Lipidomics Reveals Myocardial Lipid Composition in a Murine Model of Insulin Resistance Induced by a High-Fat Diet.

Ectopic fat accumulation in non-adipose tissues is closely related to diabetes-related myocardial dysfunction. Nevertheless, the complete picture of the lipid metabolites involved in the metabolic-related myocardial alterations is not fully characterized. The aim of this study was to characterize the specific lipid profile in hearts in an animal model of obesity/insulin resistance induced by a high-fat diet (HFD). The cardiac lipidome profiles were assessed via liquid chromatography-mass spectrometry (LC-MS)/MS-MS and laser desorption/ionization-mass spectrometry (LDI-MS) tissue imaging in hearts from C57BL/6J mice fed with an HFD or standard-diet (STD) for 12 weeks. Targeted lipidome analysis identified a total of 63 lipids (i.e., 48 triacylglycerols (TG), 5 diacylglycerols (DG), 1 sphingomyelin (SM), 3 phosphatidylcholines (PC), 1 DihydroPC, and 5 carnitines) modified in hearts from HFD-fed mice compared to animals fed with STD. Whereas most of the TG were up-regulated in hearts from animals fed with an HFD, most of the carnitines were down-regulated, thereby suggesting a reduction in the mitochondrial ß-oxidation. Roughly 30% of the identified metabolites were oxidated, pointing to an increase in lipid peroxidation. Cardiac lipidome was associated with a specific biochemical profile and a specific liver TG pattern. Overall, our study reveals a specific cardiac lipid fingerprint associated with metabolic alterations induced by HFD.

The Lipoprotein Profile Evaluated by 1H-NMR Improves the Performance of Genetic Testing in Familial Hypercholesterolemia.

BACKGROUND: The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants. METHODS: We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug wash-out of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort. RESULTS: A formula derived from NMR lipoprotein analyses improved the identification of genetically positive FH patients beyond LDL-C levels (AUC=0.87). The parameters contributing the most to the identification formula were LDL particle number, HDL size and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation. CONCLUSIONS: NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients.

Impact of PCSK9 inhibitors in glycaemic control and new-onset diabetes.

BACKGROUND: The diabetogenic effect of statins has been well established by clinical trials, Mendelian randomisation studies and meta-analyses. According to large clinical trials, PCSK9 inhibitors (PCSK9i) have no deleterious impact on glucose metabolism. However, few real-life studies have yet evaluated the long-term effects of these drugs on glucose homeostasis and their impact on new-onset diabetes (NODM). METHODS: We studied 218 patients treated with either alirocumab or evolocumab (70% with familial hypercholesterolemia) for at least three years (PCSK9iG). We studied the NODM rate in the nondiabetic group at baseline (168) and overall glucose metabolism control in the whole group. Incidental DM was compared with two groups. The first was a propensity score matching (PSM)-selected group (n = 168) from the database of patients attending the Reus lipid unit (Metbank, n = 745) who were not on PCSK9i (PSMG). The second was a subgroup with a similar age range (n = 563) of the Di@bet.es study (Spanish prospective study on diabetes development n = 5072) (D@G). The incidence was reported as the percentage of NODM cases per year. RESULTS: The fasting glucose (FG) level of the subjects with normoglycaemia at baseline increased from 91 (86-95.5) to 93 (87-101) mg/dL (p = 0.014). There were 14 NODM cases in the PCSK9i group (2.6%/y), all among people with prediabetes at baseline. The incidence of NODM in PSMG and D@G was 1.8%/y (p = 0.69 compared with the PCSK9iG). The incidence among the subjects with prediabetes was 5.1%/y in the PCSK9iG, 4.8%/y in the PSMG and 3.9%/y in the D@G (p = 0.922 and p = 0.682, respectively). In the multivariate analysis, only the FG level was associated with the development of NODM in the PCSK9iG (OR 1.1; 95% CI: 1.0-1.3; p = 0.027). Neither FG nor A1c levels changed significantly in patients with DM at baseline. CONCLUSION: A nonsignificant increase in NODM occurred in the PCSK9iG, particularly in patients with prediabetes, compared with the PSMG and D@G groups. Baseline FG levels were the main variable associated with the development of DM. In the subjects who had DM at baseline, glucose control did not change. The impact of PCSK9i on glucose metabolism should not be of concern when prescribing these therapies.

