Fasting apoB Research Articles

Apolipoprotein B-48 and late graft failure in kidney transplant recipients.

Transplant vasculopathy resembles atherosclerotic plaque formation and is a major contributor to late graft failure in kidney transplant recipients (KTR). Remnant lipoproteins and associated triglycerides are causal risk factors for atherosclerotic plaques and have been implicated in late kidney graft failure. However, whether remnants derived from liver (containing apolipoprotein [apo] B100) or intestine (containing apoB48) are clinically more important is unclear. The current study investigated the association between baseline fasting apoB48 levels and late kidney graft failure. 481 KTR with a functioning graft for at least 1 year were included in this retrospective, observational longitudinal single center cohort study. The primary endpoint was death-censored late graft failure, defined as need for initiation of dialysis or re-transplantation. ApoB48 was measured by enzyme-linked immunosorbent assay. During a median follow-up of 9.5 years, 61 KTR developed graft failure (12.7%). At baseline, KTR with higher apoB48 levels had lower eGFR (P<.001), lower high-density lipoprotein (HDL) cholesterol (P<.001), increased triglycerides (P<.001) and used cyclosporine more frequently (P=.003). Cox regression showed that higher baseline apoB48 was associated with higher risk of late graft failure [hazard ratio (95% confidence interval), 1.59 (1.22, 2.07), P<.001], independent of stepwise adjustment for potential confounders, including age and sex, immunosuppression type and proteinuria, triglycerides, and waist circumference (fully adjusted HR, 1.78 (1.29, 2.47), P<.001]. ApoB48 is strongly associated with late graft failure, independent of potential confounders. Since apoB48-containing lipoproteins originate from the intestine, this study provides a rationale for considering pharmacological interventions targeting lipid absorption to improve graft outcome.

Circulating Apolipoprotein B-48 as a Biomarker of Parenteral Nutrition Dependence in Adult Patients with Short Bowel Syndrome.

Short bowel syndrome (SBS) is a rare but serious condition that may lead to chronic intestinal failure. Citrulline concentrations are currently used to reflect the residual intestinal mass in patients with SBS, although this method has several limitations. In a cohort of patients with SBS, we quantified apolipoprotein B-48 (ApoB-48), which is exclusively synthesized by enterocytes and secreted associated with dietary lipids and investigated the relationship between ApoB-48 and clinical and biological data as well as PN dependence. A total of 51 adult patients were included, 36 of whom were PN-dependent. We found a robust positive correlation between circulating ApoB-48 and residual small bowel length, which was also found in the subgroup of patients with jejunocolic anastomosis. Fasting ApoB-48 levels were significantly lower in PN-dependent patients than in PN-weaned patients and negatively correlated with parenteral nutrition dependence. Our results suggest that ApoB-48 could be proposed as a marker of intestinal absorptive function and could be an interesting follow-up marker in patients with SBS.

Postprandial Hyperlipidemia: Its Pathophysiology, Diagnosis, Atherogenesis, and Treatments.

Postprandial hyperlipidemia showing postprandial increases in serum triglyceride (TG) is associated with the development of atherosclerotic cardiovascular disease (ASCVD). To diagnose postprandial hyperlipidemia, the oral fat loading test (OFLT) should be performed; however, this test is very time-consuming and is difficult to perform. Elevated serum TG levels reflect an increase in TG-rich lipoproteins (TRLs), such as chylomicrons (CM), very low-density lipoproteins (VLDL), and their remnants (CM remnants [CMRs] and VLDL remnants [VLDLRs]). Understanding of elevation in CMR and/or VLDLR can lead us to understand the existence of postprandial hyperlipidemia. The measurement of apo B48, which is a constituent of CM and CMR; non-fasting TG, which includes TG content in all lipoproteins including CM and CMR; non-high-density lipoprotein cholesterol (non-HDL-C), which includes TRLs and low-density lipoprotein; and remnant cholesterol are useful to reveal the existence of postprandial hyperlipidemia. Postprandial hyperlipidemia is observed in patients with familial type III hyperlipoproteinemia, familial combined hyperlipidemia, chronic kidney disease, metabolic syndrome and type 2 diabetes. Postprandial hyperlipidemia is closely related to postprandial hyperglycemia, and insulin resistance may be an inducing and enhancing factor for both postprandial hyperlipidemia and postprandial hyperglycemia. Remnant lipoproteins and metabolic disorders associated with postprandial hyperlipidemia have various atherogenic properties such as induction of inflammation and endothelial dysfunction. A healthy diet, calorie restriction, weight loss, and exercise positively impact postprandial hyperlipidemia. Anti-hyperlipidemic drugs such pemafibrate, fenofibrate, bezafibrate, ezetimibe, and eicosapentaenoic acid have been shown to improve postprandial hyperlipidemia. Anti-diabetic drugs including metformin, alpha-glucosidase inhibitors, pioglitazone, dipeptidyl-peptidase-4 inhibitors and glucagon-like peptide 1 analogues have been shown to ameliorate postprandial hyperlipidemia. Although sodium glucose cotransporter-2 inhibitors have not been proven to reduce postprandial hyperlipidemia, they reduced fasting apo B48 and remnant lipoprotein cholesterol. In conclusion, it is important to appropriately understand the existence of postprandial hyperlipidemia and to connect it to optimal treatments. However, there are some problems with the diagnosis for postprandial hyperlipidemia. Postprandial hyperlipidemia cannot be specifically defined by measures such as TG levels 2 h after a meal. To study interventions for postprandial hyperlipidemia with the outcome of preventing the onset of ASCVD, it is necessary to define postprandial hyperlipidemia using reference values such as IGT.

