Abstract Elevated numbers of atherogenic lipoproteins (apoB) predict the incidence of type 2 diabetes (T2D). We reported that this may be mediated via the activation of the NLRP3 inflammasome, as low-density lipoproteins (LDL) induce interleukin-1 beta (IL-1β) secretion from human white adipose tissue (WAT) and macrophages. However, mitigating nutritional approaches remained unknown. We tested whether omega-3 eicosapentaenoic and docosahexaenoic acids (EPA and DHA) treat LDL-induced upregulation of WAT IL-1β-secretion and its relation to T2D risk factors. Twelve-week intervention with EPA and DHA (2.7 g/day, Webber Naturals) abolished baseline group-differences in WAT IL-1β-secretion between subjects with high-apoB (N = 17) and low-apoB (N = 16) separated around median plasma apoB. Post-intervention LDL failed to trigger IL-1β-secretion and inhibited it in lipopolysaccharide-stimulated WAT. Omega-3 supplementation also improved β-cell function and postprandial fat metabolism in association with higher blood EPA and mostly DHA. It also blunted the association of WAT NLRP3 and IL1B expression and IL-1β-secretion with multiple cardiometabolic risk factors including adiposity. Ex vivo, EPA and DHA inhibited WAT IL-1β-secretion in a dose-dependent manner. In conclusion, EPA and DHA treat LDL-induced upregulation of WAT NLRP3 inflammasome/IL-1β pathway and related T2D risk factors. This may aid in the prevention of T2D and related morbidities in subjects with high-apoB. Clinical Trail Registration 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.

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.

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-1β) 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-1β-secretion than subjects with low-apoB, (2) WAT IL-1β-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-1β-secretion in the presence of ATP in WAT and macrophages. Subjects with high-apoB had higher WAT IL-1β-secretion independently of covariates. The direction of association of LDL-induced WAT IL-1β-secretion to T2D risk factors was consistently pathological in high-apoB subjects only. Adjustment for IL-1β-secretion eliminated the association of plasma apoB with T2D risk factors. In conclusion, subjects with high-apoB have higher WAT IL-1β-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.

Background and Hypothesis: Elevated plasma apoB-lipoproteins (hyperapoB, mostly LDL) predicts the incidence of type 2 diabetes (T2D) and its risk factors including systemic activation of the interleukin-1 system (measured as plasma IL-1 receptor antagonist, IL-1Ra) . Moreover, native LDL induce white adipose tissue (WAT) dysfunction. Underlying mechanisms for these findings remain unclear. Activation of WAT NLRP3 inflammasome and secretion of IL-1β promotes WAT dysfunction and related risk factors for T2D. We hypothesized that native LDL upregulate WAT NLRP3 inflammasome/IL-1β pathway. Methods: This data represents baseline analysis of a 3-month clinical trial with omega-3 fatty acid supplementation in nondiabetic men (N=13) and women (N=27) . We assessed insulin secretion and sensitivity by Botnia clamps, postprandial fat metabolism after a high-fat-meal (68% fat) , and priming and/or activation of NLRP3 inflammasome in subject hip WAT biopsies ex vivo using native LDL, lipopolysaccharides (LPS) (priming control) and/or ATP (activation control) . Results: Incubation of WAT with native LDL (1.2 g apoB/L) increased IL-1β secretion in ATP- but not LPS-treated WAT. Subjects with higher than median plasma apoB (1.23±0.15 g/L) had higher WAT IL-1β-secretion than those with lower apoB, using multiple combination of LDL, LPS and/or ATP, independent of adiposity, macronutrient intake or plasma lipids. WAT NLRP3 mRNA expression and IL-1β secretion correlated positively with hyperinsulinemia, insulin resistance, postprandial hypertriglyceridemia and hyperchylomicronemia and plasma IL-1Ra. Adjusting for sex and WAT IL-1β-secretion or sex and plasma IL-1Ra eliminated the association of plasma apoB with these risk factors (except hypertriglyceridemia) . Conclusion: Native LDL are priming signals of WAT NLRP3 inflammasome, which may explain higher risk for T2D in subjects with hyperapoB. ClinicalTrials.gov (NCT04496154) . Disclosure S.Bissonnette: None. V.Lamantia: None. Y.Cyr: None. M.Devaux: None. R.Rabasa-lhoret: Consultant; HLS Therapeutics Inc., Pfizer Inc., Other Relationship; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi, Vertex Pharmaceuticals Incorporated, Research Support; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, Fondation Francophone pour la Recherche en Diabète (FFRD) , JDRF, National Institutes of Health, Société Francophone du Diabète (SFD) , Speaker's Bureau; Canadian Medical & Surgical Knowledge Translation Research Group (CMS) , CPD Network, Tandem Diabetes Care, Inc. M.Chretien: None. M.Saleh: None. M.Faraj: None. Funding Canadian Institutes of Health Research (CIHR) (FRN# 123409)

