The double burden: type 1 diabetes and heart failure-a comprehensive review.

Heart failure (HF) is increasing at an alarming rate, primary due to the rising in aging, obesity and diabetes. Notably, individuals with type 1 diabetes (T1D) face a significantly elevated risk of HF, leading to more hospitalizations and increased case fatality rates. Several risk factors contribute to HF in T1D, including poor glycemic control, female gender, smoking, hypertension, elevated BMI, and albuminuria. However, early and intensive glycemic control can mitigate the long-term risk of HF in individuals with T1D. The pathophysiology of diabetes-associated HF is complex and multifactorial, and the underlying mechanisms in T1D remain incompletely elucidated. In terms of treatment, much of the evidence comes from type 2 diabetes (T2D) populations, so applying it to T1D requires caution. Sodium-glucose cotransporter 2 inhibitors have shown benefits in HF outcomes, even in non-diabetic populations. However, most of the information about HF and the evidence from cardiovascular safety trials related to glucose lowering medications refer to T2D. Glycemic control is key, but the link between hypoglycemia and HF hospitalization risk requires further study. Glycemic variability, common in T1D, is an independent HF risk factor. Technological advances offer the potential to improve glycemic control, including glycemic variability, and may play a role in preventing HF. In summary, HF in T1D is a complex challenge with unique dimensions. This review focuses on HF in individuals with T1D, exploring its epidemiology, risk factors, pathophysiology, diagnosis and treatment, which is crucial for developing tailored prevention and management strategies for this population.

FTY720-P, a Biased S1PR Ligand, Increases Mitochondrial Function through STAT3 Activation in Cardiac Cells.

FTY720 is an FDA-approved sphingosine derivative drug for the treatment of multiple sclerosis. This compound blocks lymphocyte egress from lymphoid organs and autoimmunity through sphingosine 1-phosphate (S1P) receptor blockage. Drug repurposing of FTY720 has revealed improvements in glucose metabolism and metabolic diseases. Studies also demonstrate that preconditioning with this compound preserves the ATP levels during cardiac ischemia in rats. The molecular mechanisms by which FTY720 promotes metabolism are not well understood. Here, we demonstrate that nanomolar concentrations of the phosphorylated form of FTY720 (FTY720-P), the active ligand of S1P receptor (S1PR), activates mitochondrial respiration and the mitochondrial ATP production rate in AC16 human cardiomyocyte cells. Additionally, FTY720-P increases the number of mitochondrial nucleoids, promotes mitochondrial morphology alterations, and induces activation of STAT3, a transcription factor that promotes mitochondrial function. Notably, the effect of FTY720-P on mitochondrial function was suppressed in the presence of a STAT3 inhibitor. In summary, our results suggest that FTY720 promotes the activation of mitochondrial function, in part, through a STAT3 action.

Beneficial effects of olive oil and Mediterranean diet on cancer physio-pathology and incidence.

Virgin olive oil is a characteristic component and the main source of fat of the Mediterranean diet. It is a mix of high-value health compounds, including monounsaturated fatty acids (mainly oleic acid), simple phenols (such as hydroxytyrosol and tyrosol), secoiridoids (such as oleuropein, oleocanthal), flavonoids, and terpenoids (such as squalene). Olive oil consumption has been shown to improve different aspects of human health and has been associated with a lower risk of cancer. However, the underlying cellular mechanisms involved in such effects are still poorly defined, but seem to be related to a promotion of apoptosis, modulation of epigenetic patterns, blockade of cell cycle, and angiogenesis regulation. The aim of this review is to update the current associations of cancer risk with the Mediterranean diet, olive oil consumption and its main components. In addition, the identification of key olive oil components involved in anticarcinogenic mechanisms and pathways according to experimental models is also addressed.

The novel inflammatory biomarker GlycA and triglyceride-rich lipoproteins are associated with the presence of subclinical myocardial dysfunction in subjects with type 1 diabetes mellitus.