The effects of pemafibrate and omega-3 fatty acid ethyl on apoB-48 in dyslipidemic patients treated with statin: A prospective, multicenter, open-label, randomized, parallel group trial in Japan (PROUD48 study).

We compared the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apolipoprotein (apo) B-48 (apoB-48), a marker that reflects postprandial hypertriglyceridemia, which is one of the residual risks for atherosclerotic cardiovascular disease (ASCVD) with statin treatment. This prospective, multicenter, open-label, randomized, parallel group trial was conducted at 4 medical institutions between April 2020 and May 2022. A total of 126 ambulatory patients with dyslipidemia receiving statin treatment for more than 4 weeks, aged 20-79 years with fasting triglyceride (TG) levels of ≥177 mg/dl were randomly assigned to 16-week pemafibrate 0.4 mg per day treatment group (PEMA, n = 63) or omega-3 fatty acid ethyl 4 g per day treatment group (OMEGA-3, n = 63). The primary endpoint was the percentage change in fasting apoB-48 from baseline to week 16. The percentage changes in fasting apoB-48 in PEMA and OMEGA-3 were -50.8% (interquartile range -62.9 to -30.3%) and -17.5% (-38.3 to 15.3%) (P < 0.001), respectively. As the secondary endpoints, the changes in fasting apoB-48 in PEMA and OMEGA-3 were -3.10 μg/ml (-5.63 to -1.87) and -0.90 μg/ml (-2.95 to 0.65) (P < 0.001), respectively. Greater decreases with significant differences in the percentage changes in TG, remnant lipoprotein cholesterol, apoC-III, fasting plasma glucose, alanine aminotransferase, gamma-glutamyl transpeptidase, and alkaline phosphatase were observed in PEMA, compared with OMEGA-3. Greater increases with significant differences in those in high-density lipoprotein (HDL) cholesterol, apoA-I, and apoA-II were observed in PEMA, compared with OMEGA-3. PEMA showed anti-atherosclerotic lipoprotein profiles in gel-permeation high-performance liquid chromatography analyses, compared with OMEGA-3. Although adverse events occurred in 9 of 63 (14.3%) patients in PEMA and 3 of 63 (4.8%) patients in OMEGA-3, no serious adverse events associated with drug were observed in either group. This is the first randomized trial to compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl on fasting apoB-48. We concluded that pemafibrate was superior to omega-3 fatty acid ethyl in lowering effect of fasting apoB-48. Pemafibrate is expected to reduce the residual risk for ASCVD with statin treatment. https://rctportal.niph.go.jp/en, identifier jRCTs071200011.

Study protocol of the PROUD48 study comparing the effects of pemafibrate and omega-3 fatty acid ethyl esters on ApoB-48 in statin-treated patients with dyslipidaemia: a prospective, multicentre, open-label, randomised, parallel group trial in Japan

IntroductionThis study will compare the lowering effects of pemafibrate and omega-3 fatty acid ethyl esters on fasting apolipoprotein B-48 (apoB-48), a surrogate marker reflecting postprandial hypertriglyceridaemia, which is a residual...

