 2079) were used for cross-sectional TG and Lp(a) relationship. Lp(a) intrasubject variation was studied in AWHS participants and HUMS patients with repeated measurements. TG-rich lipoproteins were quantified by nuclear magnetic resonance in a subsample from AWHS. Apolipoproteins B and E were quantified by Luminex in very low-density lipoprotein (VLDL) isolated by ultracentrifugation, from HUMS samples. APOE genotyping was carried in AWHS and HUMS participants. Regression models adjusted for age and sex were used to study the association. The 3 studies showed an inverse relationship between TG and Lp(a). Increased VLDL number, size, and TG content were associated with significantly lower Lp(a). There was an inverse association between the apoE concentration in VLDL and Lp(a). No significant association was observed for apolipoprotein (apo)B. Subjects carrying the apoE2/E2 genotype had significantly lower levels of Lp(a). Our results show an inverse relationship Lp(a)-TG. Subjects with larger VLDL size have lower Lp(a), and lower values of Lp(a) were present in patients with apoE-rich VLDL and apoE2/E2 subjects. Our results suggest that bigger VLDLs and VLDLs enriched in apoE are inversely involved in Lp(a) plasma concentration.

Relationship between noninvasive scores of nonalcoholic fatty liver disease and nuclear magnetic resonance lipoprotein abnormalities: A focus on atherogenic dyslipidemia

Nonalcoholic fatty liver disease (NAFLD) is an emerging, highly prevalent, cardiovascular risk factor, and lipoprotein proatherogenic disturbances likely explain a large part of this risk. However, information regarding associations between detailed nuclear magnetic resonance (NMR) lipoprotein changes and noninvasive NAFLD scores is lacking. The objective of the study was to investigate the NMR-assessed atherogenic lipoprotein profile according to noninvasive NAFLD status. Lipoprotein profiles by NMR spectroscopy and NAFLD status by fatty liver index (FLI) and Gholam's models. We assessed 173 participants (55% males), mean age 60.8±7.8years, 87% overweight/obese, 53% with diabetes. An FLI <30, 30 to 60, and >60 was found in 32, 50, and 91 participants, respectively. Individuals with FLI >60 had lower high-density lipoprotein (HDL)-cholesterol (P<.001), higher triglyceride (P<.001), and similar non-HDL-cholesterol (P=.912) concentrations. In NMR analysis, FLI was related with very-low-density lipoprotein (VLDL) and HDL parameters in a dose-dependent manner. VLDL particle number (P<.001) and VLDL size (39.1±0.99, 39.7±0.96, 40.8±1.19nm, P<.001) increased with increased FLI (<30, 30-60, and >60, respectively). Conversely, although total HDL particle number did not differ by FLI (P=.377), larger HDL particles (P<.001), amount of cholesterol within HDL particles (P<.001), and HDL size (median [p25-p75]: 8.23 [8.08-8.41], 8.12 [8.03-8.29], 8.04 [7.93-8.16]nm, P<.001) decreased as FLI increased. FLI >60 (vs <60) was associated with a higher proportion of small LDL particles (P=.010) and lower LDL size (19.85±0.34 vs 19.98±0.25nm; P=.005). Similar findings were found for Gholam's model. Simple and noninvasive NAFLD scores are useful to detect many of the proatherogenic changes (especially in VLDL and HDL), beyond conventional lipids parameters that are common in individuals with this high-risk condition.

Steatohepatitis and liver fibrosis are predicted by the characteristics of very low density lipoprotein in nonalcoholic fatty liver disease.