BACKGROUND: Subjects with Type 1 diabetes mellitus (T1DM) have an increased incidence of heart failure (HF). Several pathophysiological mechanisms have been involved in its development. The aim of this study was to analyze the potential contribution of the advanced lipoprotein profile and plasma glycosylation (GlycA) to the presence of subclinical myocardial dysfunction in subjects with T1DM. METHODS: We included subjects from a Danish cohort of T1DM subjects (Thousand & 1 study) with either diastolic and/or systolic subclinical myocardial dysfunction, and a control group without myocardial dysfunction, matched by age, sex and HbA1c. All underwent a transthoracic echocardiogram and an advanced lipoprotein profile obtained by using the NMR-based Liposcale® test. GlycA NMR signal was also analyzed. Systolic dysfunction was defined as left ventricular ejection fraction ≤ 45% and diastolic dysfunction was considered as E/e'≥12 or E/e' 8-12 + volume of the left atrium > 34 ml/m2. To identify a metabolic profile associated with the presence of subclinical myocardial dysfunction, a multivariate supervised model of classification based on least squares regression (PLS-DA regression) was performed. RESULTS: One-hundred forty-six subjects had diastolic dysfunction and 18 systolic dysfunction. Compared to the control group, patients with myocardial dysfunction had longer duration of diabetes (p = 0.005), and higher BMI (p = 0.013), serum NTproBNP concentration (p = 0.001), systolic blood pressure (p < 0.001), albuminuria (p < 0.001), and incidence of advanced retinopathy (p < 0.001). The supervised classification model identified a specific pattern associated with myocardial dysfunction, with a capacity to discriminate patients with myocardial dysfunction from controls. PLS-DA showed that triglyceride-rich lipoproteins (TGRLs), such as VLDL (total VLDL particles, large VLDL subclass and VLDL-TG content) and IDL (IDL cholesterol content), as well as the plasma concentration of GlycA, were associated with the presence of subclinical myocardial dysfunction. CONCLUSION: Proatherogenic TGRLs and the proinflammatory biomarker Glyc A are strongly associated to myocardial dysfunction in T1DM. These findings suggest a pivotal role of TGRLs and systemic inflammation in the development of subclinical myocardial dysfunction in T1DM.

Association of α-klotho with subclinical carotid atherosclerosis in subjects with type 1 diabetes mellitus.

BACKGROUND: Compelling evidence suggests that the fibroblast growth factor 23 (FGF23) / α-klotho axis is impaired in subjects with diabetes mellitus. We examined the relationship between parameters related to calcium/phosphate homeostasis, including FGF23 and α-klotho, and subclinical carotid atherosclerosis burden in type 1 diabetes mellitus (T1D) subjects. METHODS: This cross-sectional study involved 226 subjects with T1D and 147 age-, sex- and plaque-matched, non-diabetic (non-T1D) subjects, both with normal renal function. Carotid ultrasound was performed to determine the presence and burden of atheromatous plaques. Concentrations of the intact form of FGF23 and α-klotho were assessed by ELISA. Calcium, phosphate, parathyroid hormone, and vitamin D levels were also determined. Negative binomial regression models were used to examine relationship between parameters studied and subclinical carotid atherosclerosis. RESULTS: Only FGF23 was increased in T1D compared with non-diabetic subjects (> 2-fold; p < 0.05). α-klotho was higher in subjects with subclinical carotid atherosclerosis (1.4-fold, p < 0.05). Regression analysis revealed that the log α-klotho concentration was positively associated with the presence of subclinical carotid atherosclerosis both in T1D subjects (incidence rate ratio [IRR]: 1.41; 95% confidence interval [CI], 1.06-1.89; p < 0.05) and in non-T1D subjects (IRR: 1.65; 95% CI, 1.02-2.75; p < 0.05). The models also showed that age, smoking and albuminuria-to-creatinine ratio were positively associated with subclinical carotid atherosclerosis in T1D subjects. Interestingly, sex-related protection against plaque was also revealed in T1D women. CONCLUSION: Higher α-klotho was associated with subclinical carotid atherosclerotic in the absence of kidney dysfunction. This finding also points to a new pathophysiological pathway involved in the development and progression of this complication.

LDL Receptor Regulates the Reverse Transport of Macrophage-Derived Unesterified Cholesterol via Concerted Action of the HDL-LDL Axis: Insight From Mouse Models.