Simultaneous Evaluation of Postchallenge Glycemia and Lipidemia in Young Women

<i>Aim:</i> To determine the effects of simultaneously ingesting glucose and fat on postchallenge glycemia and lipidemia in 12 healthy young Japanese women. <i>Methods:</i> Three test trials were administered in a randomized crossover design: glucose (1 g/kg, G trial); fat cream (0.35 g/kg as fat; F trial); glucose + fat cream (GF trial). Blood samples were taken before and at 0.5, 1, 2, 4, and 6 h post-ingestion. <i>Results:</i> The GF trial's serum glucose peak value was lower than the G trial's, and its remnant lipoprotein-cholesterol (RLP-C) increase was less than the F trial's. The GF trial's apolipoprotein (Apo) B48 increase happened faster than the F trial's. The G and GF trials' insulinogenic index (I/G30) values were negatively correlated with the area under the curve (AUC) of glucose for 2 h. Fasting insulin level and HOMA-IR were positively (and QUICKI and I/G30 were negatively) correlated with the AUC of insulin for 2 h. The F and GF trials' fasting TG, RLP-C, ApoB48, and ApoC-III levels were positively correlated with the AUC of TG and RLP-C for 6 h. The fasting ApoB48 level predicted the AUC of ApoB48 for 6 h. <i>Conclusion:</i> The glucose peak was ameliorated by co-ingesting fat. I/G30 predicted an early postchallenge (0–2 h) glucose rise. The fasting insulin level, HOMA-IR, QUICKI, and I/G30 predicted an insulin rise. The RLP-C rise by fat ingestion was ameliorated by co-ingesting glucose. Fasting TG, RLP-C, ApoB48, and ApoC-III levels predicted postchallenge TG and RLP-C rises. The fasting ApoB48 level predicted postchallenge apoB48, i.e., a rise in intestinal lipoprotein.

SUN-022 Metformin-Fish Oil Adjunct Therapy Improves apoB-Remnant Lipoprotein and Triglyceride Levels in Women with Polycystic Ovary Syndrome

Background: Polycystic ovary syndrome (PCOS) is highly associated with the metabolic syndrome (MetS): obesity, insulin resistance and atherogenic dyslipidemia. Women with PCOS-MetS are at higher risk of developing ischemic cardiovascular disease (CVD) and Type-2 Diabetes. First-line intervention in PCOS-MetS includes targeting diet and lifestyle, and metformin is commonly prescribed to treat insulin resistance, however these interventions have shown limited effectiveness to improve dyslipidemia. At present there are limited safe and efficious options to target atherogenic dyslipidemia in young women with PCOS. Fish oil (FO) and Icosapentyl ethyl supplementation have been shown to reduce fasting TG, apoB and to improve ischemic CVD outcomes. The efficacy of FO or as an adjunct therapy to metformin to improve ApoB-remnant lipemia in PCOS-MetS is unknown. The aim of this pilot study was to determine the effect of metformin, FO and FO-metformin combination treatment on fasting and non-fasting plasma TG and apoB-remnant lipoprotein metabolism in patients with PCOS-MetS. Methods: Participants diagnosed with PCOS aged 18-30yrs received dietary counselling and were randomly assigned to receive FO (n=8), metformin (n=7) or FO-metformin (n=12) treatment for 12 wks. Plasma lipids (TG and cholesterol), ApoB48 and ApoB100 lipoprotein metabolism were assessed in the fasting and non-fasting state using a standardized high-fat meal test. Results: At baseline, the fasting plasma TG, ApoB48 and ApoB100 was 238.0 ± 21.0 mg/dL, 9.00 ± 1.12 ug/ml and 290 ± 18.00 mg/dL. FO and FO-metformin decreased fasting plasma TG by 10% and 30% compared to the metformin treatment group (7%). Fasting ApoB48 was reduced 45%, 16% and 19% in FO-metformin, FO and metformin treatment groups, respectively. Non-fasting plasma TG and apoB48 lipoprotein area under the curve were reduced by 30% in the FO-metformin treatment group. Conclusion: These pilot findings demonstrate FO-metformin adjunct therapy may have greater efficacy to improve atherogenic apoB-dyslipidemia compared to metformin or FO alone in high-risk patients with PCOS-MetS. A larger clinical trial is warranted to determine the long term effects of FO-metformin intervention on apoB-dyslipidemia and atherosclerotic cardiovascular disease indices.

A placebo-controlled proof-of-concept study of alirocumab on postprandial lipids and vascular elasticity in insulin-treated patients with type 2 diabetes mellitus.

