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1.
Sci Rep ; 13(1): 18848, 2023 11 01.
Artigo em Inglês | MEDLINE | ID: mdl-37914804

RESUMO

Elevated plasma numbers of atherogenic apoB-lipoproteins (apoB), mostly as low-density lipoproteins (LDL), predict diabetes risk by unclear mechanisms. Upregulation of the NLRP3 inflammasome/interleukin-1 beta (IL-1ß) system in white adipose tissue (WAT) is implicated in type 2 diabetes (T2D); however, metabolic signals that stimulate it remain unexplored. We hypothesized that (1) subjects with high-apoB have higher WAT IL-1ß-secretion than subjects with low-apoB, (2) WAT IL-1ß-secretion is associated with T2D risk factors, and (3) LDL prime and/or activate the WAT NLRP3 inflammasome. Forty non-diabetic subjects were assessed for T2D risk factors related to systemic and WAT glucose and fat metabolism. Regulation of the NLRP3 inflammasome was explored using LDL without/with the inflammasome's priming and activation controls (LPS and ATP). LDL induced IL1B-expression and IL-1ß-secretion in the presence of ATP in WAT and macrophages. Subjects with high-apoB had higher WAT IL-1ß-secretion independently of covariates. The direction of association of LDL-induced WAT IL-1ß-secretion to T2D risk factors was consistently pathological in high-apoB subjects only. Adjustment for IL-1ß-secretion eliminated the association of plasma apoB with T2D risk factors. In conclusion, subjects with high-apoB have higher WAT IL-1ß-secretion that may explain their risk for T2D and may be related to LDL-induced priming of the NLRP3 inflammasome.ClinicalTrials.gov (NCT04496154): Omega-3 to Reduce Diabetes Risk in Subjects With High Number of Particles That Carry "Bad Cholesterol" in the Blood-Full Text View-ClinicalTrials.gov.


Assuntos
Diabetes Mellitus Tipo 2 , Inflamassomos , Humanos , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Lipoproteínas LDL/farmacologia , Interleucina-1beta/metabolismo , Diabetes Mellitus Tipo 2/metabolismo , Macrófagos/metabolismo , Apolipoproteínas B , Tecido Adiposo Branco/metabolismo , Trifosfato de Adenosina
2.
Int J Mol Sci ; 24(7)2023 Mar 24.
Artigo em Inglês | MEDLINE | ID: mdl-37047103

RESUMO

Sex-specific differences exist in insulin secretion (ISec) and sensitivity (IS) in humans. However, current fasting indices used to estimate them, such as HOMA and QUICKI, are not sex-specific. We aimed to develop sex-specific models to improve the prediction of ISec and IS by fasting measures in adults with overweight/obesity. A post hoc analysis was conducted on baseline data of two clinical trials completed between 2010 and 2020 (37 men and 61 postmenopausal women, 45-73 years, BMI > 25 kg/m2, without chronic disease). Glucose-induced insulin or C-peptide secretions and IS were measured using gold-standard Botnia-clamps, which is a 1 h intravenous glucose tolerance test followed by a 3 h hyperinsulinemic-euglycemic clamp. Stepwise regression analysis using anthropometric and fasting plasma glucose, insulin, and lipoprotein-related measures was used to predict ISec and IS. First-phase, second-phase and total glucose-induced ISec were predicted by a combination of fasting plasma insulin and apoB without or with plasma glucose, triglyceride, and waist circumference in women (R2 = 0.58-0.69), and by plasma insulin and glucose without or with BMI and cholesterol in men (R2 = 0.41-0.83). Plasma C-peptide, alone in men or followed by glucose in women, predicted C-peptide secretion. IS was predicted by plasma insulin and waist circumference, followed by HDL-C in women (R2 = 0.57) or by glucose in men (R2 = 0.67). The sex-specific models agreed with the Botnia-clamp measurements of ISec and IS more than with HOMA or QUICKI. Sex-specific models incorporating anthropometric and lipoprotein-related parameters allowed better prediction of ISec and IS in subjects with overweight or obesity than current indices that rely on glucose and insulin alone.