RATIONALE: The HDL (high-density lipoprotein)-mediated stimulation of cellular cholesterol efflux initiates macrophage-specific reverse cholesterol transport (m-RCT), which ends in the fecal excretion of macrophage-derived unesterified cholesterol (UC). Early studies established that LDL (low-density lipoprotein) particles could act as efficient intermediate acceptors of cellular-derived UC, thereby preventing the saturation of HDL particles and facilitating their cholesterol efflux capacity. However, the capacity of LDL to act as a plasma cholesterol reservoir and its potential impact in supporting the m-RCT pathway in vivo both remain unknown. OBJECTIVE: We investigated LDL contributions to the m-RCT pathway in hypercholesterolemic mice. METHODS AND RESULTS: Macrophage cholesterol efflux induced in vitro by LDL added to the culture media either alone or together with HDL or ex vivo by plasma derived from subjects with familial hypercholesterolemia was assessed. In vivo, m-RCT was evaluated in mouse models of hypercholesterolemia that were naturally deficient in CETP (cholesteryl ester transfer protein) and fed a Western-type diet. LDL induced the efflux of radiolabeled UC from cultured macrophages, and, in the simultaneous presence of HDL, a rapid transfer of the radiolabeled UC from HDL to LDL occurred. However, LDL did not exert a synergistic effect on HDL cholesterol efflux capacity in the familial hypercholesterolemia plasma. The m-RCT rates of the LDLr (LDL receptor)-KO (knockout), LDLr-KO/APOB100, and PCSK9 (proprotein convertase subtilisin/kexin type 9)-overexpressing mice were all significantly reduced relative to the wild-type mice. In contrast, m-RCT remained unchanged in HAPOB100 Tg (human APOB100 transgenic) mice with fully functional LDLr, despite increased levels of plasma APO (apolipoprotein)-B-containing lipoproteins. CONCLUSIONS: Hepatic LDLr plays a critical role in the flow of macrophage-derived UC to feces, while the plasma increase of APOB-containing lipoproteins is unable to stimulate m-RCT. The results indicate that, besides the major HDL-dependent m-RCT pathway via SR-BI (scavenger receptor class B type 1) to the liver, a CETP-independent m-RCT path exists, in which LDL mediates the transfer of cholesterol from macrophages to feces. Graphical Abstract: A graphical abstract is available for this article.

Importance of cerebrospinal fluid storage conditions for the Alzheimer's disease diagnostics on an automated platform.

OBJECTIVES: Alzheimer's disease (AD) is considered the most common cause of dementia in older people. Cerebrospinal fluid (CSF) Aß1-42, Aß1-40, total Tau (t-Tau), and phospho Tau (p-Tau) are important biomarkers for the diagnosis, however, they are highly dependent on the pre-analytical conditions. Our aim was to investigate the potential influence of different storage conditions on the simultaneous quantification of these biomarkers in a fully-automated platform to accommodate easier pre-analytical conditions for laboratories. METHODS: CSF samples were obtained from 11 consecutive patients. Aß1-42, Aß1-40, p-Tau, and t-Tau were quantified using the LUMIPULSE G600II automated platform. RESULTS: Temperature and storage days significantly influenced Aß1-42 and Aß1-40 with concentrations decreasing with days spent at 4 °C. The use of the Aß1-42/Aß1-40 ratio could partly compensate it. P-Tau and t-Tau were not affected by any of the tested storage conditions. For conditions involving storage at 4 °C, a correction factor of 1.081 can be applied. Diagnostic agreement was almost perfect in all conditions. CONCLUSIONS: Cutoffs calculated in samples stored at -80 °C can be safely used in samples stored at -20 °C for 15-16 days or up to two days at RT and subsequent freezing at -80 °C. For samples stored at 4 °C, cutoffs would require applying a correction factor, allowing to work with the certainty of reaching the same clinical diagnosis.

Epigenetic Regulation by microRNAs in Hyperhomocysteinemia-Accelerated Atherosclerosis.