Type 2 diabetes mellitus (T2DM) is associated with an increased risk of cardiovascular disease (CVD) linked to atherogenic dyslipidaemia and postprandial hyperlipidaemia. Alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, improves CVD risk by reducing the concentration of low-density lipoprotein-cholesterol (LDL-C). However, effects of PCK9 inhibitors on other aspects of diabetic dyslipidaemia, particularly in the postprandial situation, are less clear. Twelve male patients with T2DM on an intensive insulin regimen completed a 6-week randomized, double-blind, placebo-controlled, proof-of-concept study. Participants received three biweekly dosages of subcutaneous alirocumab (150 mg) or placebo. Before and after the intervention, fasting and postprandial triglyceride (TG) plasma levels, apolipoprotein (apo) B48, lipoprotein composition isolated by ultracentrifugation, vascular function and markers of inflammation were evaluated. Alirocumab treatment reduced fasting plasma TG levels (between group median change -24.7%; P = 0.018) and fasting apoB48 serum levels (-35.9%; P = 0.039) compared with placebo. Alirocumab reduced the plasma TG area under the curve (AUC) (-26.4%; P = 0.006) and apoB48 AUC (-55.7%; P = 0.046), as well as plasma TG incremental AUC (-21.4%; P = 0.04) and apoB48 incremental AUC (-26.8%; P = 0.02). In addition, alirocumab reduced fasting and postprandial TG levels in very low-density lipoprotein (VLDL) and LDL. Alirocumab improved fasting pulse wave velocity, but no changes in postprandial markers of inflammation were observed. In addition to the well-known LDL-C-reducing effects, 6 weeks of alirocumab treatment lowered both fasting and postprandial plasma TG levels by reducing the TG levels in VLDL and LDL and the concentration of intestinal remnants.

Fasting apolipoprotein B48 is associated with large artery atherosclerotic stroke: a case-control study

Fasting Apolipoprotein B48 (ApoB48) is reported to be a well surrogate marker for postprandial lipidemia and have been repeatedly associated with cardiovascular disease. However, whether ApoB48 is also a risk factor for ischemic stroke have not been reported. In this study, our object is to explore the relationship between fasting plasma ApoB48 levels and the large artery atherosclerotic (LAA) stroke.A 1:1 age-(±2), gender-matched case-control study was conducted. LAA patients and healthy controls admitted to our center were prospectively recruited. Clinical data were collected and enzyme-linked immunosorbent assay (ELISA) was used to measure the fasting plasma ApoB48 levels.A cohort of 234 LAA stroke patients and 234 controls were enrolled. Fasting plasma ApoB48 levels were significantly higher in LAA stroke patients than in controls (4.76(3.46) vs 4.00(2.4), P < 0.001). Conditional multivariable analyses indicated that fasting ApoB48 levels were associated with LAA stroke (odds ratio: 1.18; 95% confidence interval: 1.04–1.35; P = 0.014).Our study indicates that increased fasting plasma ApoB48 may be a risk factor for LAA stroke.

Associations of the APOB rs693 and rs17240441 polymorphisms with plasma APOB and lipid levels: a meta-analysis

BackgroundThe associations of the apolipoprotein B gene (APOB) rs693 and rs17240441 polymorphisms with plasma levels of APOB and lipids have been widely explored, but the results were inconclusive. This meta-analysis aimed to clarify the associations of the rs693 and rs17240441 polymorphisms with fasting APOB and lipid levels.MethodsSixty-one studies (50,018 subjects) and 23 studies (8425 subjects) were respectively identified for the rs693 and rs17240441 polymorphisms by searching in PubMed, Google Scholar, Web of Science, Cochrane Library, Wanfang, VIP and CNKI databases. The following information was collected for each study: first author, age, gender, ethnicity, health condition, sample size, genotyping, lipid assay method, mean and standard deviation or standard error of APOB and lipid variables by genotypes. A dominant model was used for this meta-analysis.ResultsThe carriers of the rs693 variant allele (T) had higher levels of APOB [standardized mean difference (SMD) = 0.26, 95% confidence interval (CI) = 0.16–0.36, P < 0.01], triglycerides (TG) (SMD = 0.12, 95% CI = 0.05–0.20, P < 0.01), total cholesterol (TC) (SMD = 0.24, 95% CI = 0.17–0.30, P < 0.01) and low-density lipoprotein cholesterol (LDL-C) (SMD = 0.22, 95% CI = 0.14–0.30, P < 0.01), and lower levels of high-density lipoprotein cholesterol (HDL-C) (SMD = −0.06, 95% CI = −0.11–0.01, P = 0.01) than the non-carriers. The carriers of the rs17240441 deletion allele had higher levels of APOB (SMD = 0.13, 95% CI = 0.06–0.20, P < 0.01), TC (SMD = 0.17, 95% CI = 0.07–0.26, P < 0.01) and LDL-C (SMD = 0.15, 95% CI = 0.07–0.23, P < 0.01) than the non-carriers.ConclusionsThe rs693 polymorphism is significantly associated with higher levels of APOB, TG, TC and LDL-C, and lower levels of HDL-C. The rs17240441 polymorphism is significantly associated with higher levels of APOB, TC and LDL-C. Further studies are needed to elucidate the underlying mechanisms.

Postprandial Hyperlipidemia and Remnant Lipoproteins.

