The chylomicron saga: time to focus on postprandial metabolism

Since statins have had such tremendous therapeutic success over the last three decades, the field of atherosclerosis has become somewhat LDL-centric, dismissing the relevance of triglycerides (TG), particularly chylomicrons, in atherogenesis. Nonetheless, 50% of patients who take statins are at risk of developing atherosclerotic cardiovascular disease (ASCVD) and are unable to achieve their goal LDL-C levels. This residual risk is mediated, in part by triglyceride rich lipoproteins (TRL) and their remnants. Following his seminal investigation on the subject, Zilversmit proposed that atherosclerosis is a postprandial event in 1979 (1–4). In essence, the concept suggests that remnant cholesterol-rich chylomicron (CM) and very-low density lipoprotein (VLDL) particles play a role in atherogenesis. Given the foregoing, this narrative review addresses the most recent improvements in our understanding of postprandial dyslipidemia. The primary metabolic pathways of chylomicrons are discussed, emphasizing the critical physiological role of lipoprotein lipase and apoCIII, the importance of these particles’ fluxes in the postprandial period, their catabolic rate, the complexities of testing postprandial metabolism, and the role of angiopoietin-like proteins in the partition of CM during the fed cycle. The narrative is rounded out by the dysregulation of postprandial lipid metabolism in insulin resistance states and consequent CVD risk, the clinical evaluation of postprandial dyslipidemia, current research limits, and potential future study directions

Paraoxonase 1 in Chronic Kidney Failure

In this review we summarize the findings from the literature and our own laboratory on the decreased PON1 activity in renal failure, the mechanisms proposed and the effect of interventions. In addition to profound alterations in lipoproteins, reduced serum PON1 activity has been clearly established in the past decade and could contribute to accelerated development of atherosclerosis in ESRD and in HD. PON1 lactonase activity is lower in ESRD patients. Hemodialysis partially restores PON1 lactonase and the other activities. PON1 activity recovery after dialysis suggests that uremic toxins may play a mechanistic role in PON1 inactivation. Lower PON1 activity in CRF patients is associated with low thiol concentration, high CRP, and is beneficially enhanced with vitamin C and flavonoids. Changes in HDL subclasses, namely lower HDL3 in these patients may also play a role in PON1 lower activity. Future research should focus on: (1) mechanistic studies on causes for low PON1 activity and mass; (2) prospective studies focusing on whether there is an added predictive value in measuring PON1 activity (and PON1 activity in HDL3) in this patient population; (3) intervention studies attempting to increase PON1 activity

Paraoxonase 1, HDL Subclasses and Post Surgery Acute Inflammation: A Pilot Study.

High density lipoproteins (HDL) structure and function studies are needed to better understand the heterogeneous nature of the HDL particle, and its interaction with associated proteins such as apolipoprotein A-1 (ApoA-1), paraoxonase 1 (PON1) and the environment. Our study assesses the effects of acute inflammation on PON1 and HDL subclasses in post-surgical colorectal cancer patients. PON1 was measured kinetically through its arylesterase and lactonase activity and HDL sub-classes were measured using Quantimetrix Lipoprint® System. White blood cells (WBC) counts, c-reactive protein (CRP) and serum amyloid A (SAA) levels were also analyzed using standard techniques. Our findings show that baseline PON1 activity is lower in colorectal cancer patients and significant reductions are observed in the acute inflammatory state post-surgery. PON1 changes are also inversely related to inflammatory markers such as SAA and CRP. In addition, our preliminary findings show that small and intermediate HDL decreases post-op Day 1. In conclusion, our study demonstrates the effects of chronic and acute inflammation on PON1. Specifically, PON1 arylesterase and lactonase activity is lower in states of chronic inflammation and further decreased in the acute inflammatory state. Additionally, in our limited sample size, while changes in PON1 and HDL subclasses may be variable in the acute inflammatory period, small HDL decreased with a loss of PON1 activity in the subacute phase

Correlation of Ischemia-Modified Albumin with SOFA and APACHE II Scores in Preoperative Patients with Colorectal Cancer