A major challenge in the management of nonalcoholic fatty liver disease (NAFLD) is to identify patients with nonalcoholic steatohepatitis (NASH) and early liver fibrosis. The progression of NAFLD is accompanied by distinctive changes in very low density lipoprotein (VLDL), a lipoprotein particle produced exclusively in the liver. Herein, we sought to determine the characteristics of VLDL profiles associated with NASH and liver fibrosis. We evaluated VLDL profiles of 128 patients from a single centre NAFLD registry, and examined VLDL size, total and subclass VLDL concentrations in relation to NAFLD activity score (NAS), steatohepatitis and liver fibrosis as determined by liver biopsy. A near linear relationship was observed between mean VLDL particle size and NAFLD activity score (NAS). In multivariate models, VLDL particle size was significantly associated with both NAS and NASH, after adjustment for BMI and diabetes. A decrease in small VLDL particle concentration was associated with more advanced liver fibrosis. In receiver operative characteristic analyses, mean VLDL size performed similarly to cytokeratin 18 in predicting NASH, whereas small VLDL particle concentration had similar performance to NAFLD fibrosis score in predicting stage 2 or above liver fibrosis. The increase in mean VLDL size in NASH and decrease in small VLDL particle concentration in liver fibrosis likely reflect changes in the number and state of hepatocytes associated with NASH and fibrosis. In addition to its value in risk stratification of cardiovascular diseases, circulating VLDL profile may provide information for the staging of NAFLD disease severity.

Associations of insulin resistance, inflammation and liver synthetic function with very low-density lipoprotein: The Cardiovascular Health Study

IntroductionProduction of very low-density lipoprotein (VLDL) is increased in states of metabolic syndrome, leading to hypertriglyceridemia. However, metabolic syndrome is often associated with non-alcoholic fatty liver disease, which leads to liver fibrosis and inflammation that may decrease VLDL production. In this study, we aim to determine the interactive impact on VLDL profiles from insulin resistance, impairment in liver synthetic function and inflammation. MethodsWe examined cross-sectional associations of insulin sensitivity, inflammation, and liver synthetic function with VLDL particle (VLDL-P) concentration and size among 1,850 older adults in the Cardiovascular Health Study. ResultsIndices for high insulin sensitivity and low liver synthetic function were associated with lower concentrations of VLDL-P. In addition, insulin resistance preferentially increased concentration of large VLDL and was associated with mean VLDL size. Indices for inflammation however demonstrated a nonlinear relationship with both VLDL-P concentration and VLDL size. When mutually adjusted, one standard deviation (SD) increment in Matsuda index and C-reactive protein (CRP) were associated with 4.9nmol/L (−8.2 to −1.5, p=0.005) and 6.3nmol/L (−11.0 to −1.6, p=0.009) lower VLDL-P concentration respectively. In contrast, one-SD increment in factor VII, a marker for liver synthetic function, was associated with 16.9nmol/L (12.6–21.2, p<0.001) higher VLDL-P concentration. Furthermore, a one-SD increment in the Matsuda index was associated with 1.1nm (−2.0 to −0.3, p=0.006) smaller mean VLDL size, whereas CRP and factor VII were not associated with VLDL size. ConclusionInsulin sensitivity, inflammation and markers for liver synthetic function differentially impact VLDL-P concentration and VLDL size. These results underscore the complex effects of insulin resistance and its complications on VLDL production.

Hepatic Leptin Signalling Modulates ApoB Containing Lipoprotein Size and Triglyceride Content

Leptin treatment has been shown to ameliorate aberrant glucose and lipid metabolism seen in models of diabetes. Interestingly, leptin can have diverse effects on various tissues in the body and many studies have investigated how leptin may be acting to improve diabetic symptoms. Because the liver is involved in both glucose and lipid homeostasis, we hypothesized that leptin may influence lipid metabolism by acting through the liver. To test this hypothesis, we generated mice with a hepatocyte-specific ablation of leptin receptors. Previously, we have shown that these mice have an accumulation of triglycerides and cholesterol in the liver and exhibit increased hepatic insulin sensitivity. We now show that these mice have altered lipoprotein profiles resulting in 18% less plasma apolipoprotein B levels yet larger, more triglyceride-rich very low density lipoprotein (VLDL) particles. This suggests that triglyceride incorporation into VLDL or triglyceride depletion from lipoproteins in the plasma may be modified. Interestingly, this change in VLDL size was accompanied by a 30% decrease in hepatic lipase activity and a 4.5-fold increase in lipoprotein lipase activity in the liver, resulting in an overall elevation in total triglyceride lipase activity in the liver. Alterations in total liver lipase composition may contribute to the increase in lipid droplets in the liver of these mice. Taken together, we have revealed a novel role of hepatic leptin signalling in the modulation of triglyceride metabolism by affecting VLDL size, composition, and modification through liver lipases, providing insight into how leptin is related to dyslipidemia in diabetes.

