Oral Fat Load Research Articles

The anti-adipogenic effect of peripheral blood mononuclear cells is absent with PCSK9 loss-of-function variants.

To determine the effect of (1) an oral fat load and (2) pro-protein convertase subtilisin/kexin type (PCSK) 9 loss-of-function (LOF) variant status on the ability of peripheral blood mononuclear cells (PBMC) to inhibit human adipogenesis. PBMC from subjects with one or more PCSK9 LOF variants versus non-variant controls were compared in the fasting state and after an oral fat load. Fasting triglyceride (TG) levels were lower in the LOF variant versus non-variant group but rose to the same level after the oral fat load. Conditioned medium from PBMC was obtained in fasting (PBMC-CM-F) and 4-h postprandial (PBMC-CM-PP) states. PBMC-CM-PP from non-variant controls inhibited adipogenesis of human preadipocytes more than did PBMC-CM-F. In contrast, PBMC-CM-F or -PP from PCSK9 LOF variant subjects had no effect on adipogenesis. After the oral fat load, PBMC from PCSK9 LOF variant subjects showed significant increases in mRNA levels of interleukin-1β, tumor necrosis factor-α, sterol regulatory element binding protein-1c, CD36, and monocyte chemoattractant protein-1 (MCP-1), only MCP-1 mRNA levels increased in PBMC from non-variant controls. The absence of anti-adipogenic action of PBMC from PCSK9 LOF variant subjects points to a novel role for PCSK9 in PBMC-adipose cell interactions.

Unsaturated Oral Fat Load Test Improves Glycemia, Insulinemia and Oxidative Stress Status in Nondiabetic Subjects with Abdominal Obesity.

AimsTo evaluate the changes in glycemia, insulinemia, and oxidative stress markers during an oral fat load test in nondiabetic subjects with abdominal obesity and to analyze the association between postprandial oxidative stress markers and postprandial glucose and insulin responses.MethodsWe included 20 subjects with abdominal obesity (waist circumference > 102 cm for men and > 88 cm for women) and 20 healthy lean controls (waist circumference < 102 cm for men and < 88 cm for women). After 12 hours of fasting we performed a standardized fat load test (0–8 hours) with supracal® (50 g/m2). We determined metabolic parameters, oxidized and reduced glutathione, and malondialdehyde.ResultsIn both groups, insulin, HOMA, oxidized/reduced glutathione ratio, and malondialdehyde significantly decreased in the postprandial state after the OFLT. All these parameters were significantly higher in the abdominal obesity group at baseline and during all the postprandial points, but the reduction from the baseline levels was significantly higher in the abdominal obesity group.ConclusionUnsaturated fat improves insulin resistance and oxidative stress status. It is possible that a consumption of unsaturated fat could be beneficial even in subjects with abdominal obesity in postprandial state.

Hepatic insulin resistance both in prediabetic and diabetic patients determines postprandial lipoprotein metabolism: from the CORDIOPREV study.

Background/aimsPrevious evidences have shown the presence of a prolonged and exaggerated postprandial response in type 2 diabetes mellitus (T2DM) and its relation with an increase of cardiovascular risk. However, the response in prediabetes population has not been established. The objective was to analyze the degree of postprandial lipemia response in the CORDIOPREV clinical trial (NCT00924937) according to the diabetic status.Methods1002 patients were submitted to an oral fat load test meal (OFTT) with 0.7 g fat/kg body weight [12 % saturated fatty acids (SFA), 10 % polyunsaturated fatty acids (PUFA), 43 % monounsaturated fatty acids (MUFA), 10 % protein and 25 % carbohydrates]. Serial blood test analyzing lipid fractions were drawn at 0, 1, 2, 3 and 4 h during postprandial state. Postprandial triglycerides (TG) concentration at any point >2.5 mmol/L (220 mg/dL) has been established as undesirable response. We explored the dynamic response in 57 non-diabetic, 364 prediabetic and 581 type 2 diabetic patients. Additionally, the postprandial response was evaluated according to basal insulin resistance subgroups in patients non-diabetic and diabetic without pharmacological treatment (N = 642).ResultsPrevalence of undesirable postprandial TG was 35 % in non-diabetic, 48 % in prediabetic and 59 % in diabetic subgroup, respectively (p < 0.001). Interestingly, prediabetic patients displayed higher plasma TG and large triacylglycerol-rich lipoproteins (TRLs-TG) postprandial response compared with those non-diabetic patients (p < 0.001 and p = 0.003 respectively). Moreover, the area under the curve (AUC) of TG and AUC of TRLs-TG was greater in the prediabetic group compared with non-diabetic patients (p < 0.001 and p < 0.005 respectively). Patients with liver insulin resistance (liver-IR) showed higher postprandial response of TG compared with those patients with muscle-IR or without any insulin-resistance respectively (p < 0.001).ConclusionsOur findings demonstrate that prediabetic patients show a lower phenotypic flexibility after external aggression, such as OFTT compared with nondiabetic patients. The postprandial response increases progressively according to non-diabetic, prediabetic and type 2 diabetic state and it is higher in patients with liver insulin-resistance. To identify this subgroup of patients is important to treat more intensively in order to avoid future cardiometabolic complications.

