Sugar and Dyslipidemia: A Double-Hit, Perfect Storm.

The availability of sugar has expanded over the past 50 years, due to improved industrial processes and corn subsidies, particularly in the form of sweetened beverages. This correlates with a surge in the prevalence of cardiometabolic disorders, which has brought this issue back into the spotlight for public health. In this narrative review, we focus on the role of fructose in the genesis of cardiometabolic dyslipidemia (an increase in serum triglyceride-rich lipoproteins (TRL): VLDL, chylomicrons (CM), and their remnants) bringing together the most recent data on humans, which demonstrates the crucial interaction between glucose and fructose, increasing the synthesis while decreasing the catabolism of these particles in a synergistic downward spiral. After reviewing TRL metabolism, we discuss the fundamental principles governing the metabolism of fructose in the intestine and liver and the effects of dysregulated fructolysis, in conjunction with the activation of carbohydrate-responsive element-binding protein (ChREBP) by glucose and the resulting crosstalk. The first byproduct of fructose catabolism, fructose-1-P, is highlighted for its function as a signaling molecule that promotes fat synthesis. We emphasize the role of fructose/glucose interaction in the liver, which enhances de novo lipogenesis, triglyceride (TG) synthesis, and VLDL production. In addition, we draw attention to current research that demonstrates how fructose affects the activity of lipoprotein lipase by increasing the concentration of inhibitors such as apolipoprotein CIII (apoCIII) and angiopoietin-like protein 3 (ANGPTL3), which reduce the catabolism of VLDL and chylomicrons and cause the building up of their atherogenic remnants. The end outcome is a dual, synergistic, and harmful action that encourages atherogenesis. Thus, considering the growing concerns regarding the connection between sugar consumption and cardiometabolic disease, current research strongly supports the actions of public health organizations aimed at reducing sugar intake, including dietary guidance addressing "safe" limits for sugar consumption.

Paraoxonase 1 Activity and Renal Replacement Therapy for Chronic Renal Failure: A Meta-Analysis.

Chronic renal failure (CRF) is associated with the development of cardiovascular disease (CVD). Paraoxonase 1 (PON1), an antioxidant enzyme, shows cardioprotective properties and has been proposed as a therapeutic marker for CRF. A systematic analysis of the literature assessing the association between PON1 activity and renal replacement therapy (RRT) of CRF is currently lacking. Therefore, we set out to perform a meta-analysis of the available data on PON1 in RRT of CRF. We searched three electronic databases for studies on PON1 activity in CRF patients with RRT such as hemodialysis (HD), peritoneal dialysis (PD), or renal transplantation (RTx), published before June 2023. A random-effects and network meta-analysis were performed. A total of 53 studies were eligibly identified. Compared to CRF patients without RRT, RTx patients had higher paraoxonase activity (standard mean difference (SMD), 1.76, 95% confidence interval (CI), 0.76-2.75), followed by HD (SMD, 0.73; 95% CI, 0.02-1.45) and PD patients. Likewise, RTx patients had higher arylesterase activity (SMD, 1.84, 95% CI, 0.18-3.50), followed by HD and PD patients. Also, paraoxonase activity was increased after HD (SMD, 0.59, 95% CI, 0.16-1.03). In conclusion, the overall data demonstrated that PON1 activity is higher in CRF patients with RRT, particularly RTx, followed by that of HD and PD. Measuring PON1 activity can also be included to the paraclinical toolbox for the management of RRT, in addition to the understanding of CRF-related pathophysiology. Regarding the selection of RRT types and their potential to prevent CVD, more research is required.

Triglyceride-Rich Lipoprotein Metabolism: Key Regulators of Their Flux.