Lipoprotein particle distribution and skeletal muscle lipoprotein lipase activity after acute exercise.

BackgroundMany of the metabolic effects of exercise are due to the most recent exercise session. With recent advances in nuclear magnetic resonance spectroscopy (NMRS), it is possible to gain insight about which lipoprotein particles are responsible for mediating exercise effects.MethodsUsing a randomized cross-over design, very low density lipoprotein (VLDL) responses were evaluated in eight men on the morning after i) an inactive control trial (CON), ii) exercising vigorously on the prior evening for 100 min followed by fasting overnight to maintain an energy and carbohydrate deficit (EX-DEF), and iii) after the same exercise session followed by carbohydrate intake to restore muscle glycogen and carbohydrate balance (EX-BAL).ResultsThe intermediate, low and high density lipoprotein particle concentrations did not differ between trials. Fasting triglyceride (TG) determined biochemically, and mean VLDL size were lower in EX-DEF but not in EX-BAL compared to CON, primarily due to a reduction in VLDL-TG in the 70–120 nm (large) particle range. In contrast, VLDL-TG was lower in both EX-DEF and EX-BAL compared to CON in the 43–55 nm (medium) particle range. VLDL-TG in smaller particles (29–43 nm) was unaffected by exercise. Because the majority of VLDL particles were in this smallest size range and resistant to change, total VLDL particle concentration was not different between any of these conditions. Skeletal muscle lipoprotein lipase (LPL) activity was also not different across these 3 trials. However, in CON only, the inter-individual differences in LPL activity were inversely correlated with fasting TG, VLDL-TG, total, large and small VLDL particle concentration and VLDL size, indicating a regulatory role for LPL in the non-exercised state.ConclusionsThese findings reveal a high level of differential regulation between different sized triglyceride-rich lipoproteins following exercise and feeding, in the absence of changes in LPL activity.

Dyslipidaemia and lipoprotein pattern in systemic lupus erythematosus (SLE) and SLE‐related cardiovascular disease

Objective: This study focused on lipoprotein composition and properties in systemic lupus erythematosus (SLE).Methods: The size distribution of plasma lipoproteins was studied by nuclear magnetic resonance (NMR). Cholesteryl ester transfer protein (CETP) activity was determined by enzyme‐linked immunosorbent assay (ELISA). The affinity of low density lipoprotein (LDL) for proteoglycans was assayed. Twenty‐six women (aged 52±8.2 years) with SLE and a history of cardiovascular disease (CVD) (SLE cases) were compared with 26 age‐matched women with SLE and without CVD (SLE controls) and 26 age‐matched population‐based control women (controls).Results: Very low density lipoprotein (VLDL) particles (nmol/L) were more prevalent among SLE cases than SLE controls (0.039) and tended to be more common in SLE cases than in controls (p = 0.073). By contrast, high density lipoprotein (HDL) particles (nmol/L) were more prevalent among controls than SLE cases (p = 0.024) whereas the number of LDL particles (nmol/L) did not differ significantly. Small dense (sd)LDL (nmol/L) were more common in controls and tended to be more common in SLE cases than in SLE controls (p = 0.036 and 0.086, respectively). Small high density lipoproteins (sHDL) (nmol/L) were more prevalent in controls than in SLE controls and SLE cases (p = 0.002 and p<0.001, respectively). VLDL or LDL size (nm) did not differ significantly between groups (data not shown) whereas HDL size (nm) was increased among SLE controls as compared to controls (p = 0.024) and tended to be increased among SLE cases as compared to controls (p = 0.070). The affinity of LDL for proteoglycans or CETP activity did not differ between groups (data not shown).Conclusions: sdLDL was not increased and SLE cases and SLE controls had decreased levels of sHDL. VLDL differentiates between SLE cases and SLE controls. The lipid pattern in SLE‐related CVD was thus not similar to the pattern seen in diabetes or in CVD in general.