Background and Hypothesis: Elevated plasma apoB-lipoproteins (hyperapoB, mostly LDL) predicts the incidence of type 2 diabetes (T2D) and its risk factors including systemic activation of the interleukin-1 system (measured as plasma IL-1 receptor antagonist, IL-1Ra) . Moreover, native LDL induce white adipose tissue (WAT) dysfunction. Underlying mechanisms for these findings remain unclear. Activation of WAT NLRP3 inflammasome and secretion of IL-1β promotes WAT dysfunction and related risk factors for T2D. We hypothesized that native LDL upregulate WAT NLRP3 inflammasome/IL-1β pathway. Methods: This data represents baseline analysis of a 3-month clinical trial with omega-3 fatty acid supplementation in nondiabetic men (N=13) and women (N=27) . We assessed insulin secretion and sensitivity by Botnia clamps, postprandial fat metabolism after a high-fat-meal (68% fat) , and priming and/or activation of NLRP3 inflammasome in subject hip WAT biopsies ex vivo using native LDL, lipopolysaccharides (LPS) (priming control) and/or ATP (activation control) . Results: Incubation of WAT with native LDL (1.2 g apoB/L) increased IL-1β secretion in ATP- but not LPS-treated WAT. Subjects with higher than median plasma apoB (1.23±0.15 g/L) had higher WAT IL-1β-secretion than those with lower apoB, using multiple combination of LDL, LPS and/or ATP, independent of adiposity, macronutrient intake or plasma lipids. WAT NLRP3 mRNA expression and IL-1β secretion correlated positively with hyperinsulinemia, insulin resistance, postprandial hypertriglyceridemia and hyperchylomicronemia and plasma IL-1Ra. Adjusting for sex and WAT IL-1β-secretion or sex and plasma IL-1Ra eliminated the association of plasma apoB with these risk factors (except hypertriglyceridemia) . Conclusion: Native LDL are priming signals of WAT NLRP3 inflammasome, which may explain higher risk for T2D in subjects with hyperapoB. ClinicalTrials.gov (NCT04496154) . Disclosure S.Bissonnette: None. V.Lamantia: None. Y.Cyr: None. M.Devaux: None. R.Rabasa-lhoret: Consultant; HLS Therapeutics Inc., Pfizer Inc., Other Relationship; Abbott Diabetes, AstraZeneca, Boehringer Ingelheim International GmbH, Dexcom, Inc., Eli Lilly and Company, Insulet Corporation, Janssen Pharmaceuticals, Inc., Medtronic, Merck & Co., Inc., Novo Nordisk Canada Inc., Sanofi, Vertex Pharmaceuticals Incorporated, Research Support; Canadian Institutes of Health Research, Cystic Fibrosis Canada, Diabetes Canada, Fondation Francophone pour la Recherche en Diabète (FFRD) , JDRF, National Institutes of Health, Société Francophone du Diabète (SFD) , Speaker's Bureau; Canadian Medical & Surgical Knowledge Translation Research Group (CMS) , CPD Network, Tandem Diabetes Care, Inc. M.Chretien: None. M.Saleh: None. M.Faraj: None. Funding Canadian Institutes of Health Research (CIHR) (FRN# 123409)

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-1 beta) 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-1 beta secretion (AlphaLISA), and function (H-3-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-1 beta secretion (+284%), plasma IL-1 receptor-antagonist (+85%), and postprandial hypertriglyceridemia, and lower WAT pro-IL-1 beta 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.