The residual risk for arteriosclerotic cardiovascular disease after optimal statin treatment may amount to 50% and is the consequence of both immunological and lipid disturbances. Regarding the lipid disturbances, the role of triglyceride-rich lipoproteins (TRLs) and their remnants has come to the forefront in the past decade. Triglycerides (TGs) stand as markers of the remnants of the catabolism of TRLs that tend to contain twice as much cholesterol as compared to LDL. The accumulation of circulating TRLs and their partially lipolyzed derivatives, known as "remnants", is caused mainly by ineffective triglyceride catabolism. These cholesterol-enriched remnant particles are hypothesized to contribute to atherogenesis. The aim of the present narrative review is to briefly summarize the main pathways of TRL metabolism, bringing to the forefront the newly discovered role of apolipoproteins, the key physiological function of lipoprotein lipase and its main regulators, the importance of the fluxes of these particles in the post-prandial period, their catabolic rates and the role of apo CIII and angiopoietin-like proteins in the partition of TRLs during the fast-fed cycle. Finally, we provide a succinct summary of the new and old therapeutic armamentarium and the outcomes of key current trials with a final outlook on the different methodological approaches to measuring TRL remnants, still in search of the gold standard.

Beyond LDL: Understanding Triglyceride-Rich Lipoproteins to Tackle Residual Risk.

For the past 30 years, statin therapy has been the cornerstone for the reduction in the risk of atherosclerotic cardiovascular disease (ASCVD) [...].

Paraoxonase 1 and Chronic Kidney Disease: A Meta-Analysis.

Oxidative stress is known to be associated with the pathophysiology of chronic kidney disease (CKD). Paraoxonase 1 (PON1) is an antioxidant enzyme that has been proposed as a biomarker for CKD. While several studies have reported an association between serum PON1 activity and CKD, consensus based on systematically analyzed data remains necessary. We set out to conduct a meta-analysis of literature on PON1 in CKD. Electronic databases, such as MEDLINE, Embase and CENTRAL, were searched for available studies on PON1 activity in patients with CKD (without dialysis) as published before December 2022. A random-effects meta-analysis was performed. In total, 24 studies (22 studies on paraoxonase and 11 on arylesterase activity) were eligibly identified. Patients with CKD showed a lower activity of paraoxonase (standard mean difference [SMD], -1.72; 95% confidence interval [CI], -2.15 to -1.29) and arylesterase (SMD, -2.60; 95%CI, -3.96 to -1.24) than healthy controls. In the subgroup analyses, paraoxonase activity was lower in chronic kidney failure (CKF), an advanced stage of CKD, than in non-CKF. In summary, PON1 activity is low in patients with CKD, suggesting that the antioxidant defense by PON1 is impaired in CKD. The decrease in enzyme activity is pronounced in advanced CKD showing some variability depending on the substrate employed to measure PON1 activity. Further studies are warranted.

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.

Biomarkers of dysfunctional visceral fat.

Dysfunctional visceral fat plays a key role in the initiation and maintenance of chronic inflammation, liver steatosis and subsequent systemic insulin resistance that primes the body for development of metabolic syndrome. These changes, occurring with or without obesity, lead to type 2 diabetes. In this chapter, we first provide a brief overview of the factors that lead to dysfunctional visceral fat and their relative importance. Adipose tissue has a great plasticity which allows for cell hypertrophy and, when needed, angiogenesis to sustain hypertrophy. Due to the prevalence of inexpensive and widely available "junk food," i.e., those enriched in fat, carbohydrate and sugar, this response becomes maladaptive. Hypertrophied adipocytes become hypoxic. Some undergo necrosis which induces macrophage recruitment forming crown structures wherein macrophages and leukocytes surround injured adipocytes. This leads to the ominous triad: inflammation, fibrosis (extracellular matrix hypertrophy) and impaired angiogenesis as well as consequent unresolved hypoxia. Adipokines and cytokines secreted by these crown structures as well as the palmitate fluxes due to excessive lipolysis are released from visceral adipose tissue to portal blood. They inundate the liver causing insulin resistance. In this review we explore the actions of adipokines, proteins and macrophage cytokines (adiponectin, leptin, FABP4, resistin, PAI-1, ANGPT3/4, IL-6 and TNFα) that normally intervene but whose action goes awry in the presence of inflammation and insulin resistance. We provide an assessment of their relative clinical utility as well as challenges associated with their use as biomarkers.

Serum Fatty Acid-Binding Protein 4 Levels in Adolescents: Effect of Insulin Resistance.