Fasting hypertriglyceridemia is positively associated with the morbidity of coronary heart disease (CHD), and postprandial (non-fasting) hypertriglyceridemia is also correlated with the risk status for CHD, which is related to the increase in chylomicron (CM) remnant lipoproteins produced from the intestine. CM remnant particles, as well as oxidized low density lipoprotein (LDL) or very low density lipoprotein (VLDL) remnants, are highly atherogenic and act by enhancing systemic inflammation, platelet activation, coagulation, thrombus formation, and macrophage foam cell formation. The cholesterol levels of remnant lipoproteins significantly correlate with small, dense LDL; impaired glucose tolerance (IGT) and CHD prevalence. We have developed an assay of apolipoprotein (apo)B-48 levels to evaluate the accumulation of CM remnants. Fasting apoB-48 levels correlate with the morbidity of postprandial hypertriglyceridemia, obesity, type III hyperlipoproteinemia, the metabolic syndrome, hypothyroidism, chronic kidney disease, and IGT. Fasting apoB-48 levels also correlate with carotid intima-media thickening and CHD prevalence, and a high apoB-48 level is a significant predictor of CHD risk, independent of the fasting TG level. Diet interventions, such as dietary fibers, polyphenols, medium-chain fatty acids, diacylglycerol, and long-chain n-3 polyunsaturated fatty acids (PUFA), ameliorate postprandial hypertriglyceridemia, moreover, drugs for dyslipidemia (n-3 PUFA, statins, fibrates or ezetimibe) and diabetes concerning incretins (dipeptidyl-peptidase IV inhibitor or glucagon like peptide-1 analogue) may improve postprandial hypertriglyceridemia. Since the accumulation of CM remnants correlates to impaired lipid and glucose metabolism and atherosclerotic cardiovascular events, further studies are required to investigate the characteristics, physiological activities, and functions of CM remnants for the development of new interventions to reduce atherogenicity.

Adiposity in Children and CVD Risk: ApoB48 Has a Stronger Association With Central Fat Than Classic Lipid Markers.

Atherosclerotic vascular disease begins in childhood and while progression is multifactorial, obesity in early life is an important risk factor for its development. To determine whether fasting apoB48 remnant lipoproteins (relative to classic lipid markers), is elevated with increasing central adiposity over time in a cohort of Canadian children with a family history of obesity. Data were drawn from the ongoing prospective cohort of 630 Caucasian families in Québec, Canada, recruited to assess determinants and effects of childhood obesity (Québec Adiposity and Lifestyle Investigation in Youth [QUALITY]cohort). Children who attended baseline and first followup clinic visits (n =570; age 9.6 y). Trunk fat mass was determined by dual energy x-ray absorptiometry. Central fat mass index was calculated as CFMI = trunk fat mass/height(2) (kg/m(2)) and groups created (CFMI <1.5; 1.5-3.0; ≥3.0 kg/m(2)) to suggest lower, moderate, or higher central adiposity. Changes over time in outcomes (apoB48, triglyceride and total, low-, and high-density lipoprotein cholesterol) were compared using paired t test and multiple regression that adjusted for age, sex, and Tanner stage. Classic lipid markers (total and low-density lipoprotein cholesterol) improved at followup, whereas apoB48 became worse (increased). ApoB48 increased with increasing central adiposity, highest (37%) in children who transitioned from lower- to moderate-CFMI groups (ΔapoB48 = 1.5 μg/mL). For every 1 kg/m(2) increase in central adiposity over the 2-y period, an increase in apoB48 was 14-fold greater among children with lower baseline CFMI, compared with higher CFMI. Increased fasting concentrations of apoB48 may be representative of changes in adiposity at lower levels of central fat (early periods of risk).

Increased postprandial apolipoprotein B-48 level after a test meal in diabetic patients: A multicenter, cross-sectional study

ObjectiveTo evaluate plasma apolipoprotein B (ApoB)-48 concentrations among Korean diabetic subjects with normal to moderately high levels of low-density-lipoprotein cholesterol (LDL-C). MethodsThis multicenter, cross-sectional study included subjects with LDL-C levels between 100 and 160mg/dL who had not been treated with a lipid-lowering agent for over 6weeks prior to baseline. Blood tests to assess lipid-profile parameters were conducted in both fasting and postprandial states. This study compared ApoB-48 and other lipid-profile parameters in diabetic and nondiabetic subjects. ResultsOf the 93 subjects enrolled, 88 (42 diabetic; 46 nondiabetic) completed the study. Significantly higher mean incremental area under curve (0–6h; iAUC0–6h) of postprandial ApoB-48 levels was noted among diabetic subjects than nondiabetic subjects (p=0.0078). The mean postprandial ApoB-48 peak level was higher in diabetic subjects; however, the difference was not statistically significant. The fasting ApoB-48 level was similar in both groups: 5.9 (3.5) in diabetics and 7.3 (5.8) in nondiabetics (p=0.18). The iAUC0–6h of postprandial total cholesterol (TC), triglyceride (TG), LDL-C, non–high-density-lipoprotein cholesterol (non-HDL-C), ApoB-100, and remnant cholesterol was similar in both groups. The ApoB-48 level was moderately correlated with TG and non-HDL-C for both groups (p<0.05). ConclusionWithout lipid-lowering treatment, the postprandial increment in ApoB-48 level was significantly higher in Korean diabetic subjects compared with nondiabetic subjects, irrespective of similar LDL-C levels.