Assuntos
Resistência à Insulina , Sobrepeso , Adulto , Masculino , Humanos , Feminino , Secreção de Insulina , Glicemia , Peptídeo C , Obesidade , Insulina/metabolismo , Glucose , Insulina Regular Humana
3.
Food Res Int ; 140: 110085, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33648303

RESUMO

Ultraviolet-C (UV-C) light is a non-thermal method for improving the safety and shelf-life of cold-pressed juices with minimal impact on quality and nutrition. Most previous studies have investigated fruit juices as opposed to particulate dense leafy green juices with very low UV transmittance (UVT). Pure kale juice is a common juice ingredient and represents the worst-case scenario in terms of low UVT green juices. This study validated the use of continuous benchtop UV-C treatment at 253.7 nm for 5-log reduction of non-pathogenic Escherichia coli P36 in kale juice. An average absorbed fluence of 108.3 mJ cm-2 resulted in a 5.8 log reduction of E. coli P36. At a fluence comparable to that reported for commercial juice processing (74.0 mJ cm-2), kale juice exhibited a decrease in absorption coefficient, while sedimentation, supernatant browning and pectin methylesterase activity increased with no effect on the chlorophyll content, colour, viscosity or antioxidant content.


Assuntos
Brassica , Escherichia coli , Microbiologia de Alimentos , Sucos de Frutas e Vegetais , Raios Ultravioleta
4.
Physiol Rep ; 9(3): e14721, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33527668

RESUMO

BACKGROUND: LDL-cholesterol lowering variants that upregulate receptor uptake of LDL, such as in PCSK9 and HMGCR, are associated with diabetes via unclear mechanisms. Activation of the NLRP3 inflammasome/interleukin-1 beta (IL-1ß) pathway promotes white adipose tissue (WAT) dysfunction and type 2 diabetes (T2D) and is regulated by LDL receptors (LDLR and CD36). We hypothesized that: (a) normocholesterolemic subjects with lower plasma PCSK9, identifying those with higher WAT surface-expression of LDLR and CD36, have higher activation of WAT NLRP3 inflammasome and T2D risk factors, and; (b) LDL upregulate adipocyte NLRP3 inflammasome and inhibit adipocyte function. METHODOLOGY: Post hoc analysis was conducted in 27 overweight/ obese subjects with normal plasma LDL-C and measures of disposition index (DI during Botnia clamps) and postprandial fat metabolism. WAT was assessed for surface-expression of LDLR and CD36 (immunohistochemistry), protein expression (immunoblot), IL-1ß secretion (AlphaLISA), and function (3 H-triolein storage). RESULTS: Compared to subjects with higher than median plasma PCSK9, subjects with lower PCSK9 had higher WAT surface-expression of LDLR (+81%) and CD36 (+36%), WAT IL-1ß secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1ß protein (-66%), WAT function (-62%), and DI (-28%), without group-differences in body composition, energy intake or expenditure. Adjusting for WAT LDLR or CD36 eliminated group-differences in WAT function, DI, and postprandial hypertriglyceridemia. Native LDL inhibited Simpson-Golabi Behmel-syndrome (SGBS) adipocyte differentiation and function and increased inflammation. CONCLUSION: Normocholesterolemic subjects with lower plasma PCSK9 and higher WAT surface-expression of LDLR and CD36 have higher WAT NLRP3 inflammasome activation and T2D risk factors. This may be due to LDL-induced inhibition of adipocyte function.


Assuntos
Tecido Adiposo Branco/metabolismo , Antígenos CD36/metabolismo , Colesterol/sangue , Inflamassomos/metabolismo , Proteína 3 que Contém Domínio de Pirina da Família NLR/metabolismo , Obesidade/sangue , Pró-Proteína Convertase 9/sangue , Receptores de LDL/metabolismo , Adipócitos Brancos/imunologia , Adipócitos Brancos/metabolismo , Adipogenia , Tecido Adiposo Branco/imunologia , Idoso , Biomarcadores/sangue , Células Cultivadas , Diabetes Mellitus Tipo 2/etiologia , Regulação para Baixo , Feminino , Humanos , Interleucina-1beta/metabolismo , Masculino , Pessoa de Meia-Idade , Obesidade/complicações , Obesidade/enzimologia , Obesidade/imunologia , Medição de Risco , Fatores de Risco
5.
Obesity (Silver Spring) ; 28(12): 2357-2367, 2020 12.
Artigo em Inglês | MEDLINE | ID: mdl-33043593