Background: Fatty acid-binding protein 4 (FABP4) is an adipokine that plays a causative role in obesity and diabetes. In a stratified cross-sectional study with adolescents, we explored whether changes in FABP4 are already present in lean adolescents, provided they display elements of insulin resistance (IR). Methods: Adolescents were divided in four groups according to body mass index and homeostasis model assessment-IR. Results: In metabolically unhealthy lean (MUL) adolescents (MUL, lean with IR), FABP4 was 33% higher than in healthy counterparts (metabolically healthy lean [MHL]). Obese adolescents without IR (metabolically healthy obesity [MHO]) had 50% higher levels of FABP4 than their lean counterparts (MHL), while levels of FABP4 in obese adolescents with IR (metabolically unhealthy obese [MUO]) were 220% higher than those of MUL adolescents. The differences were significant at least with P < 0.005. MUO > MHO > MUL. Our data demonstrate that the known FABP4 defect in adults with obesity also occurs in youth and even in lean adolescents, suggesting an early association between impaired glucose metabolism and FABP4 irrespective of body weight. FABP4 was more sensitive in discerning each of our 4 subgroups than either adiponectin or leptin. Moreover, evidence for a putative early adiponectin resistance in MUL suggests a combined defect in these adolescents that call for early detection and prevention of the metabolic disturbance that should stay away from concentrating only in subjects with obesity. Conclusions: Our data may serve to draw the considerable attention that is currently paid to FABP4 to the adolescent population, irrespective of the presence of obesity. Further studies with larger cohorts and analyses of visceral and liver fat are warranted.

Larrea divaricata: anti-inflammatory and antioxidant effects of on macrophages and low density lipoproteins.

BACKGROUND: The oxidized low density lipoprotein (ox-LDL) contributes to inflammation and oxidative stress through the activation of macrophages under hyperglycemia contributing to the development of diabetes mellitus and to atherosclerosis. Plants are a source of effective and innocuous antioxidants. Larrea divaricata Cav. (Zygophyllaceae) is used in Argentina folk medicine for its anti-inflammatory properties. METHODS: The aim of this work was to study the antioxidant and anti-inflammatory effects of the aqueous extract (AE) of L. divaricata on macrophages under glucose stimulation and on human LDL and HDL particles under free radical generators. RESULTS: AE reduced the lipid peroxidation (17%), nitric oxide (NO) (47-50%), tumor necrosis factor-α (TNF-α) (32%) and free radicals (50%) induced by glucose on macrophages. Also prevented HDL nitration (28%), thus preserving its function and structure and inhibited LDL oxidation. The effect on the nitrosative stress was mainly driven by nordihydroguaiaretic acid (NDGA). CONCLUSIONS: These results suggest a potential usefulness of AE as an adjuvant phytotherapy in patients with diabetes mellitus and atherosclerosis.

Optimized sensitive and inexpensive method to measure D-lactate as a surrogate marker of methylglyoxal fluxes in metabolically relevant contexts.

INTRODUCTION: Plasma D-lactate levels can be considered a surrogate indicator of MG flux. There are commercial methods specifically designed to cover pathological ranges (mmol/l in sepsis or leaky gut) that are not suitable to encompass the metabolically relevant ranges. MATERIAL AND METHODS: We modified and optimized the D-lactate Colorimetric Assay kit MAK058 from Sigma adding an ultracentrifugation step, kinetic reading and increasing reaction temperature. RESULTS AND CONCLUSIONS: We present a modified, optimized and validated method to measure serum D-lactate using a commercial kit to increase the sensitivity of the method to 2 orders of magnitude lower as well as minimizing interferences so that it may be used by researchers to explore the D-lactate pathway in metabolic disorders at a low cost (colorimetric method and a plate reader) and with a much higher specificity.

Lean adolescents with insulin resistance display higher angiopoietin like protein 3, ApoC-III and chylomicron remnant dyslipidemia.