In vivo evidence for chylomicrons as mediators of postprandial inflammation

Background and aimsThe postprandial situation is a pro-inflammatory condition most likely linked to the development of atherosclerosis. We evaluated the relationship between apolipoprotein (apo) B48 and fasting and postprandial leukocyte activation markers. MethodsLeukocyte activation markers and apo B48 were determined in 80 subjects with and without coronary artery disease (CAD). Twelve healthy subjects underwent an oral fat loading test (up to 8 h). ResultsFasting apo B48 was significantly higher in patients with CAD (n = 47, 8.1 ± 5.2 mg/L) than in subjects without CAD (n = 33, 5.9 ± 3.9 mg/L, p = 0.022). Fasting apo B48 and triglycerides correlated positively with fasting monocyte CD11b and neutrophil CD66b expression. Plasma apo B48 and leukocyte activation markers increased after an oral fat load. No correlations were found between fasting or postprandial triglycerides and postprandial leukocyte activation markers. We observed no correlations between postprandial apo B48 and postprandial neutrophil CD11b or CD66b expression. ConclusionThis study suggests that chylomicron remnants may be responsible for postprandial leukocyte activation in the circulation. The postprandial chylomicron response may be a stronger mediator of postprandial inflammation than postprandial triglyceridemia.

Extreme Contrast of Postprandial Remnant-Like Particles Formed in Abetalipoproteinemia and Homozygous Familial Hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) and abetalipoproteinemia (ABL) are rare inherited forms of hypolipidemia. Their differential diagnosis is important for predicting of the prognosis and selecting appropriate therapy. Genetic analysis was performed in two patients with primary hypocholesterolemia born from consanguineous parents. The oral fat tolerance test (OFTT) was performed in one patient with FHBL (apoB-87.77) and one with ABL as well as in four normal control subjects. After overnight fasting, blood samples were drawn. Serum lipoprotein and remnant-like particle (RLP) fractions were determined by HPLC analysis. Both patients with homozygous FHBL were asymptomatic probably because of preserved levels of fat-soluble vitamins, especially vitamin E. The patients with FHBL were homozygous because of novel apoB-83.52 and apoB-87.77 mutations, and although one of them (apoB-87.77) had fatty liver disease, microscopic findings suggesting nonalcoholic steatohepatitis were absent. Fasting apoB-48 and RLP-triglyceride levels in the patient with homozygous FHBL, which were similar to those in normal control subjects, increased after OFTT both in normal control subjects and the patient with FHBL but not in the patient with ABL, suggesting that the fat load administered was absorbed only in the patient with FHBL. Although lipid levels in the patients with homozygous FHBL and ABL were comparable, fasting, postoral fat loading of apoB-48, as well as RLP-triglyceride levels, may help in the differential diagnosis of FHBL and ABL and provide a prompt diagnosis using genetic analysis in the future.

Abstract 216: PCSK9 Loss-of-Function Mutation Q152H is Associated with Reduced Dietary Fat Clearance and Insulin Resistance in Humans

Introduction: PCSK9 regulates plasma LDL-C concentrations. Loss-of-function (LOF) mutations are associated with cardiovascular protection via increased clearance of LDL particles. Work from our and other labs has shown that increased cellular uptake of LDL is proapoptotic for pancreatic β-cells and impairs adipose tissue function. Moreover, obese women with high concentration of LDL (ie plasma apoB) have lower insulin sensitivity and delayed dietary fat clearance. We recently identified a novel PCSK9 LOF mutation, Q152H, causing a 79% reduction of plasma PCSK9 and 48% reduction of plasma LDL-C. The impact of this mutation on the metabolic profile remains unexplored. Hypothesis: We hypothesize that despite a cardioprotective profile, carriers of Q152H have delayed dietary TG clearance and impaired insulin sensitivity similar to subjects with high apoB. Methods/Results: The heterozygous Q152H proband woman was compared to 2 groups of obese, age, sex and BMI-matched controls with low (n=6) and high (n=7) apoB. Fasting apoB, PCSK9, total cholesterol and LDL-C concentrations were lower in the proband (0.84g/l,126ng/ml, 4.22mM and 2.11mM, respectively) compared to low apoB (0.75 ± 0.05 g/l, 267 ± 18ng/ml, 5.1 ± 0.2mM and 2.8 ± 0.3nM, respectively) and high apoB (1.25 ± 0.09 g/l, 412 ± 79ng/ml, 6.9 ± 0.4mM and 4.3 ± 0.3nM, respectively). Women with high apoB had delayed dietary TG clearance over 6 hours as compared to women with low apoB (incremental TG AUC: 6.75 ± 1.65 vs 4.06 ± 0.77 mM/6h, p=NS). Incremental AUC TG in the proband was 106% greater than that of women with high apoB and 243% greater than that of low apoB. Botnia clamp was also conducted to measure insulin secretion and sensitivity. There was no difference in insulin secretion between the proband and the control groups measured via an intravenous glucose tolerance test. However, insulin sensitivity, as measured by glucose infusion rates (GIR) during a hyperinsulinemia clamp, was 7.5mg/kg/min in the proband, 32% lower than women with high apoB (11.1 ± 1.1 mg/kg/min) and 48% lower than women with low apoB (14.3 ± 0.9 mg/kg/min). Conclusion: PCSK9 deficiency favours a cardioprotective profile; however increased clearance of LDL by peripheral tissue may induce peripheral insulin resistance in obese subjects.