RESUMO

OBJECTIVE: Human conditions with upregulated receptor uptake of low-density lipoproteins (LDL) are associated with diabetes risk, the reasons for which remain unexplored. LDL induce metabolic dysfunction in murine adipocytes. Thus, it was hypothesized that white adipose tissue (WAT) surface expression of LDL receptor (LDLR) and/or CD36 is associated with WAT and systemic metabolic dysfunction. Whether WAT LDLR and CD36 expression is predicted by plasma lipoprotein-related parameters was also explored. METHODS: This was a cross-sectional analysis of 31 nondiabetic adults (BMI > 25 kg/m2 ) assessed for WAT surface expression of LDLR and CD36 (immunohistochemistry), WAT function, WAT and systemic inflammation, postprandial fat metabolism, and insulin resistance (IR; hyperinsulinemic-euglycemic clamp). RESULTS: Fasting WAT surface expression of LDLR and CD36 was negatively associated with WAT function (3 H-triglyceride storage, r = -0.45 and -0.66, respectively) and positively associated with plasma IL-1 receptor antagonist (r = 0.64 and 0.43, respectively). Their expression was suppressed 4 hours postprandially, and reduced LDLR was further associated with IR (M/Iclamp , r = 0.61 women, r = 0.80 men). Plasma apolipoprotein B (apoB)-to-PCSK9 ratio predicted WAT surface expression of LDLR and CD36, WAT dysfunction, WAT NLRP3 inflammasome priming and disrupted cholesterol-sensing genes, and systemic IR independent of sex and body composition. CONCLUSIONS: Higher fasting and lower postprandial WAT surface expression of LDLR and CD36 is associated with WAT dysfunction, systemic inflammation, and IR in adults with overweight/obesity, anomalies that are predicted by higher plasma apoB-to-PCSK9 ratio.


Assuntos
Tecido Adiposo Branco/metabolismo , Antígenos CD36/metabolismo , Diabetes Mellitus Tipo 2/genética , Obesidade/metabolismo , Receptores de LDL/metabolismo , Idoso , Estudos Transversais , Diabetes Mellitus Tipo 2/metabolismo , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Fatores de Risco
6.
J Nutr ; 149(1): 57-67, 2019 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-30535058

RESUMO

Background: δ-5 and δ-6 desaturases (D5D and D6D) catalyze the endogenous conversion of n-3 (ω-3) and n-6 (ω-6) polyunsaturated fatty acids (PUFAs). Their activities are negatively and positively associated with type 2 diabetes (T2D), respectively, by unclear mechanisms. Elevated plasma apoB-lipoproteins (measured as plasma apoB), which can be reduced by n-3 PUFA intake, promote T2D risk factors. Objective: The aim of this study was to test the hypothesis that the association of D5D and D6D activities with T2D risk factors is dependent on plasma apoB. Methods: This is a pooled analysis of 2 populations recruited for 2 different metabolic studies. It is a post hoc analysis of baseline data of these subjects [n = 98; 60% women (postmenopausal); mean ± SD body mass index (in kg/m2): 32.8 ± 4.7; mean ± SD age: 57.6 ± 6.3 y]. Glucose-induced insulin secretion (GIIS) and insulin sensitivity (IS) were measured using Botnia clamps. Plasma clearance of a high-fat meal (600 kcal/m2, 66% fat) and white adipose tissue (WAT) function (storage of 3H-triolein-labeled substrate) were assessed in a subpopulation (n = 47). Desaturase activities were estimated from plasma phospholipid fatty acids. Associations were examined using Pearson and partial correlations. Results: While both desaturase activities were positively associated with percentage of eicosapentaenoic acid, only D5D was negatively associated with plasma apoB (r = -0.30, P = 0.003). Association of D5D activity with second-phase GIIS (r = -0.23, P = 0.029), IS (r = 0.33, P = 0.015, in women) and 6-h area-under-the-curve (AUC6h) of plasma chylomicrons (apoB48, r = -0.47, P = 0.020, in women) was independent of age and adiposity, but was eliminated after adjustment for plasma apoB. D6D activity was associated in the opposite direction with GIIS (r = 0.24, P = 0.049), IS (r = -0.36, P = 0.004) and AUC6h chylomicrons (r = 0.52, P = 0.004), independent of plasma apoB. Both desaturases were associated with plasma interleukin-1-receptor antagonist (D5D: r = -0.45, P < 0.001 in women; D6D: r = -0.33, P = 0.007) and WAT function (trend for D5D: r = 0.30, P = 0.05; D6D: r = 0.39, P = 0.027) independent of any adjustment. Conclusions: Association of D5D activity with IS, lower GIIS, and plasma chylomicron clearance is dependent on plasma apoB in overweight and obese adults.