Lipidomics of triglyceride-rich lipoproteins derived from hyperlipidemic patients on inflammation.

BACKGROUND AND AIM: Triglyceride-rich lipoproteins (TRLs) can have an important role in atherosclerosis development due to their size and ability to penetrate the endothelium. While high plasma triglyceride (TG) levels and chronic inflammation are relevant in metabolic diseases, it remains unclear whether TGs are atherogenic or which TRL-TG-derived metabolites are responsible for inflammation. Here, we aimed to study the lipidome modifications of TRL particles enriched in TG in patients with hyperlipidemia and their associations with a proinflammatory status both in vivo and in vitro. METHODS: Using proton nuclear magnetic resonance (1 H-NMR), we analysed the plasma levels of glycoprotein acetyls and the TRL lipidomic profile of 307 patients with dyslipidemia. THP-1-derived macrophages were used as an in vitro model to explore the molecular inflammatory effects mediated by TRL. RESULTS: In vivo, higher TRL-TG levels were associated with higher circulating levels of NMR-measured glycoproteins (Glyc-A, Glyc-B and Glyc-F; p < .001). Lipidomic analysis showed that TRL-TG enrichment led to decreased cholesterol and phospholipid content (p < .01), an increase in omega-9, and a decrease in saturated fatty acids (p < .001). THP-1 macrophages exposed to increasing TRL particle concentrations augmented the secretion of IL-1ß and TNF-α, which varied based on particle composition. Particles with higher cholesterol and phospholipid contents exerted higher cytokine secretion. The activation of MAPK, Akt/NFκB, and caspase-1 was concurrent with this proinflammatory response. CONCLUSIONS: High TRL-TG levels are associated with a higher systemic inflammatory status and increased particle concentrations. In vitro, higher particle numbers increase proinflammatory cytokine secretion, with cholesterol and phospholipid-rich TRL being more proinflammatory.

Plasma Expression of Carotid Plaque Presence-Related MicroRNAs Is Associated with Inflammation in Patients with Rheumatoid Arthritis.

Rheumatoid arthritis (RA) is associated with problems beyond the joints such as cardiovascular (CV) disease. MicroRNA-24, -146 and -Let7a are associated with carotid plaque presence in RA patients. We evaluated whether these microRNAs were involved in the inflammatory state of RA, and we studied their gene targets to understand their role in inflammation and atherosclerosis. A total of 199 patients with RA were included. Inflammatory variables such as disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR) were quantified. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were used for analysis. The multivariate models showed that diminished expression of microRNA-146 was associated with inferior levels of DAS28-ESR, and the decreased expression of microRNA-24, -146 and -Let7a were associated with lowered ESR in the overall cohort. When microRNAs were evaluated globally, a global increase was associated with increased DAS28-ESR and ESR in the overall cohort. Sex-stratified analyses showed different associations of these microRNAs with the inflammatory variables. Finally, random forest models showed that microRNAs have a pivotal role in classifying patients with high and low inflammation. Plasmatic expressions of microRNA-24, -146 and -Let7a were associated with inflammatory markers of RA. These microRNAs are associated with both inflammation and atherosclerosis and are potential therapeutic targets for RA.

Serum branch-chained amino acids are increased in type 2 diabetes and associated with atherosclerotic cardiovascular disease.