Different Serum Free Fatty Acid Profiles in NAFLD Subjects and Healthy Controls after Oral Fat Load.

Background: Free fatty acid (FFA) metabolism can impact on metabolic conditions, such as obesity and nonalcoholic fatty liver disease (NAFLD). This work studied the increase in total FFA shown in NAFLD subjects to possibly characterize which fatty acids significantly accounted for the whole increase. Methods: 21 patients with NAFLD were selected according to specified criteria. The control group consisted of nine healthy subjects. All subjects underwent an oral standard fat load. Triglycerides; cholesterol; FFA; glucose and insulin were measured every 2 h with the determination of fatty acid composition of FFA. Results: higher serum FFA levels in NAFLD subjects are mainly due to levels of oleic, palmitic and linoleic acids at different times. Significant increases were shown for docosahexaenoic acid, linolenic acid, eicosatrienoic acid, and arachidonic acid, although this was just on one occasion. In the postprandial phase, homeostatic model assessment HOMA index positively correlated with the ω3/ω6 ratio in NAFLD patients. Conclusions: the higher serum levels of FFA in NAFLD subjects are mainly due to levels of oleic and palmitic acids which are the most abundant circulating free fatty acids. This is almost exactly corresponded with significant increases in linoleic acid. An imbalance in the n-3/n-6 fatty acids ratio could modulate postprandial responses with more pronounced effects in insulin-resistant subjects, such as NAFLD patients.

Postprandial Changes in Chemokines Related to Early Atherosclerotic Processes in Familial Hypercholesterolemic Subjects: A Preliminary Study

Familial hypercholesterolemia (FH) is associated with higher levels of inflammatory mediators such as chemokines, which contribute to an increased risk of premature atherosclerosis in these patients. We studied the response of chemokines related to early atherosclerotic processes during an oral unsaturated fat load test (OFLT) in patients with heterozygous FH and compared this response to normolipidemic and normoglycemic subjects. Blood samples were taken from 12 FH patients and 20 healthy controls with a similar age, gender distribution, and body mass index. Plasma chemokine levels were determined in both groups in a fasting state and at 2, 4, 6, and 8h after an OFLT using human cytokine multiplex kits (Linco) and a Luminex LABScan™100 system. In the fasting state MIP-1β, MIP-1α, IP-10, IFN-γ, MCP-1, and IL-8 were significantly increased in the FH group compared to the healthy controls (p <0.05). In addition, a significant decrease in postprandial chemokine plasma values were found in the FH group compared to fasting values after the OFLT. In normolipidemic nondiabetic controls no significant changes were found in the postprandial state. There was a postprandial decrease in chemokines related to early atherosclerotic processes after an OFLT in FH patients. These results confirm the influence of dietary patterns in this group of patients.

The effect of orlistat on postprandial hypertriglyceridemia by oral fat loading test. A systematic review

Orlistat induces weight loss by blocking hydrolysis of triglyceride in the intestine, and has thereby been associated with favorable changes in postprandial triglycerides (ppTGL). Some epidemiological studies have identified ppTGL concentrations as a significant risk factor for cardiovascular disease. Oral fat loading test (OFLT) has been used for screening of elevated levels of ppTGL. The objective of the present systematic review is to present available data on the effects of orlistat on OFLT.We found 11 studies, seven of which studied the effect of a single dose of orlistat on OFLT in three healthy volunteers, one with obesity, two with type-2 diabetes and one with hyperlipidemic patients. The other four studied the effect of orlistat on OFLT, but after a previous period of time with daily treatment with orlistat: 1 healthy volunteer, 2 obese volunteers, and one patient with hyperlipidemia.Our systematic review suggests that orlistat can help to reduce postprandial hypertriglyceridemia in obese, dyslipemic and type-2 diabetic patients. Regarding free fatty acids, they could be reduced but not all the authors have found the same results. In relation to type-2 diabetic patients, we have found three studies with conflicting results on the immediate effect of orlistat on the postprandial GLP-1 response.In conclusion, orlistat can help to reduce postprandial plasmatic TGL, especially in patients with postprandial hypertriglyceridemia related to obesity, dyslipidemia or type-2 diabetes.