Assuntos
Apolipoproteínas B/sangue , Diabetes Mellitus Tipo 2/metabolismo , Ácidos Graxos Dessaturases/metabolismo , Sobrepeso/metabolismo , Dessaturase de Ácido Graxo Delta-5 , Ácidos Graxos Dessaturases/genética , Feminino , Regulação Enzimológica da Expressão Gênica , Humanos , Masculino , Pessoa de Meia-Idade , Fatores de Risco
7.
Am J Clin Nutr ; 108(1): 62-76, 2018 07 01.
Artigo em Inglês | MEDLINE | ID: mdl-29917037

RESUMO

Background: To optimize the prevention of type 2 diabetes (T2D), high-risk obese subjects with the best metabolic recovery after a hypocaloric diet should be targeted. Apolipoprotein B lipoproteins (apoB lipoproteins) induce white adipose tissue (WAT) dysfunction, which in turn promotes postprandial hypertriglyceridemia, insulin resistance (IR), and hyperinsulinemia. Objective: The aim of this study was to explore whether high plasma apoB, or number of plasma apoB lipoproteins, identifies subjects who best ameliorate WAT dysfunction and related risk factors after a hypocaloric diet. Design: Fifty-nine men and postmenopausal women [mean ± SD age: 58 ± 6 y; body mass index (kg/m2): 32.6 ± 4.6] completed a prospective study with a 6-mo hypocaloric diet (-500 kcal/d). Glucose-induced insulin secretion (GIIS) and insulin sensitivity (IS) were measured by 1-h intravenous glucose-tolerance test (IVGTT) followed by a 3-h hyperinsulinemic-euglycemic clamp, respectively. Ex vivo gynoid WAT function (i.e., hydrolysis and storage of 3H-triolein-labeled triglyceride-rich lipoproteins) and 6-h postprandial plasma clearance of a 13C-triolein-labeled high-fat meal were measured in a subsample (n = 25). Results: Postintervention first-phase GIISIVGTT and total C-peptide secretion decreased in both sexes, whereas second-phase and total GIISIVGTT and clamp IS were ameliorated in men (P < 0.05). Baseline plasma apoB was associated with a postintervention increase in WAT function (r = 0.61) and IS (glucose infusion rate divided by steady state insulin (M/Iclamp) r = 0.30) and a decrease in first-phase, second-phase, and total GIISIVGTT (r = -0.30 to -0.35) without sex differences. The association with postintervention amelioration in WAT function and GIISIVGTT was independent of plasma cholesterol (total, LDL, and HDL), sex, and changes in body composition. Subjects with high baseline plasma apoB (1.2 ± 0.2 g/L) showed a significant increase in WAT function (+105%; P = 0.012) and a decrease in total GIISIVGTT (-34%; P ≤ 0.001), whereas sex-matched subjects with low plasma apoB (0.7 ± 0.1 g/L) did not, despite equivalent changes in body composition and energy intake and expenditure. Conclusions: High plasma apoB identifies obese subjects who best ameliorate WAT dysfunction and glucose-induced hyperinsulinemia, independent of changes in adiposity after consumption of a hypocaloric diet. We propose that subjects with high plasma apoB represent an optimal target group for the primary prevention of T2D by hypocaloric diets. This trial was registered at BioMed Central as ISRCTN14476404.