BACKGROUND AND AIM: Circulating biomarkers of metabolic and cardiovascular diseases can help in the early detection and prevention of those diseases. Using proton nuclear magnetic resonance (1H-NMR), we aimed to study the plasma levels of low-molecular-weight metabolites (LMWMs) in a cohort of 307 patients with metabolic diseases to assess their relationships with type-2 diabetes (T2D) and incident atherosclerotic cardiovascular disease (ASCVD). METHODS: We conducted a cross-sectional and prospective study. We included 307 patients attending the Lipid Unit of our University Hospital for the treatment of the following metabolic disturbances and associated disorders: T2D (73.9%), obesity (58.7%), and hypertension (55.1%). 1H-NMR was used to study the plasma levels of 13 LMWMs. LMWM serum concentrations were evaluated in patients with and without T2D. and the correlations with several parameters and their associations with T2D were analyzed. The association between LMWM levels at baseline and the development of ASCVD in patients with T2D after 10 years of follow-up was also evaluated. RESULTS: Among the LMWMs measured, the branched-chain amino acids (BCAAs) valine, leucine and isoleucine showed a positive association with several clinical and lipid-related biochemical parameters and inflammatory markers (p < 0.05). Likewise, these three BCAAS were associated with diabetes even after adjusting for covariates (p < 0.05). During the follow-up period of 10 years, 29 of the 185 patients with diabetes at baseline (15.68%) developed ASCVD. After adjusting for clinical covariates, baseline levels of valine and alanine were associated with the development of ASCVD (p < 0.05). CONCLUSION: Overall, our results indicated that plasma levels of LMWMs measured by 1H-NMR could be potential biomarkers associated with T2D. Moreover, alanine and valine can help in the early detection of the cardiovascular risk associated with this metabolic disease.

Economic Burden Associated with the Treatment with a Cardiovascular Polypill in Secondary Prevention in Spain: Cost-Effectiveness Results of the NEPTUNO Study.

Purpose: The aim of this study was to estimate health-care resources utilization, costs and cost-effectiveness associated with the treatment with CNIC-Polypill as secondary prevention of atherosclerotic cardiovascular disease (ASCVD) compared to other treatments, in clinical practice in Spain. Patients and Methods: An observational, retrospective study was performed using medical records (economic results [healthcare perspective], NEPTUNO-study; BIG-PAC-database) of patients who initiated secondary prevention between 2015 and 2018. Patients were followed up to 2 years (maximum). Four cohorts were balanced with a propensity-score-matching (PSM): 1) CNIC-Polypill (aspirin+atorvastatin+ramipril), 2) Monocomponents (same separate drugs), 3) Equipotent (equipotent drugs) and 4) Other therapies ([OT], other cardiovascular drugs). Incidence of cardiovascular events, health-care resources utilization and healthcare and non-healthcare costs (2020 Euros) were compared. Incremental cost-effectiveness ratios per cardiovascular event avoided were estimated. Results: After PSM, 1614 patients were recruited in each study cohort. The accumulated incidence of cardiovascular events during the 24-month follow-up was lower in the CNIC-Polypill cohort vs the other cohorts (19.8% vs Monocomponents: 23.3%, Equipotent: 25.5% and OT: 26.8%; p<0.01). During the follow-up period, the CNIC-Polypill cohort also reduced the health-care resources utilization per patient compared to the other cohorts, particularly primary care visits (16.6 vs Monocomponents: 18.7, Equipotent: 18.9 and OT: 21.0; p<0.001) and hospitalization days (2.3 vs Monocomponents: 3.4, Equipotent: 3.7 and OT: 4.0; p<0.001). The treatment cost in the CNIC-Polypill cohort was lower than that in the other cohorts (€4668 vs Monocomponents: €5587; Equipotent: €5682 and OT: €6016; p<0.001) (Difference: -€919, -€1014 and -€1348, respectively). Due to the reduction of cardiovascular events and costs, the CNIC-Polypill is a dominant alternative compared to the other treatments. Conclusion: CNIC-Polypill reduces recurrent major cardiovascular events and costs, being a cost-saving strategy as secondary prevention of ASCVD.

NMR-based metabolomic profiling identifies inflammation and muscle-related metabolites as predictors of incident type 2 diabetes mellitus beyond glucose: The Di@bet.es study.