Nuclear magnetic resonance‐determined lipoprotein subclass profile in the DCCT/EDIC cohort: associations with carotid intima‐media thickness

To relate nuclear magnetic resonance lipoprotein subclass profiles (NMR-LSP) and other lipoprotein-related factors with carotid intima-media thickness (IMT) in Type 1 diabetes. Lipoprotein-related factors were determined in sera (obtained in 1997-1999) from 428 female [age 39 +/- 7 years (mean +/- SD)] and 540 male (age 40 +/- 7 years) Diabetes Control and Complications Trial (DCCT)/Epidemiology of Diabetes Interventions and Complications (EDIC) participants. NMR quantifies chylomicrons, three very low-density lipoprotein (VLDL) subclasses, intermediate density lipoprotein (IDL), three low-density lipoprotein (LDL) subclasses, two high-density lipoprotein (HDL) subclasses, mean VLDL, LDL and HDL size, and LDL particle concentration. Conventional lipids, ApoA1, ApoB and Lp(a) and in vitro LDL oxidizibility were also measured. IMT was determined (in 1994-1995) using high-resolution B-mode ultrasound. Relationships between IMT and lipoproteins were analysed by multiple linear regression, controlling for age, diabetes-related factors, and cardiovascular disease (CVD) risk factors. IMT associations with lipoproteins were stronger for the internal than the common carotid artery, predominantly involving LDL. Internal carotid IMT was positively (P < 0.05) associated with NMR-based LDL subclasses and particle concentration, and with conventional LDL-cholesterol and ApoB in both genders. Common carotid IMT was associated, in men only, with large VLDL, IDL, conventional LDL cholesterol and ApoB. NMR-LSP reveals significant associations with carotid IMT in Type 1 diabetic patients, even 4 years after IMT measurement. NMR-LSP may aid early identification of high-risk diabetic patients and facilitate monitoring of interventions. Longer DCCT/EDIC cohort follow-up will yield CVD events and IMT progression, permitting more accurate assessment of pre-morbid lipoprotein profiles as determinants of cardiovascular risk in Type 1 diabetes.

Effect of a High Saturated Fat and No-Starch Diet on Serum Lipid Subfractions in Patients With Documented Atherosclerotic Cardiovascular Disease

To determine whether a diet of high saturated fat and avoidance of starch (HSF-SA) results in weight loss without adverse effects on serum lipids in obese nondiabetic patients. Twenty-three patients with atherosclerotic cardiovascular disease participated in a prospective 6-week trial at the Christiana Care Medical Center in Newark, Del, between August 2000 and September 2001. All patients were obese (mean +/- SD body mass index [BMI], 39.0+/-7.3 kg/m2) and had been treated with statins before entry in the trial. Fifteen obese patients with polycystic ovary syndrome (BMI, 36.1+/-9.7 kg/m2) and 8 obese patients with reactive hypoglycemia (BMI, 46.8+/-10 kg/m2) were monitored during an HSF-SA diet for 24 and 52 weeks, respectively, between 1997 and 2000. In patients with atherosclerotic cardiovascular disease, mean +/- SD total body weight (TBW) decreased 5.2%+/-2.5% (P<.001) as did body fat percentage (P=.02). Nuclear magnetic resonance spectroscopic analysis of lipids showed decreases in total triglycerides (P<.001), very low-density lipoprotein (VLDL) triglycerides (P<.001), VLDL size (P<.001), large VLDL concentration (P<.001), and medium VLDL concentration (P<.001). High-density lipoprotein (HDL) and LDL concentrations were unchanged, but HDL size (P=.01) and LDL size (P=.02) increased. Patients with polycystic ovary syndrome lost 14.3%+/-20.3% of TBW (P=.008) and patients with reactive hypoglycemia lost 19.9%+/-8.7% of TBW (P<.001) at 24 and 52 weeks, respectively, without adverse effects on serum lipids. An HSF-SA diet results in weight loss after 6 weeks without adverse effects on serum lipid levels verified by nuclear magnetic resonance, and further weight loss with a lipid-neutral effect may persist for up to 52 weeks.