Effects of extended-release niacin on the postprandial metabolism of Lp(a) and ApoB-100-containing lipoproteins in statin-treated men with type 2 diabetes mellitus.

The effects of extended-release niacin (ERN; 1-2 g/d) on the metabolism of lipoprotein(a) (Lp(a)) and apolipoprotein (apo) B-100-containing lipoproteins were investigated in 11 statin-treated white men with type 2 diabetes mellitus in a randomized, crossover trial of 12-weeks duration. The kinetics of Lp(a) and very low-density lipoprotein (VLDL), intermediate-density lipoprotein, and low-density lipoprotein (LDL) apoB-100 were determined following a standardized oral fat load (87% fat) using intravenous administration of D3-leucine, gas chromatography-mass spectrometry, and compartmental modeling. ERN significantly decreased fasting plasma total cholesterol, LDL cholesterol, and triglyceride concentrations. These effects were achieved without significant changes in body weight or insulin resistance. ERN significantly decreased plasma Lp(a) concentration (-26.5%) and the production rates of apo(a) (-41.5%) and Lp(a)-apoB-100 (-32.1%); the effect was greater in individuals with elevated Lp(a) concentration. ERN significantly decreased VLDL (-58.7%), intermediate-density lipoprotein (-33.6%), and LDL (-18.3%) apoB-100 concentrations and the corresponding production rates (VLDL, -49.8%; intermediate-density lipoprotein, -44.7%; LDL, -46.1%). The number of VLDL apoB-100 particles secreted increased in response to the oral fat load. Despite this, total VLDL apoB-100 production over the 10-hour postprandial period was significantly decreased with ERN (-21.9%). In statin-treated men with type 2 diabetes mellitus, ERN decreased plasma Lp(a) concentrations by decreasing the production of apo(a) and Lp(a)-apoB-100. ERN also decreased the concentrations of apoB-100-containing lipoproteins by decreasing VLDL production and the transport of these particles down the VLDL to LDL cascade. Our study provides further mechanistic insights into the lipid-regulating effects of ERN.

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.

Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia.

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of low-density lipoprotein (LDL)-cholesterol and apolipoprotein B (apoB). The objective was to examine the effect of heterozygous APOB L343V FHBL on postprandial triglyceride-rich lipoprotein (TRL) and fasting lipoprotein metabolism. Plasma incremental area under the curve apoB-48 and apoB-48 kinetics were determined after ingestion of a standardized oral fat load using compartmental modeling. Very low-density lipoprotein (VLDL)-, intermediate-density lipoprotein (IDL)-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. The postprandial incremental area under the curve (0-10 h) in FHBL subjects (n = 3) was lower for large TRL-triglyceride (-77%; P < .0001), small TRL-cholesterol (-83%; P < .001), small TRL-triglyceride (-88%; P < .001), and for plasma triglyceride (-70%; P < .01) and apoB (-63%; P < .0001) compared with controls. Compartmental analysis showed that apoB-48 production was lower (-91%; P < .05) compared with controls. VLDL-apoB concentrations in FHBL subjects (n = 2) were lower by more than 75% compared with healthy, normolipidemic control subjects (P < .01). The VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects (P = .07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show lower TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, whereas the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

Differential Patterns and Determinants of Cardiac Autonomic Nerve Dysfunction during Endotoxemia and Oral Fat Load in Humans.