AIMS: The aim of this study was to combine nuclear magnetic resonance-based metabolomics and machine learning to find a glucose-independent molecular signature associated with future type 2 diabetes mellitus development in a subgroup of individuals from the Di@bet.es study. METHODS: The study group included 145 individuals developing type 2 diabetes mellitus during the 8-year follow-up, 145 individuals matched by age, sex and BMI who did not develop diabetes during the follow-up but had equal glucose concentrations to those who did and 145 controls matched by age and sex. A metabolomic analysis of serum was performed to obtain the lipoprotein and glycoprotein profiles and 15 low molecular weight metabolites. Several machine learning-based models were trained. RESULTS: Logistic regression performed the best classification between individuals developing type 2 diabetes during the follow-up and glucose-matched individuals. The area under the curve was 0.628, and its 95% confidence interval was 0.510-0.746. Glycoprotein-related variables, creatinine, creatine, small HDL particles and the Johnson-Neyman intervals of the interaction of Glyc A and Glyc B were statistically significant. CONCLUSIONS: The model highlighted a relevant contribution of inflammation (glycosylation pattern and HDL) and muscle (creatinine and creatine) in the development of type 2 diabetes as independent factors of hyperglycemia.

Lipid lowering combination therapy: From prevention to atherosclerosis plaque treatment.

Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of statins is mainly mediated by the lowering of LDLc. According to scientific evidence, the current international guidelines recommend very low LDLc goals in patients at high/very high cardiovascular risk because they are associated with fewer CV events and improvements in atherosclerotic plaques. However, these goals often cannot be obtained with statins alone. Recent RCTs have demonstrated that these CV benefits can also be obtained with nonstatin LDLc-lowering drugs such as PCSK9 inhibitors (alirocumab and evolocumab), ezetimibe and bempedoic acid, while evidence with inclisiran is upcoming. Icosapent ethyl, a lipid metabolism modifier, has also shown an effect on event reduction. Physicians should take advantage of the currently available lipid-lowering therapies, choosing the drug or combination of drugs that is most appropriate for each patient according to his or her CV risk and baseline LDLc concentration. Strategies implementing combination therapies from early stages or even from the outset may increase the number of patients attaining LDLc goals, thereby preventing new CV episodes and improving existing atherosclerotic lesions.

Fatty Acid Binding Proteins 3 and 4 Predict Both All-Cause and Cardiovascular Mortality in Subjects with Chronic Heart Failure and Type 2 Diabetes Mellitus.

Subjects with type 2 diabetes mellitus (T2D) are at increased risk for heart failure (HF). The cardiac-specific (FABP3) and adipose-tissue-specific (FABP4) types of the fatty acid binding proteins have been associated with both all-cause and cardiovascular (CV) mortality. The aim of this study was to explore the prognosis value of FABP3 and FABP4 in ambulatory subjects with chronic HF (CHF), with and without T2D. A prospective study involving 240 ambulatory CHF subjects was performed. Patients were followed-up for a mean of 5.78 ± 3.30 years and cause of death (if any) was recorded. Primary endpoints were defined as all-cause and CV death, and a composite endpoint that included CV death or hospitalization for HF was included as a secondary endpoint. Baseline serum samples were obtained and the serum FABP3 and FABP4 concentrations were assessed by sandwich enzyme-linked immunosorbent assay. Survival analysis was performed with multivariable Cox regressions, using Fine and Gray competing risks models when needed, to explore the prognostic value of FABP3 and FABP4 concentrations, adjusting for potential confounders. Type 2 diabetes mellitus was highly prevalent, accounting for 47.5% for total subjects with CHF. Subjects with T2D showed higher mortality rates (T2D: 69.30%; non-T2D: 50.79%, p = 0.004) and higher serum FABP3 (1829.3 (1104.9-3440.5) pg/mL vs. 1396.05 (820.3-2362.16) pg/mL, p = 0.007) and FABP4 (45.5 (27.6-79.8) ng/mL vs. 34.1 (24.09-55.3) ng/mL, p = 0.006) concentrations compared with non-T2D CHF subjects. In the whole study cohort, FABP3 was independently associated with all-cause death, and both FABP3 and FABP4 concentrations were associated with CV mortality. The predictive values of these two molecules for all-cause (FABP3: HR 1.25, 95% CI 1.09-1.44; p = 0.002. FABP4: HR 2.21, 95% CI 1.12-4.36; p = 0.023) and CV mortality (FABP3: HR 1.28, 95% CI 1.09-1.50; p = 0.002. FABP4: HR 4.19, 95% CI 2.21-7.95; p < 0.001) were only statistically significant in the subgroup of subjects with T2D. Notably, FABP4 (HR 2.07, 95% CI 1.11-3.87; p = 0.022), but not FABP3, also predicted the occurrence of the composite endpoint (death or hospitalization for HF) only in subjects with T2D. All these associations were not found in CHF subjects without T2D. Our findings support the usefulness of serum FABP3 and FABP4 concentrations as independent predictors for the occurrence of all-cause and CV mortality in ambulatory subjects with CHF with T2D.

