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Frank M Sacks - One of the best experts on this subject based on the ideXlab platform.

  • abstract p020 triglyceride lowering lipoprotein lipase gene variants and improvements in lipids and lipoprotein subspecies defined by Apolipoprotein c iii pounds lost trial
    Circulation, 2021
    Co-Authors: Yoriko Heianza, Tao Zhou, George A Bray, Frank M Sacks
    Abstract:

    Introduction: Triglyceride-lowering variants in the lipoprotein lipase (LPL) gene have been associated with a lower risk of coronary heart disease. Lipoproteins are heterogeneous, and lipoprotein s...

  • Apolipoprotein c iii and its defined lipoprotein subspecies in relation to incident diabetes the multi ethnic study of atherosclerosis
    Diabetologia, 2019
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Frank M Sacks, Majken K Jensen, Kenneth J Mukamal, Robyn L Mcclelland, Michael Y Tsai
    Abstract:

    Apolipoprotein C-III (apoC-III) is a small proinflammatory protein that may play a key role in diabetes pathophysiology. However, prior observational studies have been limited to predominantly white populations, and the biological links between apoC-III and diabetes, particularly the role of apoC-III on specific lipoprotein particles, are not yet well understood. We therefore investigated associations of total apoC-III and apoC-III-defined lipoprotein subspecies with incident diabetes and glucose metabolism measures in a multi-ethnic cohort. For the current analyses, baseline (2000–2002) plasma total apoC-III and Apolipoprotein A-I concentrations of HDL containing or lacking apoC-III were newly measured via sandwich ELISA in 4579 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable Cox regression was used to examine associations of Apolipoproteins with incident diabetes until early 2012 (567 cases), and linear mixed models were used to estimate associations with longitudinally assessed continuous measures of glucose metabolism. Similar exploratory analyses of plasma Apolipoprotein B concentrations of LDL and VLDL containing or lacking apoC-III were performed in a subset of participants (LDL, n = 1545; VLDL, n = 1526). In the overall population, elevated total apoC-III concentrations were associated with a higher rate of diabetes (top vs bottom quintile, HR 1.88; 95% CI 1.42, 2.47; ptrend = 0.0002). ApoC-III-defined HDL subspecies displayed opposing associations with incidence of diabetes (p for heterogeneity = 0.02). While HDL lacking apoC-III was inversely associated with incidence of diabetes (top vs bottom quintile, HR 0.66; 95% CI 0.46, 0.93; ptrend = 0.002), HDL containing apoC-III was not associated (HR 1.11; 95% CI 0.78, 1.58; ptrend = 0.61). Similarly, only HDL lacking apoC-III was beneficially associated with plasma glucose (ptrend = 0.003), HbA1c (ptrend = 0.04) and insulin sensitivity (ptrend < 0.0001), and higher HDL containing apoC-III was associated with lower insulin sensitivity (ptrend = 0.04). Neither of the apoC-III-defined LDL subspecies was associated with incident diabetes, while VLDL was more strongly associated with the incidence of diabetes when it lacked apoC-III. Further adjustment for plasma triacylglycerols as a potential intermediate attenuated the associations of total apoC-III and apoC-III-defined lipoprotein subspecies. No statistically significant differences were observed across racial/ethnic groups. Our findings in a multi-ethnic population support the involvement of apoC-III in the development of diabetes, potentially through its association with circulating triacylglycerols. The presence of apoC-III on HDL also diminished the protective association of HDL with incident diabetes. Further investigation of apoC-III and apoC-III-defined HDL subspecies may inform the development of novel diabetes treatment and prevention strategies.

  • high density lipoprotein with Apolipoprotein c iii is associated with carotid intima media thickness among generally healthy individuals
    Atherosclerosis, 2018
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Frank M Sacks, Sarah A Aroner, Bernard Rosner, Ele Ferrannini, Simona Baldi, Michaela Kozakova
    Abstract:

    Abstract Background and aims About 6–7% of high density lipoprotein (HDL) has a protein called Apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT). Methods We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Results HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend Conclusions HDL apoC-III is a promising target for atherosclerosis prevention and treatment.

  • Apolipoprotein c iii and high density lipoprotein subspecies defined by Apolipoprotein c iii in relation to diabetes risk
    American Journal of Epidemiology, 2017
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Frank M Sacks, Ming Yang, Anne Tjonneland, Kim Overvad, Tianxi Cai, Majken K Jensen
    Abstract:

    Apolipoprotein C-III (apoC-III) is a potentially novel biomarker that may play an important role in the pathogenesis of diabetes, particularly when present on the surface of high-density lipoprotein (HDL). In a case-cohort study carried out among 434 incident diabetes cases occurring before 2007 and 3,101 noncases in the Danish Diet, Cancer, and Health Study, we examined associations of baseline (1993-1997) plasma concentrations of apoC-III and subspecies of HDL defined by the presence or absence of apoC-III with risk of diabetes using Cox regression. ApoC-III was strongly associated with risk of diabetes (for top quintile vs. bottom quintile, hazard ratio (HR) = 3.43, 95% confidence interval (CI): 1.75, 6.70; P-trend < 0.001). The cholesterol concentration of HDL (HDL cholesterol (HDL-C)) without apoC-III was inversely associated with risk of diabetes (HR = 0.48, 95% CI: 0.27, 0.85; P-trend = 0.002), more so than total HDL-C (HR = 0.60, 95% CI: 0.35, 1.03; P-trend = 0.04), whereas HDL-C with apoC-III was not associated (HR = 1.05, 95% CI: 0.50, 2.21; P-trend = 0.44) (for HDL-C with apoC-III vs. HDL-C without apoC-III, P-heterogeneity = 0.002). ApoC-III itself is a strong risk marker for diabetes, and its presence on HDL may impair the antidiabetogenic properties of HDL. ApoC-III has potential to be a therapeutic target for the prevention of diabetes.