Levels and correlates of LDL and VLDL particle sizes among children: the Bogalusa heart study

Levels of lipids and lipoproteins among children vary by sex and race/ethnicity, and are correlated with age, obesity, and other characteristics. There is, however, little information on the distribution and correlates of low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) subclasses in early life. We used nuclear magnetic resonance (NMR) spectroscopy to determine mean LDL and VLDL particle sizes among 10- to 17-year-olds ( n=918) who participated in the 1992–94 examination of the Bogalusa heart study. As compared with girls, boys had a smaller (0.1 nm) mean LDL particle size and a larger (0.9 nm) mean VLDL size; furthermore, the average size of VLDL particles increased with age among white boys but not among other children. Although there were also black/white differences in particle sizes, with black children having larger LDL and smaller VLDL particles, these racial contrasts could be attributed to differences in lipid levels. Levels of triglycerides, insulin, and relative weight were associated with the size of VLDL (positive) and LDL (negative) particles. These results suggest that the analysis of lipoprotein subclasses may provide a better understanding of the role of various risk factors in the development of coronary heart disease

Overfeeding increases very low density lipoprotein diameter and causes the appearance of a unique lipoprotein particle in association with failed yolk deposition.

Structurally specific very low density lipoprotein (VLDL) particles are presumed to redirect VLDL uptake during yolk deposition. Egg production is an energy intensive process, but energy excess negatively affects egg production. This study sought to determine whether overfeeding changed hen lipoprotein profiles, and if so, whether changes were related to egg production. Overfeeding caused 33% of hens to stop yolk deposition and reabsorb unovulated follicles (involute). VLDL of control hens possessed characteristic small particle size (30 nm) and composition indicative of limited intravascular metabolism. Overfeeding generally increased VLDL diameter, the effect being slight (+6.6 nm) in overfed laying hens when compared to overfed-involuted hens (+51.2 nm). Changes in composition indicated that increased intravascular metabolism of VLDL parallelled increases in particle diameter. Overfed-involuted hens showed significant elevations of plasma low density lipoprotein, VLDL cholesteryl ester, and high density lipoprotein (HDL) triacylglycerol content. Overfeeding increased plasma HDL, and in association with involution, caused redistribution of HDL particle sizes, including the appearance of novel HDL approximately 20 nm in diameter, termed HDLR, and a 97 kDa protein within the HDL fraction. The overfed hen model may provide new insight into the role of lipoprotein physical properties in determining the metabolism of triacylglycerol-rich lipoprotein, and the process of reverse lipid transport. Overfeeding generally increases VLDL size and plasma HDL levels suggesting that increased peripheral metabolism, and perhaps mechanical exclusion of enlarged VLDL by the granulosa basal lamina, contribute to the obesity and impaired yolk deposition observed in hens with excessive energy intakes. Temporal definition of massive VLDL enlargement relative to follicular collapse remains to be established.(ABSTRACT TRUNCATED AT 250 WORDS)

Increased turnover of very low density lipoprotein triglyceride during treatment with cholestyramine in familial hypercholesterolaemia

Kinetics of very low density lipoprotein (VLDL) triglyceride were determined in seven patients with heterozygous familial hypercholesterolaemia, using a 3H-glycerol technique. The study was repeated after 5-7 weeks of therapy with the bile acid-binding resin, cholestyramine. The rate of synthesis of VLDL triglyceride was increased by 85% (P less than 0.05) during resin therapy. Simultaneously, the fractional catabolic rate of VLDL was increased by 40% (P less than 0.02), so that only a moderate increase in plasma concentration was observed. Repeated measurements of VLDL size by electron microscopy (before, 1 week, and 5-7 weeks after initiation of therapy) indicated that a transient increase in VLDL size occurred in response to cholestyramine. The results are consistent with a stimulatory effect of bile acid sequestrants on VLDL triglyceride production and indicate that, in most subjects, a compensatory increase in VLDL triglyceride removal occurs.