Assuntos
Tecido Adiposo Branco/metabolismo , Apolipoproteínas B/sangue , Ingestão de Energia/fisiologia , Glucose/farmacologia , Hiperinsulinismo/sangue , Obesidade/metabolismo , Feminino , Humanos , Insulina/metabolismo , Masculino , Pessoa de Meia-Idade , Período Pós-Prandial , Fatores de Risco
8.
J Clin Lipidol ; 11(1): 34-45.e2, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28391908

RESUMO

BACKGROUND: Elevated plasma apoB is an independent predictor of T2D; however, underlying mechanisms remain unclear. Chronic reduction in white adipose tissue (WAT) function promotes T2D. We reported that differentiation of preadipocytes and acute incubation of human WAT with LDL induce their dysfunction (decreased hydrolysis and storage of triglyceride-rich lipoproteins [TRL]). OBJECTIVE: To examine the hypothesis that the association of plasma apoB with T2D risk factors, hypertriglyceridemia (hyperTG), insulin resistance (IR), and hyperinsulinemia, was dependent on WAT dysfunction. METHODS: Thirty normoglycemic subjects were enrolled (≥27 kg/m2, 45-74 years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a 13C-triolein-labeled-high-fat meal. WAT function was measured ex vivo as the hydrolysis and storage of 3H-triolein-labeled-TRL as 3H-lipids over 4 hours. Insulin sensitivity and secretion were measured by Botnia clamps. RESULTS: WAT function correlated with higher insulin sensitivity (M/Iclamp r = 0.60) and faster plasma clearance of chylomicrons in women (iAUC6hrs apoB48, r = -0.60). Plasma apoB correlated with WAT dysfunction (r = -0.52), postprandial hyperTG (iAUC6hrs-TG, r = 0.51, 13C-TG, r = 0.48), IR (M/Iclamp r = -0.38) and hyperinsulinemia (second phase-glucose-induced-insulin-secretion, r = 0.41). Co-incubation of subjects' WAT with their LDL increased medium accumulation of 3H-TRL and 3H-NEFA with no sex differences. Adjusting for WAT function eliminated the association of plasma apoB with IR independent of sex and body fat or adipocyte diameter. Its association with other risk factors was unaffected. CONCLUSIONS: Association of plasma apoB with IR in obese subjects is dependent on gynoid WAT dysfunction. We propose that targeting hyperapoB, without increasing their uptake into nonhepatic peripheral tissues, ameliorates WAT function and risk for T2D.


Assuntos
Tecido Adiposo Branco/patologia , Apolipoproteínas B/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/patologia , Tamanho Celular , Feminino , Humanos , Resistência à Insulina , Masculino , Pessoa de Meia-Idade , Fatores de Risco
9.
J Nutr ; 147(5): 754-762, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28356429