PCSK9 Inhibitors Have Apolipoprotein C-III-Related Anti-Inflammatory Activity, Assessed by 1H-NMR Glycoprotein Profile in Subjects at High or very High Cardiovascular Risk.

Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.

Women with familial hypercholesterolemia phenotype are undertreated and poorly controlled compared to men.

Familial hypercholesterolemia (FH) is an autosomal dominant disease that has a prevalence of approximately 1/250 inhabitants and is the most frequent cause of early coronary heart disease (CHD). We included 1.343.973 women and 1.210.671 men with at least one LDL-c measurement from the Catalan primary care database. We identified 14.699 subjects with Familial hypercholesterolemia-Phenotype (FH-P) based on LDL-c cut-off points by age (7.033 and 919 women, and 5.088 and 1659 men in primary and secondary prevention, respectively). Lipid lower therapy (LLT), medication possession ratio (MPR) as an indicator of adherence, and number of patients that reached their goal on lipid levels were compared by sex. In primary and secondary prevention, 69% and 54% of women (P = 0.001) and 64% and 51% of men (P = 0.001) were on low-to-moderate-potency LLT. Adherence to LLT was reduced in women older than 55 years, especially in secondary prevention (P = 0.03), where the percentage of women and men with LDL-c > 1.81 mmol/L were 99.9% and 98.9%, respectively (P = 0.001). Women with FH-P are less often treated with high-intensity LLT, less adherent to LLT, and have a lower probability of meeting their LDL-c goals than men, especially in secondary prevention.

A panel of plasma microRNAs improves the assessment of surrogate markers of cardiovascular disease in rheumatoid arthritis patients.

OBJECTIVE: Patients with RA present increased risk of cardiovascular (CV) disease compared with the general population. Moreover, CV risk factors that have a causal relationship with atherosclerosis do not seem to fully explain the accelerated process that they exhibit. We evaluated the association of a 10 microRNAs panel with surrogate markers of subclinical arteriosclerosis [carotid intima-media thickness (cIMT), carotid plaque presence (cPP), pulse wave velocity (PWV) and distensibility] in a cohort of RA patients. MATERIAL AND METHODS: A total of 199 patients with RA were included. Surrogate markers of arteriosclerosis were measured with My Lab 60 X-Vision sonographer. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were performed. RESULTS: Multivariate models showed that microRNAs-24 (ß = 15.48), 125a (ß = 9.93), 132 (ß = 11.52), 146 (ß = 15.12), 191 (ß = 13.25) and 223 (ß = 13.30) were associated with cIMT globally. MicroRNA-24 [odds ratio (OR) = 0.41], 146 (OR = 0.36) and Let7a (OR = 0.23) were associated with cPP in men. Including the microRNAs in a partial least square discriminant analysis model properly classified men with and without cPP. MicroRNA-96 (ß = -0.28) was associated with PWV in male patients. Finally, several miRNAs were also associated with cIMT, cPP and arterial stiffness in the high DAS28 group and in the earlier tertile groups of disease duration. CONCLUSION: Plasmatic expression of microRNA-24, 96, 103, 125a, 132, 146, 191, 223 and Let7a were associated with surrogate markers of CV disease and could be predictors of CV risk in patients with RA.

Glycoprotein Serum Concentrations Assessed By 1H-NMR are Increased in Patients With High Blood Pressure.