The autonomic nervous system (ANS) plays an important role in regulating the metabolic homeostasis and controlling immune function. ANS alterations can be detected by reduced heart rate variability (HRV) in conditions like diabetes and sepsis. We determined the effects of experimental conditions mimicking inflammation and hyperlipidemia on HRV and heart rate (HR) in relation to the immune, metabolic, and hormonal responses resulting from these interventions. Sixteen lean healthy subjects received intravenous (i.v.) low-dose endotoxin (lipopolysaccharide [LPS]), i.v. fat, oral fat, and i.v. glycerol (control) for 6 hours, during which immune, metabolic, hormonal, and five HRV parameters (pNN50, RMSSD, low-frequency (LF) and high-frequency (HF) power, and LF/HF ratio) were monitored and energy metabolism and insulin sensitivity (M-value) were assessed. LPS infusion induced an increase (AUC) in HR and LF/HF ratio and decline in pNN50 and RMSSD, while oral fat resulted in elevated HR and a transient (hours 1-2) decrease in pNN50, RMSSD, and HF power. During LPS infusion, ΔIL-1ra levels and ΔIL-1ra and ΔIL-1ß gene expression correlated positively with ΔLF/HF ratio and inversely with ΔRMSSD. During oral fat intake, ΔGLP-1 tended to correlate positively with ΔHR and inversely with ΔpNN50 and ΔRMSSD. Following LPS infusion, lipid oxidation correlated positively with HR and inversely with pNN50 and RMSSD, whereas HRV was not related to M-value. In conclusion, suppression of vagal tone and sympathetic predominance during endotoxemia are linked to anti-inflammatory processes and lipid oxidation but not to insulin resistance, while weaker HRV changes in relation to the GLP-1 response are noted during oral fat load.Trial RegistrationClinicalTrials.gov NCT01054989

Subcutaneous and total fat at L4–L5 and subcutaneous, visceral and total fat at L3–L4 are important contributors of fasting and postprandial adiponectin levels

Objectives: Insulin resistance and central obesity have been implicated in the pathogenesis of hypoadiponectinemia in obesity. The aim of this study is to evaluate circulating post-prandial adiponectin in relation to glucose and insulin metabolism, indexes of insulin resistance and sensitivity and, indexes of body fat accumulation and distribution in obese men. Methods: Twenty-eight non-diabetic men underwent an OGTT followed by an oral fat load and were studied at baseline and for 5 h post-prandially for serum adiponectin, glucose and insulin. Insulin resistance was estimated by Homeostasis model assessment (HOMA) and insulin sensitivity by Matsuda index. Body fat accumulation and distribution were evaluated by anthropometric indexes and multiple slices MRI of the abdomen and hip. Results: Adiponectin was negatively correlated to insulin levels. Fasting and area under the curve (AUC) adiponectin levels were negatively correlated to HOMA (both p < 0.01) and positively to Matsuda index (both p < 0.05). Negative correlations between fasting adiponectin and total fat (r = −0.408, p < 0.05), AUC adiponectin and subcutaneous, visceral and total fat (r = −0.375, −0.413 and −0.475 respectively, all p < 0.05) at L3–L4 were found, and negative correlations between fasting adiponectin and subcutaneous (r = −0.402, p < 0.05) and total fat (r = −0.491, p < 0.05) and between AUC adiponectin and subcutaneous and total fat (r = −0.506 and −0.547, respectively, both p < 0.01) were present at L4–L5. Conclusions: Circulating adiponectin is inversely correlated to both visceral and subcutaneous fat in non-diabetic men, implying that both compartments are important for adiponectin levels. The best correlation is found at measurement site L4–L5.

Endothelial function and insulin sensitivity during acute non-esterified fatty acid elevation: Effects of fat composition and gender

Background and aimsWe have reported that adverse effects on flow-mediated dilation of an acute elevation of non-esterified fatty acids rich in saturated fat (SFA) are reversed following addition of long-chain (LC) n-3 polyunsaturated fatty acids (PUFA), and hypothesised that these effects may be mediated through alterations in insulin signalling pathways. In a subgroup, we explored the effects of raised NEFA enriched with SFA, with or without LC n-3 PUFA, on whole body insulin sensitivity (SI) and responsiveness of the endothelium to insulin infusion. Methods and resultsThirty adults (mean age 27.8 y, BMI 23.2 kg/m2) consumed oral fat loads on separate occasions with continuous heparin infusion to elevate NEFA between 60 and 390 min. For the final 150 min, a hyperinsulinaemic-euglycaemic clamp was performed, whilst FMD and circulating markers of endothelial function were measured at baseline, pre-clamp (240 min) and post-clamp (390 min). NEFA elevation during the SFA-rich drinks was associated with impaired FMD (P = 0.027) whilst SFA + LC n-3 PUFA improved FMD at 240 min (P = 0.003). In males, insulin infusion attenuated the increase in FMD with SFA + LC n-3 PUFA (P = 0.049), with SI 10% greater with SFA + LC n-3 PUFA than SFA (P = 0.041). ConclusionThis study provides evidence that NEFA composition during acute elevation influences both FMD and SI, with some indication of a difference by gender. However our findings are not consistent with the hypothesis that the effects of fatty acids on endothelial function and SI operate through a common pathway.This trial was registered at clinical trials.gov as NCT01351324 on 6th May 2011.