BACKGROUND: Triglyceride-rich lipoproteins (TRL: chylomicrons and VLDL) are a key component of diabetes dyslipoproteinemia and cardiovascular risk. We have shown that it is already prevalent in obese adolescents in association with lipoprotein lipase (LPL) dysregulation. Insulin resistance (IR) suffices to produce TRL dyslipoproteinemia and LPL dysfunction even in the absence of obesity. METHODS: This cross-sectional study included euglycemic adolescents between 15 and 19 y, classified in 4 groups according to BMI, HOMA-IR and fasting lipid as: metabolically healthy lean (MHL, n = 30), metabolically unhealthy lean (MUL, n = 25), metabolically healthy obese (MHO, = 30), and metabolically unhealthy obese (MUO, n = 42). RESULTS: As compared to MHL, MUL participants showed 73% higher concentrations of ApoB-48; 84% of ApoC-III; 24% ANGPTL-3; 200% of TG; 218% of VLDL-C and 238% of TG/HDL-C c, No changes were found in LPL mass. Interestingly, the differences in these parameters between MUL and MHO were not significant. CONCLUSION: Euglycemic lean adolescents with IR display TRL dyslipoproteinemia with increased inhibition of LPL as highlighted by higher concentrations of ANGPTL-3, ApoC-III and fasting chylomicron remnants (ApoB-48).

Paraoxonase 1 and Chronic Obstructive Pulmonary Disease: A Meta-Analysis.

Oxidative stress is a driving factor in the pathophysiology of chronic obstructive pulmonary disease (COPD). While paraoxonase 1 (PON1) is an antioxidant enzyme and a potential biomarker of this disease, data regarding the status of PON-1 in COPD are inconclusive. In this regard, to shed light on this issue, we performed a meta-analysis of data on PON1 activity in COPD. Electronic databases (MEDLINE, Embase and CENTRAL) were searched for available studies on PON1 activity in patients with stable COPD published before October 2021. A meta-analysis was performed using random-effects models. Twelve studies (12 studies on paraoxonase and three on arylesterase) were identified. Patients with COPD had lower levels of paraoxonase activity (standard mean difference [SMD] -0.77, 95% confidence interval [CI] -1.35 to -0.18) and arylesterase activity (SMD -1.15, 95% CI -1.95 to -0.36) in comparison to healthy controls. In subgroup analyses, paraoxonase activity was lower in patients of studies as consisted of mainly non-severe COPD (SMD -1.42, 95% CI -2.04 to -0.79) and, by contrast, slightly higher in patients of studies including severe COPD (SMD 0.33, 95% CI 0.02 to 0.64) in comparison to healthy controls. Arylesterase activity showed a similar trend. Overall, PON1 activity was lower in patients with COPD, suggesting that PON1-related antioxidant defense is impaired in COPD. Future studies are warranted.

Higher Hepcidin Levels in Adolescents with Obesity Are Associated with Metabolic Syndrome Dyslipidemia and Visceral Fat.

Tightly regulated iron metabolism prevents oxidative stress. Hepcidin is a hormone that regulates iron flow in plasma; its production is induced by an iron overload and by inflammation. It inhibits iron entry into the circulation by blocking dietary absorption in the duodenum, the release of recycled iron from macrophages and the exit of stored iron from hepatocytes. Varied signals responding to iron stores, erythropoietic activity and host defense converge to regulate hepcidin production and thereby affect iron homeostasis. Although it is known that hepcidin increases when interleukin 6 (IL-6) increases, the relationship between hepcidin, dyslipidemia, insulin resistance (IR) and visceral adiposity index (VAI) in adolescents with obesity is unclear. In this cross-sectional study of 29 obese adolescents and 30 control subjects, we explored the difference of hepcidin, iron metabolism markers and IL-6 between obese and non-obese adolescents, and identified associations with inflammation, atherogenic dyslipidemia and IR. As compared to lean controls, obese participants showed 67% higher hepcidin: 14,070.8 ± 7213.5 vs. 8419.1 ± 4826.1 pg/mLc; 70% higher ferritin: 94.4 ± 82.4 vs. 55.1 ± 39.6 pg/mLa and 120% higher IL-6: 2.0 (1.1-4.9) vs. 0.9 (0.5-1.3) pg/mLd. Transferrin, soluble transferrin receptor and total body iron (as measured by sTFR/ferritin, log10 sTFR/ferritin ratio and sTFR/log ferritin ratios) were not different between the two cohorts. In the whole cohort, hepcidin correlated with VAI (r = 0.29a), sd-LDL (r = 0.31b), HOMA-IR (r = 0.29a) and IL-6 (r = 0.35c). In obese adolescents hepcidin correlated with TG (r = 0.47b), VLDL-C (r = 0.43b) and smaller LDL2 (r = 0.39a). Hepcidin elevation in adolescents with obesity is linked more to inflammation and metabolic alterations than to iron metabolism since the other markers of iron metabolism were not different between groups, except for ferritin. Studies addressing the long-term effects of higher hepcidin levels and their impact on subclinical anemia and iron status are warranted. a p < 0.05; b p < 0.01, c p < 0.001 dp < 0.0001.