  • associations of anthropometry and lifestyle factors with hdl subspecies according to Apolipoprotein c iii
    Journal of Lipid Research, 2017
    Co-Authors: Manja Koch, Jeremy D Furtado, Frank M Sacks, Anne Tjonneland, Kim Overvad, Tianxi Cai, Gordon Z Jiang, Brianna E Gray, Majken K Jensen
    Abstract:

    The presence of apoC-III on HDL impairs HDL's inverse association with coronary heart disease (CHD). Little is known about modifiable factors explaining variation in HDL subspecies defined according to apoC-III. The aim was to investigate cross-sectional associations of anthropometry and lifestyle with HDL subspecies in 3,631 participants from the Diet, Cancer, and Health study originally selected for a case-cohort study (36% women; age 50-65 years) who were all free of CHD. Greater adiposity and less activity were associated with higher HDL containing apoC-III and lower HDL lacking apoC-III. Per each 15 cm higher waist circumference, the level of HDL containing apoC-III was 2.8% higher (95% CI: 0.4, 5.3; P = 0.024) and the level of HDL not containing apoC-III was 4.7% lower (95% CI: -6.0, -3.4; P = <0.0001). Associations for physical activity were most robust to multivariable modeling. Each 20 metabolic equivalent task hours per week reported higher physical activity was associated with 0.9% (95% CI: -1.7, -0.1; P = 0.031) lower HDL containing apoC-III and 0.5% higher (95% CI: 0.1, 1.0; P = 0.029) HDL lacking apoC-III. Lower alcohol consumption was associated with lower HDL lacking apoC-III (percent difference per 15 g/day: 1.58 (95% CI: 0.84, 2.32; P = <0.0001). Adiposity and sedentary lifestyle were associated with a less favorable HDL subspecies profile.

Majken K Jensen - One of the best experts on this subject based on the ideXlab platform.

  • hdl containing Apolipoprotein c iii is associated with insulin sensitivity a multi center cohort study
    The Journal of Clinical Endocrinology and Metabolism, 2021
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Sarah A Aroner, Majken K Jensen, Bernard Rosner, Beverley Balkau, Andrea Natali, Ele Ferrannini
    Abstract:

    CONTEXT High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE We investigated the prospective associations between HDL subspecies containing and lacking Apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The Apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

  • association of high density lipoprotein particles and high density lipoprotein Apolipoprotein c iii content with cardiovascular disease risk according to kidney function the multi ethnic study of atherosclerosis
    Journal of the American Heart Association, 2019
    Co-Authors: Julio A Lampreamontealegre, Majken K Jensen, Robyn L Mcclelland, Manja Koch, James D Otvos, Samia Mora, Ian H De Boer
    Abstract:

    Background Chronic kidney disease is associated with structural and compositional abnormalities in high‐density lipoprotein particles (HDLp). We examined associations of HDLp size, particle subfrac...

  • Apolipoprotein c iii and its defined lipoprotein subspecies in relation to incident diabetes the multi ethnic study of atherosclerosis
    Diabetologia, 2019
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Frank M Sacks, Majken K Jensen, Kenneth J Mukamal, Robyn L Mcclelland, Michael Y Tsai
    Abstract:

    Apolipoprotein C-III (apoC-III) is a small proinflammatory protein that may play a key role in diabetes pathophysiology. However, prior observational studies have been limited to predominantly white populations, and the biological links between apoC-III and diabetes, particularly the role of apoC-III on specific lipoprotein particles, are not yet well understood. We therefore investigated associations of total apoC-III and apoC-III-defined lipoprotein subspecies with incident diabetes and glucose metabolism measures in a multi-ethnic cohort. For the current analyses, baseline (2000–2002) plasma total apoC-III and Apolipoprotein A-I concentrations of HDL containing or lacking apoC-III were newly measured via sandwich ELISA in 4579 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable Cox regression was used to examine associations of Apolipoproteins with incident diabetes until early 2012 (567 cases), and linear mixed models were used to estimate associations with longitudinally assessed continuous measures of glucose metabolism. Similar exploratory analyses of plasma Apolipoprotein B concentrations of LDL and VLDL containing or lacking apoC-III were performed in a subset of participants (LDL, n = 1545; VLDL, n = 1526). In the overall population, elevated total apoC-III concentrations were associated with a higher rate of diabetes (top vs bottom quintile, HR 1.88; 95% CI 1.42, 2.47; ptrend = 0.0002). ApoC-III-defined HDL subspecies displayed opposing associations with incidence of diabetes (p for heterogeneity = 0.02). While HDL lacking apoC-III was inversely associated with incidence of diabetes (top vs bottom quintile, HR 0.66; 95% CI 0.46, 0.93; ptrend = 0.002), HDL containing apoC-III was not associated (HR 1.11; 95% CI 0.78, 1.58; ptrend = 0.61). Similarly, only HDL lacking apoC-III was beneficially associated with plasma glucose (ptrend = 0.003), HbA1c (ptrend = 0.04) and insulin sensitivity (ptrend < 0.0001), and higher HDL containing apoC-III was associated with lower insulin sensitivity (ptrend = 0.04). Neither of the apoC-III-defined LDL subspecies was associated with incident diabetes, while VLDL was more strongly associated with the incidence of diabetes when it lacked apoC-III. Further adjustment for plasma triacylglycerols as a potential intermediate attenuated the associations of total apoC-III and apoC-III-defined lipoprotein subspecies. No statistically significant differences were observed across racial/ethnic groups. Our findings in a multi-ethnic population support the involvement of apoC-III in the development of diabetes, potentially through its association with circulating triacylglycerols. The presence of apoC-III on HDL also diminished the protective association of HDL with incident diabetes. Further investigation of apoC-III and apoC-III-defined HDL subspecies may inform the development of novel diabetes treatment and prevention strategies.

  • high density lipoprotein subspecies defined by Apolipoprotein c iii and subclinical atherosclerosis measures mesa the multi ethnic study of atherosclerosis
    Journal of the American Heart Association, 2018
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Kenneth J Mukamal, Robyn L Mcclelland, Manja Koch, James H Stein, Matthew C Tattersall, Majken K Jensen
    Abstract:

    Background Apolipoprotein C‐III (apoC‐III), a small proinflammatory protein present on 6% to 7% of high‐density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi‐ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC‐III–defined HDL subspecies and subclinical markers of atherosclerotic pathology. Methods and Results We investigated cross‐sectional associations between Apolipoprotein A‐I concentrations of apoC‐III–defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi‐Ethnic Study of Atherosclerosis) at baseline (2000–2002). HDL particles containing and lacking apoC‐III were divergently associated with coronary artery calcification in women ( P ‐heterogeneity=0.002) but not in men ( P ‐heterogeneity=0.31) and with carotid plaque score ( P ‐heterogeneity=0.02) and intima‐media thickness ( P ‐heterogeneity=0.06) in the overall study population. HDL lacking apoC‐III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73–0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84–1.00]; intima‐media thickness, overall: mean difference per SD=−14.0 µm [95% CI, −21.1 to −6.7 μm]), whereas HDL containing apoC‐III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99–1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01–1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later. Conclusions The presence of apoC‐III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC‐III in the pathophysiology of cardiovascular disease.

  • high density lipoprotein subspecies defined by presence of Apolipoprotein c iii and incident coronary heart disease in four cohorts
    Circulation, 2017
    Co-Authors: Majken K Jensen, Jeremy D Furtado, Sarah A Aroner, Anne Tjonneland, Kenneth J Mukamal, Wendy S Post, Joseph F Polak, Michael Y Tsai, Eric B Rimm, Kim Overvad
    Abstract:

    Background —The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). Methods —We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases. Results —ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies Conclusions —Our findings from four prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.

Jeremy D Furtado - One of the best experts on this subject based on the ideXlab platform.

  • hdl containing Apolipoprotein c iii is associated with insulin sensitivity a multi center cohort study
    The Journal of Clinical Endocrinology and Metabolism, 2021
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Sarah A Aroner, Majken K Jensen, Bernard Rosner, Beverley Balkau, Andrea Natali, Ele Ferrannini
    Abstract:

    CONTEXT High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE We investigated the prospective associations between HDL subspecies containing and lacking Apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The Apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

  • Apolipoprotein c iii and its defined lipoprotein subspecies in relation to incident diabetes the multi ethnic study of atherosclerosis
    Diabetologia, 2019
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Frank M Sacks, Majken K Jensen, Kenneth J Mukamal, Robyn L Mcclelland, Michael Y Tsai
    Abstract:

    Apolipoprotein C-III (apoC-III) is a small proinflammatory protein that may play a key role in diabetes pathophysiology. However, prior observational studies have been limited to predominantly white populations, and the biological links between apoC-III and diabetes, particularly the role of apoC-III on specific lipoprotein particles, are not yet well understood. We therefore investigated associations of total apoC-III and apoC-III-defined lipoprotein subspecies with incident diabetes and glucose metabolism measures in a multi-ethnic cohort. For the current analyses, baseline (2000–2002) plasma total apoC-III and Apolipoprotein A-I concentrations of HDL containing or lacking apoC-III were newly measured via sandwich ELISA in 4579 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable Cox regression was used to examine associations of Apolipoproteins with incident diabetes until early 2012 (567 cases), and linear mixed models were used to estimate associations with longitudinally assessed continuous measures of glucose metabolism. Similar exploratory analyses of plasma Apolipoprotein B concentrations of LDL and VLDL containing or lacking apoC-III were performed in a subset of participants (LDL, n = 1545; VLDL, n = 1526). In the overall population, elevated total apoC-III concentrations were associated with a higher rate of diabetes (top vs bottom quintile, HR 1.88; 95% CI 1.42, 2.47; ptrend = 0.0002). ApoC-III-defined HDL subspecies displayed opposing associations with incidence of diabetes (p for heterogeneity = 0.02). While HDL lacking apoC-III was inversely associated with incidence of diabetes (top vs bottom quintile, HR 0.66; 95% CI 0.46, 0.93; ptrend = 0.002), HDL containing apoC-III was not associated (HR 1.11; 95% CI 0.78, 1.58; ptrend = 0.61). Similarly, only HDL lacking apoC-III was beneficially associated with plasma glucose (ptrend = 0.003), HbA1c (ptrend = 0.04) and insulin sensitivity (ptrend < 0.0001), and higher HDL containing apoC-III was associated with lower insulin sensitivity (ptrend = 0.04). Neither of the apoC-III-defined LDL subspecies was associated with incident diabetes, while VLDL was more strongly associated with the incidence of diabetes when it lacked apoC-III. Further adjustment for plasma triacylglycerols as a potential intermediate attenuated the associations of total apoC-III and apoC-III-defined lipoprotein subspecies. No statistically significant differences were observed across racial/ethnic groups. Our findings in a multi-ethnic population support the involvement of apoC-III in the development of diabetes, potentially through its association with circulating triacylglycerols. The presence of apoC-III on HDL also diminished the protective association of HDL with incident diabetes. Further investigation of apoC-III and apoC-III-defined HDL subspecies may inform the development of novel diabetes treatment and prevention strategies.

  • high density lipoprotein subspecies defined by Apolipoprotein c iii and subclinical atherosclerosis measures mesa the multi ethnic study of atherosclerosis
    Journal of the American Heart Association, 2018
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Kenneth J Mukamal, Robyn L Mcclelland, Manja Koch, James H Stein, Matthew C Tattersall, Majken K Jensen
    Abstract:

    Background Apolipoprotein C‐III (apoC‐III), a small proinflammatory protein present on 6% to 7% of high‐density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi‐ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC‐III–defined HDL subspecies and subclinical markers of atherosclerotic pathology. Methods and Results We investigated cross‐sectional associations between Apolipoprotein A‐I concentrations of apoC‐III–defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi‐Ethnic Study of Atherosclerosis) at baseline (2000–2002). HDL particles containing and lacking apoC‐III were divergently associated with coronary artery calcification in women ( P ‐heterogeneity=0.002) but not in men ( P ‐heterogeneity=0.31) and with carotid plaque score ( P ‐heterogeneity=0.02) and intima‐media thickness ( P ‐heterogeneity=0.06) in the overall study population. HDL lacking apoC‐III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73–0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84–1.00]; intima‐media thickness, overall: mean difference per SD=−14.0 µm [95% CI, −21.1 to −6.7 μm]), whereas HDL containing apoC‐III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99–1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01–1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later. Conclusions The presence of apoC‐III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC‐III in the pathophysiology of cardiovascular disease.

  • high density lipoprotein with Apolipoprotein c iii is associated with carotid intima media thickness among generally healthy individuals
    Atherosclerosis, 2018
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Frank M Sacks, Sarah A Aroner, Bernard Rosner, Ele Ferrannini, Simona Baldi, Michaela Kozakova
    Abstract:

    Abstract Background and aims About 6–7% of high density lipoprotein (HDL) has a protein called Apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT). Methods We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Results HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend Conclusions HDL apoC-III is a promising target for atherosclerosis prevention and treatment.

  • high density lipoprotein subspecies defined by presence of Apolipoprotein c iii and incident coronary heart disease in four cohorts
    Circulation, 2017
    Co-Authors: Majken K Jensen, Jeremy D Furtado, Sarah A Aroner, Anne Tjonneland, Kenneth J Mukamal, Wendy S Post, Joseph F Polak, Michael Y Tsai, Eric B Rimm, Kim Overvad
    Abstract:

    Background —The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). Methods —We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases. Results —ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies Conclusions —Our findings from four prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.

Sarah A Aroner - One of the best experts on this subject based on the ideXlab platform.

  • hdl containing Apolipoprotein c iii is associated with insulin sensitivity a multi center cohort study
    The Journal of Clinical Endocrinology and Metabolism, 2021
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Sarah A Aroner, Majken K Jensen, Bernard Rosner, Beverley Balkau, Andrea Natali, Ele Ferrannini
    Abstract:

    CONTEXT High density lipoprotein (HDL) in humans is composed of a heterogeneous group of particles varying in protein composition as well as biological effects. OBJECTIVE We investigated the prospective associations between HDL subspecies containing and lacking Apolipoprotein (apo) C-III at baseline and insulin sensitivity at year 3. DESIGN, SETTING, AND PARTICIPANTS A prospective cohort study of 864 healthy volunteers drawn from the relationship between insulin sensitivity and cardiovascular disease (RISC) study, a multicenter European clinical investigation, whose recruitment initiated in 2002, with a follow-up of 3 years. MAIN MEASURES Insulin sensitivity was estimated from an oral glucose tolerance test at baseline and year 3, and by euglycemic-hyperinsulinemic clamp at baseline only. The Apolipoprotein concentrations were measured at baseline by a sandwich enzyme-linked immunosorbent assay (ELISA)-based method. RESULTS The 2 HDL subspecies demonstrated significantly opposite associations with insulin sensitivity at year 3 (P-heterogeneity = 0.004). The highest quintile of HDL containing apoC-III was associated with a 1.2% reduction in insulin sensitivity (P-trend = 0.02), while the highest quintile of HDL lacking apoC-III was associated with a 1.3% increase (P-trend = 0.01), compared to the lowest quintile. No significant association was observed for total HDL, and very low density lipoprotein (VLDL) and low density lipoprotein (LDL) containing apoC-III. ApoC-III contained in HDL was associated with a decrease in insulin sensitivity even more strongly than plasma total apoC-III. CONCLUSION Both HDL containing apoC-III and apoC-III in HDL adversely affect the beneficial properties of HDL on insulin response to glucose. Our results support the potential of HDL-associated apoC-III as a promising target for diabetes prevention and treatment.

  • Apolipoprotein c iii and its defined lipoprotein subspecies in relation to incident diabetes the multi ethnic study of atherosclerosis
    Diabetologia, 2019
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Frank M Sacks, Majken K Jensen, Kenneth J Mukamal, Robyn L Mcclelland, Michael Y Tsai
    Abstract:

    Apolipoprotein C-III (apoC-III) is a small proinflammatory protein that may play a key role in diabetes pathophysiology. However, prior observational studies have been limited to predominantly white populations, and the biological links between apoC-III and diabetes, particularly the role of apoC-III on specific lipoprotein particles, are not yet well understood. We therefore investigated associations of total apoC-III and apoC-III-defined lipoprotein subspecies with incident diabetes and glucose metabolism measures in a multi-ethnic cohort. For the current analyses, baseline (2000–2002) plasma total apoC-III and Apolipoprotein A-I concentrations of HDL containing or lacking apoC-III were newly measured via sandwich ELISA in 4579 participants from the Multi-Ethnic Study of Atherosclerosis. Multivariable Cox regression was used to examine associations of Apolipoproteins with incident diabetes until early 2012 (567 cases), and linear mixed models were used to estimate associations with longitudinally assessed continuous measures of glucose metabolism. Similar exploratory analyses of plasma Apolipoprotein B concentrations of LDL and VLDL containing or lacking apoC-III were performed in a subset of participants (LDL, n = 1545; VLDL, n = 1526). In the overall population, elevated total apoC-III concentrations were associated with a higher rate of diabetes (top vs bottom quintile, HR 1.88; 95% CI 1.42, 2.47; ptrend = 0.0002). ApoC-III-defined HDL subspecies displayed opposing associations with incidence of diabetes (p for heterogeneity = 0.02). While HDL lacking apoC-III was inversely associated with incidence of diabetes (top vs bottom quintile, HR 0.66; 95% CI 0.46, 0.93; ptrend = 0.002), HDL containing apoC-III was not associated (HR 1.11; 95% CI 0.78, 1.58; ptrend = 0.61). Similarly, only HDL lacking apoC-III was beneficially associated with plasma glucose (ptrend = 0.003), HbA1c (ptrend = 0.04) and insulin sensitivity (ptrend < 0.0001), and higher HDL containing apoC-III was associated with lower insulin sensitivity (ptrend = 0.04). Neither of the apoC-III-defined LDL subspecies was associated with incident diabetes, while VLDL was more strongly associated with the incidence of diabetes when it lacked apoC-III. Further adjustment for plasma triacylglycerols as a potential intermediate attenuated the associations of total apoC-III and apoC-III-defined lipoprotein subspecies. No statistically significant differences were observed across racial/ethnic groups. Our findings in a multi-ethnic population support the involvement of apoC-III in the development of diabetes, potentially through its association with circulating triacylglycerols. The presence of apoC-III on HDL also diminished the protective association of HDL with incident diabetes. Further investigation of apoC-III and apoC-III-defined HDL subspecies may inform the development of novel diabetes treatment and prevention strategies.

  • high density lipoprotein subspecies defined by Apolipoprotein c iii and subclinical atherosclerosis measures mesa the multi ethnic study of atherosclerosis
    Journal of the American Heart Association, 2018
    Co-Authors: Sarah A Aroner, Jeremy D Furtado, Kenneth J Mukamal, Robyn L Mcclelland, Manja Koch, James H Stein, Matthew C Tattersall, Majken K Jensen
    Abstract:

    Background Apolipoprotein C‐III (apoC‐III), a small proinflammatory protein present on 6% to 7% of high‐density lipoprotein (HDL) particles, defines a subspecies of HDL adversely associated with coronary heart disease in primarily white cohorts. In a multi‐ethnic population free of clinical cardiovascular disease, we evaluated the relationship between apoC‐III–defined HDL subspecies and subclinical markers of atherosclerotic pathology. Methods and Results We investigated cross‐sectional associations between Apolipoprotein A‐I concentrations of apoC‐III–defined HDL subspecies, measured via ELISA and imaging measures of subclinical atherosclerosis, among 4659 participants in the MESA (The Multi‐Ethnic Study of Atherosclerosis) at baseline (2000–2002). HDL particles containing and lacking apoC‐III were divergently associated with coronary artery calcification in women ( P ‐heterogeneity=0.002) but not in men ( P ‐heterogeneity=0.31) and with carotid plaque score ( P ‐heterogeneity=0.02) and intima‐media thickness ( P ‐heterogeneity=0.06) in the overall study population. HDL lacking apoC‐III was inversely associated with all outcome measures (coronary artery calcification, women: odds ratio per SD=0.81 [95% confidence interval [CI], 0.73–0.90]; carotid plaque, overall: odds ratio per SD=0.92 [95% CI, 0.84–1.00]; intima‐media thickness, overall: mean difference per SD=−14.0 µm [95% CI, −21.1 to −6.7 μm]), whereas HDL containing apoC‐III was positively associated (coronary artery calcification, women: odds ratio=1.10 [95% CI, 0.99–1.22]; plaque, overall: odds ratio=1.10 [95% CI, 1.01–1.19]) or unassociated. Neither total HDL nor HDL subspecies was associated with changes in subclinical atherosclerosis measures up to 10 years later. Conclusions The presence of apoC‐III defined a subspecies of HDL not inversely associated with baseline measures of subclinical atherosclerosis, supporting a role of apoC‐III in the pathophysiology of cardiovascular disease.

  • high density lipoprotein with Apolipoprotein c iii is associated with carotid intima media thickness among generally healthy individuals
    Atherosclerosis, 2018
    Co-Authors: Rain Yamamoto, Jeremy D Furtado, Frank M Sacks, Sarah A Aroner, Bernard Rosner, Ele Ferrannini, Simona Baldi, Michaela Kozakova
    Abstract:

    Abstract Background and aims About 6–7% of high density lipoprotein (HDL) has a protein called Apolipoprotein (apo) C-III that regulates lipoprotein metabolism and can provoke an inflammatory response. HDL without apoC-III is inversely associated with coronary heart disease (CHD), whereas HDL with apoC-III is directly associated with CHD. We investigated how the presence of apoC-III affects the association between HDL and early stages of atherosclerosis measured as carotid intima-media thickness (cIMT). Methods We examined the cross-sectional associations between the apoA-I concentrations of HDL subspecies with and without apoC-III and cIMT measured by high resolution B-mode carotid ultrasonography among 847 participants from the European multi-center Relationship between Insulin Sensitivity and Cardiovascular disease (RISC) study. Results HDL with and without apoC-III demonstrated significantly opposite associations with both cIMT indexes (p-heterogeneity of associations comparing the two subspecies was 0.002 for cIMT at common carotid artery (cIMT at CCA) and 0.006 for the maximum cIMT in any carotid segment (cIMT max)). Compared to the lowest quintile, the highest quintile of apoA-I in HDL without apoC-III was associated with 3.7% lower cIMT at CCA (p-trend = 0.01) or 7.3% lower cIMT max (p-trend = 0.003), while the highest quintile of apoA-I in HDL with apoC-III was associated with 4.4% higher cIMT at CCA (p-trend = 0.001) or 7.9% higher cIMT max (p-trend = 0.002). Total apoA-I as well as total HDL cholesterol was not associated with cIMT whereas higher levels of total apoC-III and apoC-III contained in HDL were significantly associated with higher cIMT (p-trend Conclusions HDL apoC-III is a promising target for atherosclerosis prevention and treatment.

  • high density lipoprotein subspecies defined by presence of Apolipoprotein c iii and incident coronary heart disease in four cohorts
    Circulation, 2017
    Co-Authors: Majken K Jensen, Jeremy D Furtado, Sarah A Aroner, Anne Tjonneland, Kenneth J Mukamal, Wendy S Post, Joseph F Polak, Michael Y Tsai, Eric B Rimm, Kim Overvad
    Abstract:

    Background —The causal role of high density lipoprotein (HDL) cholesterol in cardioprotection has been questioned by genetic and randomized studies. Novel measures that relate to HDL function may contribute new information to prediction of cardiovascular risk. Apolipoprotein C-III (apoC-III) is a key regulator of lipoprotein metabolism. We investigated whether subspecies of HDL defined by apoC-III are associated with coronary heart disease (CHD). Methods —We used immuno-affinity chromatography to measure the apoA-I concentrations of HDL that contains and lacks apoC-III in two prospective studies of adults free of CHD. In the Multi-Ethnic Study of Atherosclerosis (MESA), 5,657 participants (52% women; age 52-72 y) were followed for risk of CHD from 2000-2002 through 2013. In a case-cohort study nested within the Danish Diet, Cancer and Health (DCH) study, 3,642 participants (47% women; age 51-64 y) were followed from 1994-1997 through 2010. Subsequently, we conducted a meta-analysis that combined these results with the previously published findings from two cohort studies that used similar laboratory methodology to measure lipoproteins, totaling 2,997 incident cases. Results —ApoC-III was found on 6-8% of apoA-I. The two HDL subspecies showed opposing associations with risk of CHD in each of the individual cohorts and in the meta-analysis (p-heterogeneity between the two subspecies Conclusions —Our findings from four prospective studies support the hypothesis that apoC-III may mark a subfraction of HDL that is associated with higher risk of CHD. New measures reflecting HDL structure and function may provide novel insights for cardiovascular risk that extend beyond traditional plasma HDL cholesterol concentrations.