ObjectiveHuman 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.MethodsThis 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).ResultsFasting WAT surface expression of LDLR and CD36 was negatively associated with WAT function (3H‐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.ConclusionsHigher 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.

Background and aims: Higher fiber intake is associated with increased insulin sensitivity (IS) and reduced glucose-induced insulin secretion (GIIS) during isocaloric-diets; however, its role in hypocaloric-diets is unclear. We examined whether increased fiber intake predicts the amelioration in IS and GIIS following a hypocaloric-diet. Methods and results: This is a post-hoc analysis of 55 adult subjects (BMI > 27 kg/m(2)) who completed a 6-month hypocaloric-diet (-500 kcal/day). Dietary intake was assessed using 3-day food records at baseline and post-intervention. We evaluated glucose-induced insulin and C-peptide secretions as AUC of plasma insulin and C-peptide during intravenous-glucosetolerance tests (IVGTT) and IS via hyperinsulinemic-euglycemic clamps. Data analysis employed regression models and 2-way RM ANOVAs. Post-intervention % change in fiber intake was associated positively with ISclamp (r = 0.30) and negatively with % change in total (r = -0.37) and 2nd phase GIIS(IVGTT) (r = -0.44) but not C-peptide secretion. It remained associated with lower 2nd phase GIIS(IVGTT) after adjustment for sex and % changes in BMI and energy-intake, independently of other macronutrients. Subjects who increased fiber intake (to 28.7 +/- 9.0 g/day) had a greater decrease in 2nd phase GIIS(IVGTT), not C-peptide secretion, independently of sex or changes in adiposity or energy-intake compared to subjects who decreased intake (to 20.0 +/- 6.8 g/day). Conclusion: Higher fiber intake is an independent predictor of reduced 2nd phase glucose-induced hyperinsulinemia after a hypocaloric-diet. It was not associated with plasma C-peptide, suggesting a role in faster insulin clearance rather reduced insulin secretion. Promoting high-fiber intake may increase the effectiveness of hypocaloric-diets in preventing type 2 diabetes. (C) 2019 Published by Elsevier B.V. on behalf of The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University.

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.

BackgroundTo 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.ObjectiveThe 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.DesignFifty-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).ResultsPostintervention 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.ConclusionsHigh 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.

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/m(2), 45-74 years). Fasting gynoid WAT biopsy was obtained followed by the ingestion of a C-13-triolein-labeled-high-fat meal. WAT function was measured ex vivo as the hydrolysis and storage of H-3-triolein-labeled-TRL as H-3-lipids over 4 hours. Insulin sensitivity and secretion were measured by Botnia clamps.RESULTS: WAT function correlated with higher insulin sensitivity (M/I-clamp r = 0.60) and faster plasma clearance of chylomicrons in women (iAUC(6hrs) apoB48, r = -0.60). Plasma apoB correlated with WAT dysfunction (r = -0.52), postprandial hyperTG (iAUC(6hrs)-TG, r = 0.51, C-13-TG, r = 0.48), IR (M/I-clamp 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. (C) 2016 National Lipid Association. All rights reserved.

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.

Searchable abstracts of presentations at key conferences in endocrinology ISSN 1470-3947 (print) | ISSN 1479-6848 (online)

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/m2, respectively, with no sex differences. Following the ingestion of a 13C-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 13C-triolein-labeled TGs and apoB48. They also had reduced hydrolysis and storage of synthetic 3H-triolein-labeled (3H)-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, 3H-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.