RESUMO

Background: The role of plasma apolipoprotein (apo) C-I in cardiometabolic risk in humans is unclear. However, in vitro studies showed a dual role for apoC-I, both protective and harmful, depending on the carrier lipoprotein.Objective: We tested the hypothesis that triglyceride (TG)-rich lipoprotein (TRL) apoC-I, not total or HDL apoC-I, is associated with delayed postprandial plasma clearance of TRLs, independently of apoC-II, apoC-III, and apoE.Methods: This cross-sectional study examines the plasma clearance of a 13C-triolein-labeled high-fat meal (68% fat energy) in 20 postmenopausal overweight and obese women [body mass index (in kg/m2) ≥27; aged 45-74 y] as the increment change in area under the 6-h postprandial curves (iAUC6h) of TRL parameters. Lipoproteins were fractionated by fast-protein LC. Transferable apolipoproteins were measured by ELISA. TRL enrichment with apolipoproteins was calculated by dividing their TRL concentrations by TRL apoB. The effects of human apoC-I and apoC-III on the hydrolysis and storage of 3H-triolein-labeled TRLs were tested in 3T3-L1 adipocytes.Results: TRL apoC-I was positively associated with plasma apo B-48 and total and non-HDL TGs, cholesterol, and apoB (r = 0.52-0.97) and negatively with HDL cholesterol (r = -0.52) and LDL diameter (r = -0.91) (P < 0.05). Total and HDL apoC-I were correlated only with total (r = 0.62) and HDL (r = 0.75) cholesterol. Women with high fasting TRL enrichment with apoC-I (99-365 µmol apoC-I/µmol apoB), but not apoC-II, apoC-III, or apoE, had higher iAUC6h for TGs (+195%), 13C-TGs (+319%), and apo B-48 (+186%) than those with low enrichment (14-97 µmol apoC-I/µmol apoB). The 4-h postprandial increase in TRL apoC-I was associated with a 4-h increase in TRL TGs and iAUC6h for TGs, 13C-TGs, and apo B-48 (r = 0.74-0.86, P < 0.001), independently of 4-h changes in TRL apoB, apoC-II, apoC-III, or apoE. ApoC-I and apoC-III inhibited 3H-TRL clearance by adipocytes by >75% (P < 0.001).Conclusions: TRL enrichment with apoC-I is positively associated with postprandial hypertriglyceridemia and remnant accumulation in postmenopausal overweight and obese women, independently of apoC-II, apoC-III, or apoE, which may be due to inhibiting TRL clearance by adipocytes. Reducing TRL apoC-I may ameliorate delayed postprandial plasma clearance of TRLs and associated risks in humans.


Assuntos
Apolipoproteína C-I/sangue , Colesterol/sangue , Gorduras na Dieta/sangue , Hipertrigliceridemia/sangue , Obesidade/sangue , Período Pós-Prandial , Triglicerídeos/sangue , Células 3T3-L1 , Idoso , Animais , Apolipoproteína C-I/farmacologia , Apolipoproteínas/sangue , Área Sob a Curva , HDL-Colesterol/sangue , LDL-Colesterol/sangue , VLDL-Colesterol/sangue , Estudos Transversais , Dieta , Feminino , Humanos , Lipoproteínas/sangue , Camundongos , Pessoa de Meia-Idade , Sobrepeso , Pós-Menopausa
10.
J Lipid Res ; 57(6): 1074-85, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-27040450

RESUMO

Reduced white adipose tissue (WAT) LPL activity delays plasma clearance of TG-rich lipoproteins (TRLs). We reported the secretion of apoC-I, an LPL inhibitor, from WAT ex vivo in women. Therefore we hypothesized that WAT-secreted apoC-I associates with reduced WAT LPL activity and TRL clearance. WAT apoC-I secretion averaged 86.9 ± 31.4 pmol/g/4 h and 74.1 ± 36.6 pmol/g/4 h in 28 women and 11 men with BMI ≥27 kg/m(2), respectively, with no sex differences. Following the ingestion of a (13)C-triolein-labeled high-fat meal, subjects with high WAT apoC-I secretion (above median) had delayed postprandial plasma clearance of dietary TRLs, assessed from plasma (13)C-triolein-labeled TGs and apoB48. They also had reduced hydrolysis and storage of synthetic (3)H-triolein-labeled ((3)H)-TRLs in WAT ex vivo (i.e., in situ LPL activity). Adjusting for WAT in situ LPL activity eliminated group differences in chylomicron clearance; while adjusting for plasma apoC-I, (3)H-NEFA uptake by WAT, or body composition did not. apoC-I inhibited in situ LPL activity in adipocytes in both a concentration- and time-dependent manner. There was no change in postprandial WAT apoC-I secretion. WAT apoC-I secretion may inhibit WAT LPL activity and promote delayed chylomicron clearance in overweight and obese subjects. We propose that reducing WAT apoC-I secretion ameliorates postprandial TRL clearance in humans.