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  • inter relationships between proprotein convertase subtilisin kexin type 9 Apolipoprotein c iii and plasma Apolipoprotein b 48 transport in obese subjects a stable isotope study in the postprandial state
    Clinical Science, 2015
    Co-Authors: Dick C Chan, Hugh P R Barrett, Jing Pang, Annette T Y Wong, Gerald F Watts
    Abstract:

    Postprandial lipaemia, due to elevated plasma Apolipoprotein (apo) B-48 concentrations, contributes to increased cardiovascular (CV) risk in obesity. Proprotein convertase subtilisin/kexin type 9 (PCSK9) and apoC-III may play a role in regulating triacylglycerol-rich lipoprotein (TRL)-apoB-48 metabolism. We investigated the associations between plasma PCSK9 and apoC-III concentrations and the kinetics of apoB-48 in obese subjects. Seventeen obese subjects were given an oral fat load. ApoB-48 tracer/tracee ratios were measured after an intravenous 2H3-leucine administration using GC-MS. Kinetic parameters, including secretion and fractional catabolic rates (FCRs), were derived using a multi-compartmental model. Plasma PCSK9 and apoC-III concentrations were significantly and positively (P 0.05 in all) with basal secretion or the number of TRL-apoB-48 secreted over the postprandial period. In the stepwise regression analysis, plasma PCSK9 was the best predictor of the total and incremental AUCs for plasma apoB-48 and the FCR of TRL-apoB-48. The association between plasma PCSK9 and apoC-III and TRL-apoB-48 FCR remained significant (P<0.05 in all) after adjusting for age, homoeostasis model assessment (HOMA) score, hepatic lipase or lipoprotein lipase (LPL). In a multiple regression model, 31% of variance in TRL-apoB-48 FCR was accounted for by plasma PCSK9 and apoC-III concentrations (adjusted R2=0.306, P<0.05). However, their associations with TRL-apoB-48 FCR were not independent of each other. Our results suggest that the catabolism of TRL-apoB-48 in the postprandial state may be co-ordinated by PCSK9 and apoC-III in obese individuals.

  • fenofibrate concomitantly decreases serum proprotein convertase subtilisin kexin type 9 and very low density lipoprotein particle concentrations in statin treated type 2 diabetic patients
    Diabetes Obesity and Metabolism, 2010
    Co-Authors: Dick C Chan, Gilles Lambert, Sandra J Hamilton, Kerryanne Rye, Gerard T Chew, Alicia J Jenkins, Gerald F Watts
    Abstract:

    Aim: Diabetic dyslipidaemia, characterized by hypertriglyceridaemia as a result of elevated serum very-low-density lipoprotein (VLDL) concentrations, contributes to the increased risk of cardiovascular disease (CVD) in type 2 diabetes (T2DM). Proprotein convertase subtilisin/kexin type 9 (PCSK9) may play a role in regulating VLDL metabolism. We investigated the effect of fenofibrate on serum PCSK9 and VLDL particle concentrations in T2DM patients already receiving statin therapy. Methods: In a double-blind randomized crossover study, 15 statin-treated T2DM patients (63 ± 8 years, body mass index (BMI) 29 ± 3 kg/m2) were treated with fenofibrate (145 mg/day) or matching placebo for 12 weeks. Serum PCSK9 concentrations were measured by immunoassay. VLDL particle concentration and size were determined by nuclear magnetic resonance spectroscopy. Results: Fenofibrate decreased serum triglycerides (−23%), VLDL-triglycerides (−51%), total cholesterol (−11%), LDL-cholesterol (−16%), Apolipoprotein B-100 (−16%), Apolipoprotein C-III (−20%) and PCSK9 (−13%) concentrations compared with placebo (p < 0.05). Fenofibrate also decreased serum concentrations of large (−45%), medium (−66%) and small VLDL (−67%) particles (p < 0.05), without altering VLDL particle size. Serum PCSK9 reduction correlated with decreases in total (r = 0.526, p = 0.044) and small (r = 0.629, p = 0.021) VLDL particle concentrations. Conclusions: Fenofibrate concomitantly decreased serum PCSK9 and VLDL particle concentrations in statin-treated T2DM patients. These findings support a mechanistic link between PCSK9 and VLDL metabolism, possibly through an effect of PSK9 on VLDL receptor degradation.