Purpose. Critical illnesses are assessed according to the sequential organ failure assessment (SOFA) and acute physiology and chronic health evaluation (APACHE) II. Circulating ischemia-modified albumin (IMA) is a biomarker generated under ischemic and oxidative conditions and may reflect disease severity in preoperative patients. This study investigated the correlations of IMA with SOFA and APACHE II scores in inpatients admitted for colorectal surgery. Methods.We examined 27 patients with advanced colorectal cancers (mean age 69 years, men/women = 15/12). Correlations between SOFA and APACHE II scores in addition to preoperative serum IMA and C-reactive protein (CRP) levels were analyzed. Results. The mean IMA level was 0.5AU, and the median CRP level was 0.6mg/dL. Median scores for SOFA and APACHE II were 2 and 12 points, respectively. Significant positive correlations between IMA and SOFA ( = 0.45, \u3c 0.05) and IMA and APACHE II ( = 0.45, \u3c 0.05) were identified which remained significant in confounder-adjusted analyses. In contrast, weak correlations were observed between CRP and the SOFA and APACHE II scores. Conclusions.The positive correlations between IMA and both SOFA and APACHE II scores suggest that serum IMA measurements reflect the severity of systemic failure in patients admitted for colorectal surgery in the preoperative phase

Dietary Intake of Vitamin D Is Related to Blood Levels of Advanced Glycation End Products during a Weight Loss Program in Obese Women

BACKGROUND/OBJECTIVES: Advanced glycation end products (AGEs) contribute to the pathophysiology of lifestyle-related diseases. To identify nutrients associated with AGEs, this study explored the factors by investigating the relationship between nutrients changes and changes of blood AGEs during a weight loss program in obese women. SUBJECTS/METHODS: Twenty-five obese women (age: 50 ± 8 years, body mass index: 28.7 ± 3.4 kg/m2 ) underwent a weight loss program with energy-restricted meal replacement for 2 months. Three-day weighted dietary records and blood tests including blood AGEs were performed at the baseline and after the 2-month intervention. Their correlation was examined during the intervention period. RESULTS: The changes in AGEs were significantly and negatively correlated with those of intake levels of vitamin D (r = -0.54; P \u3c 0.05). CONCLUSION: Vitamin D might be a useful nutrient to reduce AGEs in obese women

D-lactate and Low Molecular AGEs Are Elevated in Obese Adolescents: Evidence for Carbonyl Stress in Adolescent Obesity

Glycation and carbonyl stress produced by methylglyoxal (MG) as a consequence of triose flux in glycolysis has been implicated in the etiology of metabolic syndrome and diabetes complications. An integrated estimation of MG flux is provided by measuring concentrations of its catabolite D-lactate in serum. However, no studies have explored the pathway in childhood obesity. Objective: Study serum concentrations of D-lactate and low molecular weight advanced glycation end-products (LMWAGE) in lean vs adolescents with obesity. Material and Methods: We conducted a cross-sectional study of 30 lean and 30 obese adolescents between the ages of 15-19 years. D-lactate was measured kinetically in serum ultrafiltrates by an adaptation of a colorimetric method from Sigma. Total and LMW-AGEs were measured by fluorescence (Excitation: λ 370 nm, Emission: λ 440 nm). The Ethical Committee of the Institution approved this study and informed consent was obtained from the participant adolescents and their parents. Results: The obesity group showed significantly (* p \u3c 0.01, ** p \u3c 0.001) higher levels of: % body fat 35.0 ± 9**, systolic BP 116.0 ± 8.1 mmHg** and diastolic BP, 72.9 ± 7.1*mmHg, waist 96.1 ± 11.6 cm** and hip circumferences 110.2 ± 8 cm**, HbA1c 5.1 ± 0.6*. D-lactate was 4.5 +/- 2.5 nmol/l in controls vs 7.4 +/- 4.2 vs. nmol/l in obese subjects **. LMW/total AGE were 0.48 (0.44-052) AU in controls vs 0.61 (0.55-0.67) AU in obese subjects**. Conclusions: D-lactate levels and LMW-AGEs are higher (64% and 27% respectively) in adolescents with obesity as compared to lean controls. Our data is compatible with the presence of an increased production of MG associated with protein modification that results in LMW-AGE (partial proteolysis of AGE proteins) increases in serum. This increased carbonyl stress may be of etiological significance. Sources of Research Support: Project supported by DAIP Universidad de Guanajuato (project 011/2015) and Touro Universit

Postprandial Paraoxonase 1 Activity Following Consumption of Recommended Amounts of Mixed Meals in Healthy Males