Inter-relationships between proprotein convertase subtilisin/kexin type 9, apolipoprotein C-III and plasma apolipoprotein B-48 transport in obese subjects: a stable isotope study in the postprandial state.

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

Metabolic phenotypes of obesity influence triglyceride and inflammation homoeostasis.

We examined the degree of postprandial triglyceride (TG) response over the day, representing a highly dynamic state, with continuous metabolic adaptations, among normal-weight, overweight and obese patients, according to their metabolically healthy or abnormal status. A total of 1002 patients from the CORDIOPREV clinical trial (NCT00924937) were submitted to an oral fat load test meal with 0·7 g fat/kg body weight (12% saturated fatty acids (SFA), 10% polyunsaturated fatty acids (PUFA), 43% monounsaturated fatty acids (MUFA), 10% protein and 25% carbohydrates). Serial blood test analysing lipid fractions and inflammation markers (high-sensitivity C-reactive protein (hs-CRP)) were drawn at 0, 1, 2, 3 and 4 h during postprandial state. We explored the dynamic response according to six body size phenotypes: (i) normal weight, metabolically healthy; (ii) normal weight, metabolically abnormal; (iii) overweight, metabolically healthy; (iv) overweight, metabolically abnormal; (v) obese, metabolically healthy; and (vi) obese, metabolically abnormal. Metabolically healthy patients displayed lower postprandial response of plasma TG and large triacylglycerol-rich lipoproteins (TRLs)-TG, compared with those metabolically abnormal, independently whether or not they were obese (P < 0·001 and P < 0·001, respectively). Moreover, the area under the curve (AUC) of TG and AUC of large TRLs-TG were greater in the group of metabolically abnormal compared with the group of metabolically healthy (P < 0·001 and P < 0·001, respectively). Interestingly, metabolically abnormal subjects displayed higher postprandial response of plasma hs-CRP than did the subgroup of normal, overweight and obese, metabolically healthy patients (P < 0·001). Our findings showed that certain types of the metabolic phenotypes of obesity are more favourable modulating phenotypic flexibility after a dynamic fat load test, through TG metabolism and inflammation homoeostasis. To identify, these phenotypes may be the best strategy for personalized treatment of obesity.

Is it time to implement a standardized oral glucose and fat load test to detect high risk patients? Probably not yet…

Is it time to implement a standardized oral glucose and fat load test to detect high risk patients? Probably not yet…

Enhanced reduction in oxidative stress and altered glutathione and thioredoxin system response to unsaturated fatty acid load in familial hypercholesterolemia

ObjectivesFamilial hypercholesterolemia (FH) is characterized by increased oxidative stress (OS) levels. In the postprandial state, lipids and lipoproteins modulate OS status through their impact on pro-oxidant and antioxidant mechanisms. The objective of this study was to evaluate in patients with FH the response to an unsaturated oral fat load test (OFLT) by analyzing the mRNA levels of genes involved in the glutathione and thioredoxin antioxidant systems. Design and MethodsWe analyzed 14 FH patients and 20 normolipidemic and normoglycemic controls. In both groups, mRNA values of antioxidant enzyme genes (glutathione and thioredoxin systems) were determined at baseline and at 2, 4, 6, and 8h after OFLT by real time PCR. ResultsIn the fasting state the mRNA levels of antioxidant enzymes GPX4 and the GSR, GSS, and GCLC enzymes (involved in glutathione regeneration and synthesis) and thioredoxin (TXN), were significantly increased in the FH group compared to the healthy controls. Some genes (GPX1 and GPX4) were increased at 4h in both groups, but values for the rest of the antioxidant enzyme mRNAs were decreased in FH patients after 4h from unsaturated OFLT and were increased in controls. ConclusionsWe concluded that an OFLT with predominantly unsaturated fat has a different effect on postprandial antioxidant enzyme mRNA levels in controls than in FH patients. Increased antioxidant enzyme mRNA is not the main way to reduce postprandial oxidative stress in FH. This difference could determine the influence of dietary patterns in these patients.