Abstract 10: Improving Postprandial Lipoprotein Apolipoprotein B-48 Metabolism in Statin-Treated Patients With Diabetes

Background: Type 2 diabetics often have elevated plasma TG and apolipoprotein B-48 (apoB-48) concentrations, particularly during the postprandial (PP) period. Evidence suggests that apoB-48 plays a central role in the development of atherosclerosis. Statins are frontline therapy to reduce CVD risk, however, residual risk still remains, suggesting that additional interventions are required to further reduce CVD risk. Aim: To compare PP apoB-48 kinetics in optimally statin-treated diabetic men with a group of normolipidemic healthy controls, and to investigate the effect of niacin on apoB-48 kinetics in these diabetic men. Methods: Twelve type 2 diabetic men and fourteen age-matched non-diabetic controls were recruited. Diabetics required a statin-treated LDL-C &lt; 2.5 mmol/L to enter the trial: they were randomized to rosuvastatin or rosuvastatin plus niacin (titrated from 1 to 2 g daily) for 12 weeks and then crossed to the alternate therapy (3 week washout). PP metabolic studies were performed at the end of each treatment period, and on a single occasion in control subjects. D3-leucine tracer was administered as subjects consumed a high-fat liquid meal. Blood samples were collected over 24 h. ApoB-48 tracer/tracee ratios were measured using GCMS. Kinetic parameters, including fractional catabolic rate (FCR) and production rate (PR), were derived using a compartmental model. Results: Fasting plasma TG (+112%, p&lt;0.01), but not apoB-48 was elevated in statin-treated diabetics compared with controls. Incremental AUC TG and apoB-48 (+194% and +79%, respectively, p&lt;0.01) were higher in diabetics. PP apoB-48 PR was higher in diabetics (+96%, p&lt;0.01) and FCR lower (-45%, p&lt;0.05), compared with controls. Niacin significantly lowered TG, plasma C, LDL-C and apoB (all p&lt;0.005). Fasting apoB-48 concentration was lowered with niacin (-33%, p=0.03). ApoB-48 FCR was not altered with niacin, but PP apoB-48 PR was lowered to control levels (-38%, p=0.02) on niacin. Conclusion: ApoB-48 PR and FCR are abnormal in statin-treated diabetics. Niacin reduces apoB-48 concentration by lowering apoB-48 PR. This effect may be beneficial for reducing atherogenic PP lipoproteins and may provide CVD risk benefit to patients with type 2 diabetes.

Effect of ω-3 Fatty Acid Ethyl Esters on Apolipoprotein B-48 Kinetics in Obese Subjects on a Weight-Loss Diet: A New Tracer Kinetic Study in the Postprandial State