Aim: Postprandial lipid level increases induce oxidative stress, which is involved in atherogenesis. The antioxidant properties of paraoxonase 1 (PON1) have attracted attention. However, changes in postprandial PON1 levels differ across prior studies, and changes in PON1 lactonase activity, potentially relevant to PON1 physiology, after the consumption of ordinary meals are unknown. Herein we evaluated postprandial serum lipid levels and PON1 changes following mixed-meal consumption of the amounts recommended for ordinary meals.Methods: Nine healthy male volunteers consumed three different meals in a randomized cross-over design. The test meals were as follows: S, white rice; SMF, S with fat-containing protein-rich main dishes; and SMFV: SMF with vegetable dishes. The serum lipid concentrations and PON1 lactonase and arylesterase activities were determined during a three-hour period after the consumption of these meals.Results: The postprandial triglyceride levels were higher after consuming the SMF and SMFV meals than after consuming the S meal. Despite postprandial high-density lipoprotein cholesterol being unchanged, PON1 lactonase activity was decreased, while PON1 arylesterase activity was increased in the postprandial state after all test meals. Postprandial changes in lactonase and arylesterase activities did not differ among the test meals.Conclusions: Inverse changes in PON1 lactonase and arylesterase activities were observed after consuming recommended ordinary meals. This observation provides useful information for choosing PON1 species as postprandial markers

Changes on the Physiological Lactonase Activity of Serum Paraoxonase 1 by a Diet Intervention for Weight Loss in Healthy Overweight and Obese Women

Low caloric diet (LCD) is used for weight loss. Paraoxonase 1 (PON-1) is associated with the antioxidant functions of high-density lipoprotein (HDL). Among limited data on the relationships between obesity and PON-1, there has been no study on the effects of a stand-alone LCD on the physiological lactonase activity of PON-1. We investigated the prospective effects of LCD intervention (2 months) for weight loss on serum PON-1 activities (lactonase, arylesterase [mono-esterase] and tri-esterase) and HDL cholesterol (HDL-C), and their association with low-density lipoprotein cholesterol (LDL-C) in overweight and non-morbidly obese but otherwise healthy women (n = 30; mean age, 50.3 years; mean body mass index [BMI], 28.5 kg/m2). In addition to the data such as BMI, blood pressure, blood glucose and lipids, PON-1 activities were examined between pre- and post-intervention. The intervention reduced all metabolic outcomes, and PON-1 lactonase activity (determined with 5-[thiobutyl]butyrolactone) significantly decreased by 6.1%, paralleled by arylesterase (by 7.3%) and tri-esterase (by 7.8%). In multiple regression analysis, the percent change of PON-1 lactonase was significantly, positively and independently correlated to that of LDL-C (β = 0.51), HDL-C (β = 0.40), and BMI (β = 0.37). Our results showed that the solo diet treatment on weight loss might reduce serum PON-1 lactonase activity with reduced HDL-C and LDL-C. The relationship between the lactonase and LDL-C may be adaptive, plausibly hypothesizing less need for PON-1 activity as an antioxidant property to protect lipoproteins. Further research is needed to confirm this prediction

Serum aspirin esterase is strongly associated with glucose and lipids in healthy subjects: different association patterns in subjects with type 2 diabetes mellitus

<p>Abstract</p> <p>Background</p> <p>Aspirin esterase (AE) activity can account for part of aspirin pharmacokinetics in the circulation, possibly being associated with the impairment of aspirin effectiveness as an inhibitor of platelet aggregation.</p> <p>Aims</p> <p>The study was aimed at investigating the correlations of serum AE activity with cholinesterase (ChE) and metabolic variables in healthy subjects in comparison to subjects with type 2 diabetes mellitus (T2DM).</p> <p>Methods</p> <p>In cardiovascular disease-free T2DM subjects and healthy controls, the AE activity levels and/or the correlation patterns between AE and the other variables were analyzed.</p> <p>Results</p> <p>Neither AE nor ChE activities were higher in the subjects with T2DM. Serum AE activity strongly correlated with ChE as well as glucose/lipids variables such as total cholesterol and triglyceride in healthy subjects, while the correlations between AE and glucose/lipids variables were not present in T2DM subjects.</p> <p>Conclusions</p> <p>These data may reflect the pathophysiological changes between healthy and T2DM subjects. Our data may thus provide the basis for future studies to unravel the mechanisms.</p