Paraoxonase 1 and Non-Alcoholic Fatty Liver Disease: A Meta-Analysis.

Oxidative stress is involved in the pathophysiology of nonalcoholic fatty liver disease (NAFLD). However, reliable biomarkers of NAFLD in relation to oxidative stress are not available. While paraoxonase 1 (PON1) is an antioxidant biomarker, there appears to be mixed data on PON-1 in patients with NAFLD. The aim of this meta-analysis was to assess the current data on PON1 activity (i.e., paraoxonase and arylesterase) in patients with NAFLD. A PubMed, CENTRAL, and Embase search identified 12 eligible articles. In the meta-analysis, the paraoxonase activity was low in patients with NAFLD (mean difference (MD) -27.17 U/L; 95% confidence interval (CI) -37.31 to -17.03). No difference was noted in the arylesterase activity (MD 2.45 U/L; 95% CI -39.83 to 44.74). In a subgroup analysis, the paraoxonase activity was low in biopsy-proven nonalcoholic steatohepatitis (MD -92.11 U/L; 95% CI -115.11 to -69.11), while the activity in NAFLD as diagnosed by ultrasonography or laboratory data was similar (MD -2.91 U/L; 95% CI -11.63 to 5.80) to that of non-NAFLD. In summary, the PON1, especially paraoxonase, activity could be a useful biomarker of NAFLD. Further studies are warranted to ascertain the relevance of PON1 measurements in patients with NAFLD.

Reduction of small dense LDL and Il-6 after intervention with Plantago psyllium in adolescents with obesity: a parallel, double blind, randomized clinical trial.

Obesity can lead children and adolescents to an increased cardiovascular disease (CVD) risk. A diet supplemented with Plantago psyllium has been shown to be effective in reducing LDL-C and IL-6 in adolescents. However, there are no studies that have explored small-dense LDL (sdLDL) or HDL subclasses. The aim of this study was to evaluate the impact of a fiber dietary intervention on LDL and HDL subclasses in adolescents with obesity. In this parallel, double blind, randomized clinical trial, the participants were assigned to Plantago psyllium or placebo (10g/day for 7 weeks). We randomized 113 participants, and evaluated and analyzed 100 adolescents (50 in each group), 15 to 19 years with a body mass index of 29-34. We measured biochemical markers LDL and HDL subclasses using the Lipoprint system (Quantimetrix) and IL-6 by ELISA. Post-treatment there was a decrease in sdLDL between the groups 2.0 (0-5.0) vs 1 (0-3.0) mg/dl (p = 0.004), IL-6 median 3.32 (1.24-5.96) vs 1.76 (0.54-3.28) pg/ml, p <0.0001. There were no differences in HDL subclasses and no adverse effects were reported in either group.Conclusions: Small dense LDL and IL-6 reduced in adolescents with obesity when consuming Plantago psyllium. This may be an early good strategy for the reduction of cardiovascular disease risk in this vulnerable population.Trial registration: ISRCTN # 14180431. Date assigned 24/08/2020 What is Known: • Supplementing the diet with Plantago psyllium lowers LDL-C levels. What is New: • First evidence that soluble fiber supplementation like Plantago psyllium decreases small dense LDL particles in association with lowered IL-6, reducing the risk of cardiovascular disease in obese adolescents.