BACKGROUND: Patients with hypertension present a permanent state of low-grade inflammation, as the disease activates several pro-inflammatory cells and inflammatory pathways. Glycoproteins A, B, and F, determined by proton nuclear magnetic resonance, provide a highly sensitive method for determining a group of liver-derived pro-inflammatory proteins, and their role has not yet been explored in patients with hypertension. In this study, we evaluated the impact of plasma concentrations of these glycoproteins in patients with hypertension. METHODS: This cross-sectional study involved 340 patients attending our vascular and metabolism medicine unit. Of them, 129 were normotensive and 211 were hypertensive. Standard biochemistry and carotid ultrasound measures were performed. Serum concentrations of glycoproteins A, B, and F were determined by proton nuclear magnetic resonance. RESULTS: Hypertensive patients presented a higher prevalence of obesity, metabolic syndrome, and diabetes and higher glycoprotein A, B, and F concentrations. Glycoproteins A, B, and F were positively correlated with systolic and diastolic blood pressure. Multivariate logistic models showed that glycoproteins A, B, and F were associated with higher odds of being hypertensive. Machine learning methods corroborated the relationship between glycoproteins and high blood pressure. The higher prevalence of carotid plaques in patients with high blood pressure was partially mediated by glycoproteins A and F. CONCLUSIONS: Patients with hypertension present systemic, subclinical inflammation as assessed by liver-derived glycoprotein A, B, and F serum levels. These results support the effect of hypertension on the mechanisms of systemic inflammation. Hypertension-associated systemic inflammation plays a role in hypertension-associated vascular injury and probably in hypertension-induced damage to other organs.

Unveiling the Role of the Fatty Acid Binding Protein 4 in the Metabolic-Associated Fatty Liver Disease.

Metabolic-associated fatty liver disease (MAFLD), the main cause of chronic liver disease worldwide, is a progressive disease ranging from fatty liver to steatohepatitis (metabolic-associated steatohepatitis; MASH). Nevertheless, it remains underdiagnosed due to the lack of effective non-invasive methods for its diagnosis and staging. Although MAFLD has been found in lean individuals, it is closely associated with obesity-related conditions. Adipose tissue is the main source of liver triglycerides and adipocytes act as endocrine organs releasing a large number of adipokines and pro-inflammatory mediators involved in MAFLD progression into bloodstream. Among the adipocyte-derived molecules, fatty acid binding protein 4 (FABP4) has been recently associated with fatty liver and additional features of advanced stages of MAFLD. Additionally, emerging data from preclinical studies propose FABP4 as a causal actor involved in the disease progression, rather than a mere biomarker for the disease. Therefore, the FABP4 regulation could be considered as a potential therapeutic strategy to MAFLD. Here, we review the current knowledge of FABP4 in MAFLD, as well as its potential role as a therapeutic target for this disease.

Patrón de metilación en ADN de sujetos hipertrigliceridémicos / DNA methylation pattern of hypertriglyceridemic subjects

ANTECEDENTES:Las quilomicronemias generalmente se diagnostican genéticamente mediante secuenciación genómica o cribado de mutaciones en genes causales con un gran efecto fenotípico. Esta estrategia ha permitido mejorar la caracterización de estos pacientes, pero aún tenemos un 30% de ellos sin un diagnóstico genético concluyente. Es por esto que hipotetizamos que añadiendo el componente epigenético podemos mejorar el diagnóstico genético y para ello hemos explorado el grado de metilación en el ADN de pacientes hipertrigliceridémicos. METODOLOGÍA: El ADN de células sanguíneas fue obtenido de 16 pacientes hipertrigliceridémicos y de 16 sujetos control emparejados por edad y sexo. El grado de metilación en el ADN de todo el genoma fue determinado mediante el Illumina® Infinium MethylationEPIC Array Analysis. RESULTADOS: Identificamos 31 citosinas diferencialmente metiladas al comparar los patrones de metilación que presentaban los pacientes hipertrigliceridémicos vs. los sujetos control. La cg03636183 en el gen F2RL3 estaba un 10% hipometilada en los pacientes hipertrigliceridémicos, y ha sido previamente asociada a un mayor riesgo cardiovascular. La cg13824500 está un 10% hipometilada en pacientes hipertrigliceridémicos y se localiza en VTI1A, que es un gen limitante en el tránsito de los quilomicrones en el enterocito a través del retículo endoplásmico y el aparato de Golgi. La cg26468118 en el gen RAB20 (13% hipometilada) y la cg21560722 en el gen SBF2 (33% hipermetilada) están implicadas en la regulación de vesículas del aparato de Golgi. CONCLUSIONES: Nuestros resultados evidencian que existen regiones diferencialmente metiladas relacionadas con la formación de los quilomicrones en pacientes hipertrigliceridémicos.

BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.

Glycoprotein and Lipoprotein Profiles Assessed by 1H-NMR and Its Relation to Ascending Aortic Dilatation in Bicuspid Aortic Valve Disease.

INTRODUCTION: The bicuspid aortic valve (BAV) confers a high risk of ascending aorta dilatation (AAoD), although its progression seems highly variable. Furthermore, the implication of lipoprotein metabolism and inflammation in the mechanisms that underlie AAoD is not fully established. The aim of this study consisted of evaluating the impact of the lipoprotein and glycoprotein profiles in AAOD as well as its progression in BAV aortopathy. METHODS: Using 1H-nuclear magnetic resonance (1H-NMR), we analyzed and compared the lipoprotein and glycoprotein profiles of plasma samples from 152 BAV patients with dilated and nondilated ascending aorta. Additionally, these profiles were also compared for 119 of these patients who were prospectively followed-up clinically and by echocardiography in the long-term (5 years). Ascending aorta dilation velocity (mm/year) was calculated for this analysis. RESULTS: Several parameters related to the lipoprotein profile including remnant cholesterol, small LDL and IDL-cholesterol were found to be significantly increased in the dilated group compared to those in the nondilated group. The glycoprotein A-nuclear magnetic resonance (NMR) signal, a novel inflammation biomarker, was also observed to be increased in the dilated group. After performing multivariate analysis, remnant cholesterol remained an independent variable related to AAoD. In the long-term follow-up, proatherogenic lipoprotein parameters were related to ascending aorta dilatation velocity ascending. After a lineal regression analysis, non-HDL particles remained as an independent predictor of ascending aorta dilation velocity. CONCLUSIONS: Patients with BAV and AAoD presented a more pro-atherogenic profile assessed by 1H-NMR, especially related to triglyceride-rich lipoproteins. This pro-atherogenic profile seems to contribute to the higher growth rate of ascending aorta diameter.

DNA methylation pattern of hypertriglyceridemic subjects. / Patrón de metilación en ADN de sujetos hipertrigliceridémicos.

BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.

Obesity Partially Mediates the Diabetogenic Effect of Lowering LDL Cholesterol.

OBJECTIVE: LDL cholesterol (LDLc)-lowering drugs modestly increase body weight and type 2 diabetes risk, but the extent to which the diabetogenic effect of lowering LDLc is mediated through increased BMI is unknown. RESEARCH DESIGN AND METHODS: We conducted summary-level univariable and multivariable Mendelian randomization (MR) analyses in 921,908 participants to investigate the effect of lowering LDLc on type 2 diabetes risk and the proportion of this effect mediated through BMI. We used data from 92,532 participants from 14 observational studies to replicate findings in individual-level MR analyses. RESULTS: A 1-SD decrease in genetically predicted LDLc was associated with increased type 2 diabetes odds (odds ratio [OR] 1.12 [95% CI 1.01, 1.24]) and BMI (ß = 0.07 SD units [95% CI 0.02, 0.12]) in univariable MR analyses. The multivariable MR analysis showed evidence of an indirect effect of lowering LDLc on type 2 diabetes through BMI (OR 1.04 [95% CI 1.01, 1.08]) with a proportion mediated of 38% of the total effect (P = 0.03). Total and indirect effect estimates were similar across a number of sensitivity analyses. Individual-level MR analyses confirmed the indirect effect of lowering LDLc on type 2 diabetes through BMI with an estimated proportion mediated of 8% (P = 0.04). CONCLUSIONS: These findings suggest that the diabetogenic effect attributed to lowering LDLc is partially mediated through increased BMI. Our results could help advance understanding of adipose tissue and lipids in type 2 diabetes pathophysiology and inform strategies to reduce diabetes risk among individuals taking LDLc-lowering medications.