  • Apolipoprotein c iii understanding an emerging cardiovascular risk factor
    Clinical Science, 2008
    Co-Authors: Hugh P R Barrett, Dick C Chan, Gerald F Watts
    Abstract:

    The concurrence of visceral obesity, insulin resistance and dyslipidaemia comprises the concept of the metabolic syndrome. The metabolic syndrome is an escalating problem in developed and developing societies that tracks with the obesity epidemic. Dyslipidaemia in the metabolic syndrome is potently atherogenic and, hence, is a major risk factor for CVD (cardiovascular disease) in these subjects. It is globally characterized by hypertriglyceridaemia, near normal LDL (low-density lipoprotein)-cholesterol and low plasma HDL (high-density lipoprotein)-cholesterol. ApoC-III (Apolipoprotein C-III), an important regulator of lipoprotein metabolism, is strongly associated with hypertriglyceridaemia and the progression of CVD. ApoC-III impairs the lipolysis of TRLs [triacylglycerol (triglyceride)-rich lipoproteins] by inhibiting lipoprotein lipase and the hepatic uptake of TRLs by remnant receptors. In the circulation, apoC-III is associated with TRLs and HDL, and freely exchanges among these lipoprotein particle systems. However, to fully understand the complex physiology and pathophysiology requires the application of tracer methodology and mathematical modelling. In addition, experimental evidence shows that apoC-III may also have a direct role in atherosclerosis. In the metabolic syndrome, increased apoC-III concentration, resulting from hepatic overproduction of VLDL (very-LDL) apoC-III, is strongly associated with delayed catabolism of triacylglycerols and TRLs. Several therapies pertinent to the metabolic syndrome, such as PPAR (peroxisome-proliferator-activated receptor) agonists and statins, can regulate apoC-III transport in the metabolic syndrome. Regulating apoC-III metabolism may be an important new therapeutic approach to managing dyslipidaemia and CVD risk in the metabolic syndrome.

  • plasma Apolipoprotein c iii transport in centrally obese men associations with very low density lipoprotein Apolipoprotein b and high density lipoprotein Apolipoprotein a i metabolism
    The Journal of Clinical Endocrinology and Metabolism, 2008
    Co-Authors: Dick C Chan, Gerald F Watts, Minh N Nguyen, Hugh P R Barrett
    Abstract:

    Context: Apolipoprotein (apo) C-III is associated with hypertriglyceridemia and progression of cardiovascular disease. Plasma apoC-III is elevated in centrally obese men, and we hypothesized that the kinetics of apoC-III are disturbed in these subjects. Objective: We developed a compartmental model to determine very low-density lipoprotein (VLDL) and high-density lipoprotein (HDL) apoC-III metabolic parameters in centrally obese men and investigated the associations with VLDL-apoB and HDL-apoA-I kinetics. Study Design: Apolipoprotein kinetics was determined using stable isotope techniques and compartmental modelling in 39 centrally obese and 12 nonobese men. Results: Compared with nonobese subjects, centrally obese subjects had increased plasma apoC-III concentration (160 ± 5 mg/liter vs. 103 ± 9 mg/liter, P < 0.001), reflecting increased concentrations of both VLDL-apoC-III and HDL-apoC-III. These related to increased production rate (PR) of VLDL-apoC-III (2.12 ± 0.14 vs. 1.56 ± 0.29 mg/kg·d, P < 0.05) a...

  • Apolipoprotein b 100 kinetics in visceral obesity associations with plasma Apolipoprotein c iii concentration
    Metabolism-clinical and Experimental, 2002
    Co-Authors: Dick C Chan, Gerald F Watts, Trevor G Redgrave, Trevor A Mori, Hugh P R Barrett
    Abstract:

    Obesity is strongly associated with dyslipidemia, which may account for the associated increased risk of atherosclerosis and coronary disease. We aimed to test the hypothesis that kinetics of hepatic Apolipoprotein B-100 (apoB) metabolism are disturbed in men with visceral obesity and to examine whether these kinetic defects are associated with elevated plasma concentration of Apolipoprotein C-III (apoC-III). Very-low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), and low-density lipoprotein (LDL) apoB kinetics were measured in 48 viscerally obese men and 10 age-matched normolipidemic lean men using an intravenous bolus injection of d(3)-leucine. ApoB isotopic enrichment was measured using gas chromatography-mass spectrometry (GCMS). Kinetic parameters were derived using a multicompartmental model (Simulation, Analysis, and Modeling Software II [SAAM-II]). Compared with controls, obese subjects had significantly elevated plasma concentrations of plasma triglycerides, cholesterol, LDL-cholesterol, VLDL-apoB, IDL-apoB, LDL-apoB, apoC-III, insulin, and lathosterol (P <.01). VLDL-apoB secretion rate was significantly higher (P =.034) in obese than control subjects; the fractional catabolic rates (FCRs) of IDL-apoB and LDL-apoB (P <.01) and percent conversion of VLDL-apoB to LDL-apoB (P <.02) were also significantly lower in obese subjects. However, the decreased VLDL-apoB FCR was not significantly different from the lean group. In the obese group, plasma concentration of apoC-III was significantly and positively associated with VLDL-apoB secretion rate and inversely with VLDL-apoB FCR and percent conversion of VLDL to LDL. In multiple regression analysis, plasma apoC-III concentration was independently and significantly correlated with the secretion rate of VLDL-apoB (regression coefficient [SE] 0.511 [0.03], P =.001) and with the percent conversion of VLDL-apoB to LDL-apoB (-0.408 [0.01], P =.004). Our findings suggest that plasma lipid and lipoprotein abnormalities in visceral obesity may be due to a combination of overproduction of VLDL-apoB particles and decreased catabolism of apoB containing particles. Elevated plasma apoC-III concentration is also a feature of dyslipidemia in obesity that contributes to the kinetic defects in apoB metabolism.