Dysregulated chylomicron metabolism may account for hypertriglyceridemia and increased risk of cardiovascular disease in obese subjects. Supplementation with ω-3 fatty acid ethyl ester (FAEE) decreases plasma triglyceride. However, its effect on postprandial chylomicron metabolism in obese subjects on a weight-loss diet has not yet been investigated. We aimed to examine the effect of ω-3 FAEE supplementation on apolipoprotein (apo) B-48 kinetics in obese subjects on a weight-loss diet. We carried out a 12-week, randomized trial of a hypocaloric diet plus 4 g/d ω-3 FAEE supplementation (46% eicosapentaenoic acid and 38% docosahexaenoic acid) (n = 13) compared with a hypocaloric diet alone (n = 12) on postprandial apoB-48 kinetics in obese subjects after ingestion of an oral load. The apoB-48 kinetics were determined using stable isotope tracer kinetics and multicompartmental modeling. We evaluated plasma total and incremental apoB-48 0- to 10-hour area under the curves (AUCs) as well as apoB-48 secretion and fractional catabolic rate. Weight loss with or without ω-3 FAEE supplementation significantly reduced body weight, total fat mass, homeostasis model assessment score, fasting triglyceride concentration, postprandial triglyceride AUC, and increased plasma high-density lipoprotein cholesterol concentration (P < .05 in all). Compared with weight loss alone, weight loss plus ω-3 FAEE significantly (all P < .05) decreased fasting triglyceride (-11%), apoB-48 (-36%) concentrations, postprandial triglyceride (-21%), and apoB-48 (-22%) total AUCs, as well as incremental postprandial triglyceride AUCs (-32%). The ω-3 FAEE also significantly decreased apoB-48 secretion in the basal state, without a significant effect during the postprandial period (3-6 hours). The fractional catabolic rate of apoB-48 increased with both interventions with no significant independent effect of ω-3 FAEE supplementation. Addition of ω-3 FAEE supplementation to a moderate weight-loss diet in obese subjects can significantly improve chylomicron metabolism by independently decreasing the secretion of apoB-48.

Effects of exercise on fasting triglyceride‐rich lipoproteins from hepatic and intestinal origin

A high fructose intake increases fasting triglyceride‐rich lipoproteins (TRL). This is due, at least in part, to a stimulation of hepatic de novo lipogenesis and TRL secretion. Unlike in rodents, the role of the enterocytes in fructose‐induced de novo lipogenesis and TRL secretion remains not established in humans. We therefore assessed the effects of a high fructose diet on fasting blood triglyceride (TG) and apob48 concentrations as well as TRL (sf 20–400) TG content. Since exercise may prevent carbohydrate‐induced dyslipidemia, we measured the effects of an isocaloric, high fructose diet both with and without daily exercise in 8 healthy male subjects.A fasting blood sample was obtained after 4 days on a low‐fructose diet without exercise (control, C), a 30% fructose diet and no exercise (HFr), and a 30% fructose diet with aerobic exercise (HFrEx).HFr increased apoB48 from 4.55 ± 0.73 to 8.13 ± 0.94 μg/mL, total TG from 0.65 ± 0.07 to 0.94 ± 0.14 and TRL‐TG from 0.43 ± 0.07 to 0.69 ± 0.13 mmol/L (all p&lt;0.05 vs C). HFrEx completely prevented the effects of HFr and restored fasting apoB48 concentrations (5.29 ± 0.85), TG (0.63 ± 0.06), TRL‐TG (0.37 ± 0.06), to values comparable to those observed after C (all p=NS vs C).Our data suggest that the gut contributes to fructose‐induced de novo lipogenesis, and can adapt to short‐term changes in the diet and to exercise.Swiss National Science Foundation supported this work.

Elevated remnant lipoproteins may increase subclinical CVD risk in pre‐pubertal children with obesity: a case‐control study

Current clinical guidelines to assess paediatric cardiovascular disease (CVD) risk heavily rely on cholesterol parameters that are generally normal for obese children. Remnant lipoproteins have emerged as a critical CVD risk factor particularly in adults with normolipidemia. We assessed remnant lipoprotein concentration (measured by apolipoprotein [apo] B48) and its relationship with other traditional CVD risk biomarkers in pre-pubertal children with obesity. Pre-pubertal children (n = 78) with obesity (n = 39, 9.9 ± 0.3 years old) as well as sex-matched normal-weight controls (n = 39, 9.8 ± 0.3 years) were assessed for anthropometry, blood pressure and fasting plasma biochemical parameters for remnant lipoprotein, lipid and glucose/insulin metabolism, and inflammatory status. Children with obesity had striking 2-fold higher apoB48-containing remnant lipoproteins concentrations relative to normal-weight peers; the magnitude of elevation in the remnant lipoproteins is comparable to the levels previously reported for adults with established CVD and type-2 diabetes. Fasting apoB48 was positively correlated with fasting triglyceride concentration in children with obesity (r = 0.51, P < 0.001) and their normal-weight peers (r = 0.45, P < 0.01). Traditional CVD biomarkers including low-density lipoprotein cholesterol showed no difference between groups and remained within the normal range for a paediatric population. Elevated apoB48-containing remnant lipoprotein is a stronger biomarker for paediatric CVD risk compared to traditional cholesterol parameters and may be associated with early adaptation of the intestine during obesity. Further investigation of abnormalities associated with the secretion and/or clearance of atherogenic remnant lipoproteins during the postprandial state may yield insight into our understanding of and therapeutic targets for managing risk for CVD in children with obesity.