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test

Gender differences on oxidative stress markers and complement component C3 plasma values after an oral unsaturated fat load test

Oxidative stress and mrna expression after an oral unsaturated fat load test in subjects with abdominal obesity

Oxidative stress and mrna expression after an oral unsaturated fat load test in subjects with abdominal obesity

Abstract 236: Lipoprotein Metabolism in APOB L343V Familial Hypobetalipoproteinemia

Familial hypobetalipoproteinemia (FHBL) is a codominant disorder of lipoprotein metabolism characterized by decreased plasma concentrations of LDL-cholesterol and apolipoprotein (apo) B. We examined the effect of heterozygous APOB L343V FHBL on fasting and postprandial lipoprotein metabolism. VLDL, IDL-, and LDL-apoB kinetics were determined in the fasting state using stable isotope methods and compartmental modeling. VLDL-apoB concentrations in FHBL subjects (n=2) were reduced by more than 75% compared to healthy, normolipidemic control subjects ( P &lt;0.01). VLDL-apoB fractional catabolic rate (FCR) was more than 5-fold higher in the FHBL subjects ( P =0.07). ApoB production rates and IDL- and LDL-apoB FCRs were not different between FHBL subjects and controls. To assess postprandial lipoprotein metabolism, a standardized oral fat load was given after a 12 h fast to heterozygous APOB L343V FHBL subjects (n=3) and normolipidemic controls. The postprandial incremental area under the curve (0-10 h) in FHBL subjects was decreased for large TRL-triglyceride (-77%; P &lt;0.0001), small TRL-cholesterol (-83%; P &lt;0.001), small TRL-triglyceride (-88%; P &lt;0.0.001) and plasma apoB (-63%; P &lt;0.0001) compared with controls. Compartmental modeling analysis showed that apoB-48 production was decreased (-91%; P &lt;0.05) compared with controls. We conclude that when compared to controls, APOB L343V FHBL heterozygotes show decreased TRL production with normal postprandial TRL particle clearance. In contrast, VLDL-apoB production was normal, while the FCR was higher in heterozygotes compared with lean control subjects. These mechanisms account for the marked hypolipidemic state observed in these FHBL subjects.

Abstract 429: Central Glucagon-Like Peptide-1 Reduces Intestinal Chylomicron Production via Melanocortin-4-Receptor Signaling

Insulin resistance and the metabolic syndrome are associated with intestinal overproduction of chylomicrons, resulting in postprandial dyslipidemia and atherogenic remnants. It is increasingly clear that a reduction in chylomicrons is achieved by the action of glucagon-like peptide-1 (GLP-1) in the periphery. However, this peptide is also generated by central neurons and regulates activity in brain regions that affect sympathetic signaling. Indeed, through sympathetic pathways GLP-1 can modulate peripheral lipogenesis. Therefore, we examined the potential role of peripheral and central GLP-1 in regulating chylomicron production. Healthy hamsters received an oral fat load followed by an intraperitoneal (IP) or intracerebroventricular (ICV) injection of the GLP-1 receptor (GLP-1R) agonist exendin-4. Postprandial triglyceride (TG) and apolipoprotein B48 (apoB48) levels from plasma TG-rich lipoproteins (TRL) were found to be reduced over 6 h. The effects of central exendin-4 were mirrored by ICV MK-0626, an inhibitor of GLP-1 degradation, and reversed by the GLP-1R antagonist exendin9-39. Given a potential link between central GLP-1 and the melanocortin-4-receptor (MC4R) system, hamsters received an MC4R antagonist ICV alongside exendin-4 and this prevented a lowering in TRL-TG levels. To determine whether subsequent communication with the gut was through sympathetic pathways, α- and β-adrenergic receptor blockers were infused intravenously prior to ICV exendin-4 treatment and prevented exendin-4 from reducing TRL-TG. Finally, to examine the interplay between central and peripheral GLP-1R signaling, exendin-4 was given IP while exendin9-39 was given ICV and vice-versa. IP exendin-4 diminished TRL-TG levels during central antagonism, while IP exendin9-39 prevented the action of ICV exendin-4. This suggests that peripheral GLP-1Rs may be potentiated by central stimulation, but can also act independently. Overall, we demonstrate a GLP-1-sensitive brain-gut axis for regulating chylomicron production, involving the MC4R system and sympathetic pathways. Future studies will investigate whether central GLP-1 signals via pro-opiomelanocortin neurons and sympathetic neurotransmitters to affect enterocyte chylomicron output.