Assuntos
Tecido Adiposo Branco/enzimologia , Apolipoproteína C-I/sangue , Lipase Lipoproteica/sangue , Obesidade/sangue , Tecido Adiposo Branco/química , Idoso , Animais , Apolipoproteína B-48/química , Apolipoproteína B-48/metabolismo , Apolipoproteínas E/química , Apolipoproteínas E/metabolismo , Índice de Massa Corporal , Isótopos de Carbono/química , Quilomícrons/sangue , Dieta Hiperlipídica , Feminino , Humanos , Lipase Lipoproteica/química , Lipase Lipoproteica/genética , Lipoproteínas HDL/sangue , Masculino , Camundongos , Pessoa de Meia-Idade , Obesidade/genética , Obesidade/patologia , Período Pós-Prandial , Triglicerídeos/sangue , Trioleína/química , Trioleína/metabolismo
11.
J Clin Lipidol ; 9(5): 664-75, 2015.
Artigo em Inglês | MEDLINE | ID: mdl-26350813

RESUMO

BACKGROUND: Proprotein convertase subtilisin/kexin type 9 (PCSK9) shuttles low-density lipoprotein (LDL) receptors for degradation, thus upregulates LDL plasma clearance. Although PCSK9 loss of function is cardioprotective, its role in metabolic risks remains unknown. Increased apoB-lipoproteins uptake into nonhepatic tissues such as white adipose tissue (WAT) induces their dysfunction, which may be favored by lower plasma PCSK9. We hypothesized that lower plasma PCSK9 relative to apoB, or higher apoB-to-PCSK9 ratio, is a better predictor of metabolic disturbances than PCSK9 alone in humans. METHODS: Thirty-three men and 48 postmenopausal women (>27 kg/m(2), aged 45-74 years, normoglycemic) underwent in-depth assessment of glucose and fat metabolism using high-fat meals, WAT biopsies, intravenous glucose-tolerance tests, and hyperinsulinemia clamps. RESULTS: Plasma apoB correlated positively with fasting and postprandial triglycerides and chylomicron clearance (R = 0.44-0.66) and glucose-stimulated insulin secretion (R = 0.24) and negatively with insulin sensitivity (R = -0.28) and gynoid WAT in situ lipoprotein lipase activity (ie, ex vivo WAT function, R(2) = 0.34). Neither PCSK9 nor LDL cholesterol associated with these risks. In regression analysis that adjusted for body mass index, lower plasma PCSK9 strengthened the association of apoB to WAT dysfunction and insulin resistance. Moreover, plasma apoB-to-PCSK9 ratio correlated positively with all these metabolic risks and further associated positively with android-to-gynoid fat ratio (R = 0.41) and negatively with gynoid fat mass (R = -0.23, all P ≤ .05). No significant sex differences existed in these associations. CONCLUSIONS: Lower plasma PCSK9 relative to apoB associates with metabolic risks and WAT dysfunction in normoglycemic obese subjects. We hypothesize that the plasma apoB-to-PCSK9 ratio provides a better clinical index than PCSK9 alone for monitoring early metabolic disturbances that may be promoted by reduction in plasma PCSK9.


Assuntos
Apolipoproteínas B/sangue , Doenças Metabólicas/sangue , Pró-Proteína Convertases/sangue , Serina Endopeptidases/sangue , Tecido Adiposo Branco/enzimologia , Idoso , Quilomícrons/metabolismo , Feminino , Humanos , Hiperinsulinismo/sangue , Hipertrigliceridemia/sangue , Resistência à Insulina , Lipase Lipoproteica/metabolismo , Masculino , Doenças Metabólicas/epidemiologia , Pessoa de Meia-Idade , Obesidade/sangue , Período Pós-Prandial , Pró-Proteína Convertase 9 , Risco
12.
J Lipid Res ; 54(5): 1466-76, 2013 May.
Artigo em Inglês | MEDLINE | ID: mdl-23417739

RESUMO

Delayed clearance of triglyceride-rich lipoprotein (TRL) by white adipose tissue (WAT) promotes hypertriglyceridemia and elevated apoB-lipoproteins, which are primarily in the form of LDL. This study examines whether LDL promotes delayed clearance of TRL by WAT. Following the ingestion of a (13)C-triolein-labeled high-fat meal, obese women with high plasma apoB (> median 0.93 g/l, N = 11, > 98% as IDL/LDL) had delayed clearance of postprandial (13)C-triglyceride and (13)C-NEFA over 6 h compared with controls. AUC6 h of plasma (13)C-triglyceride and (13)C-NEFA correlated with plasma apoB but not with LDL diameter or adipocyte area. There was no group difference in (13)C-triolein oxidation rate, which suggests lower (13)C-NEFA storage in peripheral tissue in women with high apoB. Ex vivo/in vitro plasma apoB correlated negatively with WAT (3)H-lipid following a 4 h incubation of women's WAT with synthetic (3)H-triolein-TRL. LDL-differentiated 3T3-L1 adipocytes had lower (3)H-TRL hydrolysis and (3)H-NEFA storage. Treatment of women's WAT with their own LDL decreased (3)H-TRL hydrolysis and (3)H-NEFA uptake. Finally, LDL, although not an LPL substrate, reduced LPL-mediated (3)H-TRL hydrolysis as did VLDL and HDL. Exposure to LDL decreases TRL clearance by human WAT ex vivo. This may promote production of apoB-lipoproteins and hypertriglyceridemia through a positive-feedback mechanism in vivo.


Assuntos
Hipertrigliceridemia/sangue , Lipoproteínas LDL/sangue , Gordura Subcutânea/metabolismo , Triglicerídeos/sangue , Adulto , Apolipoproteínas B/sangue , Dieta Hiperlipídica , Feminino , Humanos , Hipertrigliceridemia/patologia , Lipoproteínas/sangue , Lipoproteínas/química , Lipoproteínas LDL/química , Lipoproteínas VLDL/sangue , Pessoa de Meia-Idade , Obesidade/sangue , Gordura Subcutânea/crescimento & desenvolvimento , Triglicerídeos/química
13.
Arterioscler Thromb Vasc Biol ; 32(11): 2785-93, 2012 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-22995522

RESUMO

OBJECTIVE: White adipose tissue (WAT) dysfunction is characterized by delayed clearance of dietary triglyceride-rich lipoproteins (TRL). We reported that apolipoprotein (apo) C-I, a transferable apolipoprotein that inhibits lipoprotein lipase activity when bound to TRL, was produced by a human adipocyte model. Thus, we aimed to determine whether increased WAT apoC-I secretion is related to delayed dietary fat clearance in humans. METHODS AND RESULTS: After the ingestion of a (13)C-triolein-labeled high-fat meal, postmenopausal obese women with high-fasting WAT apoC-I secretion (median >0.81 µmol/L per g/4 hours, n=9) had delayed postprandial plasma clearance of (13)C-triglyceride and (13)C-nonesterified fatty acids over 6 hours compared with controls. WAT apoC-I secretion over 4 hours correlated with fasting total and non-high-density lipoprotein apoC-I but not with high-density lipoprotein apoC-I and was the primary predictor of 4-hour postprandial increases in TRL apoC-I. Correction for TRL apoC-I eliminated the association of WAT apoC-I with 6-hour area under the curve of plasma (13)C-triglyceride; correction for insulin sensitivity or inflammation did not. Finally, in addition to apoC-I, WAT secreted considerable amount of apoC-II, apoC-III, and apoE over 24 hours; however, only WAT apoC-I secretion was associated with 6-hour area under the curve of plasma (13)C-triglyceride. CONCLUSIONS: Increased WAT apoC-I secretion in obese women is associated with delayed postprandial dietary fat clearance mediated by increased TRL apoC-I. Thus, we hypothesize that reducing WAT apoC-I secretion ameliorates WAT dysfunction and associated cardiometabolic risks in humans.


Assuntos
Tecido Adiposo Branco/metabolismo , Apolipoproteína C-I/metabolismo , Gorduras na Dieta/sangue , Obesidade/sangue , Idoso , Apolipoproteína C-I/sangue , Área Sob a Curva , Biópsia , Gorduras na Dieta/administração & dosagem , Ácidos Graxos não Esterificados/sangue , Feminino , Humanos , Lipoproteínas HDL/sangue , Pessoa de Meia-Idade , Obesidade/fisiopatologia , Período Pós-Prandial , Quebeque , Fatores de Tempo , Triglicerídeos/sangue , Trioleína/metabolismo
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