Increased serum levels of homocysteine (Hcy) is a risk factor for cardiovascular disease and is specifically linked to various diseases of the vasculature such as atherosclerosis. However, the precise mechanisms by which Hcy contributes to this condition remain elusive. During the development of atherosclerosis, epigenetic modifications influence gene expression. As such, epigenetic modifications are an adaptive response to endogenous and exogenous factors that lead to altered gene expression by methylation and acetylation reactions of different substrates and the action of noncoding RNA including microRNAs (miRNAs). Epigenetic remodeling modulates cell biology in both physiological and physiopathological conditions. DNA and histone modification have been identified to have a crucial role in the progression of atherosclerosis. However, the potential role of miRNAs in hyperHcy (HHcy)-related atherosclerosis disease remains poorly explored and might be essential as well. There is no review available yet summarizing the contribution of miRNAs to hyperhomocystein-mediated atherogenicity or their potential as therapeutic targets even though their important role has been described in numerous studies. Specifically, downregulation of miR-143 or miR-125b has been shown to regulate VSCMs proliferation in vitro. In preclinical studies, downregulation of miR-92 or miR195-3p has been shown to increase the accumulation of cholesterol in foam cells and increase macrophage inflammation and atherosclerotic plaque formation, respectively. Another preclinical study found that there is a reciprocal regulation between miR-148a/152 and DNMT1 in Hcy-accelerated atherosclerosis. Interestingly, a couple of studies have shown that miR-143 or miR-217 may be used as potential biomarkers in patients with HHcy that may develop atherosclerosis. Moreover, the current review will also update current knowledge on miRNA-based therapies, their challenges, and approaches to deal with Hcy-induced atherosclerosis.

Reverse Cholesterol Transport Dysfunction Is a Feature of Familial Hypercholesterolemia.

PURPOSE OF REVIEW: We seek to establish whether high-density lipoprotein HDL metabolism and reverse cholesterol transport (RCT) impairment is an intrinsic feature of familial hypercholesterolemia (FH). RECENT FINDINGS: RCT from macrophages (m-RCT), a vascular cell type of major influence on atherosclerosis, is impaired in FH due to defective low-density lipoprotein receptor (LDLR) function via both the HDL- and LDL-mediated pathways. Potential mechanisms include impaired HDL metabolism, which is linked to increased LDL levels, as well as the increased transport of cellular unesterified cholesterol to LDL, which presents a defective catabolism. RCT dysfunction is consistently associated with mutation-positive FH linked to decreased HDL levels as well as impaired HDL remodeling and LDLR function. It remains to be explored whether these alterations are also present in less well-characterized forms of FH, such as cases with no identified mutations, and whether they are fully corrected by current standard treatments.

High-Density Lipoproteins and Cardiovascular Disease: The Good, the Bad, and the Future.

Epidemiological, clinical, and experimental studies have shown that low levels of plasma high-density lipoprotein cholesterol (HDL-C) are associated with increased atherosclerotic cardiovascular disease (CVD) [...].

Novel Insights into the Role of HDL-Associated Sphingosine-1-Phosphate in Cardiometabolic Diseases.

Sphingolipids are key signaling molecules involved in the regulation of cell physiology. These species are found in tissues and in circulation. Although they only constitute a small fraction in lipid composition of circulating lipoproteins, their concentration in plasma and distribution among plasma lipoproteins appears distorted under adverse cardiometabolic conditions such as diabetes mellitus. Sphingosine-1-phosphate (S1P), one of their main representatives, is involved in regulating cardiomyocyte homeostasis in different models of experimental cardiomyopathy. Cardiomyopathy is a common complication of diabetes mellitus and represents a main risk factor for heart failure. Notably, plasma concentration of S1P, particularly high-density lipoprotein (HDL)-bound S1P, may be decreased in patients with diabetes mellitus, and hence, inversely related to cardiac alterations. Despite this, little attention has been given to the circulating levels of either total S1P or HDL-bound S1P as potential biomarkers of diabetic cardiomyopathy. Thus, this review will focus on the potential role of HDL-bound S1P as a circulating biomarker in the diagnosis of main cardiometabolic complications frequently associated with systemic metabolic syndromes with impaired insulin signaling. Given the bioactive nature of these molecules, we also evaluated its potential of HDL-bound S1P-raising strategies for the treatment of cardiometabolic disease.

Human ApoA-I Overexpression Enhances Macrophage-Specific Reverse Cholesterol Transport but Fails to Prevent Inherited Diabesity in Mice.

Human apolipoprotein A-I (hApoA-I) overexpression improves high-density lipoprotein (HDL) function and the metabolic complications of obesity. We used a mouse model of diabesity, the db/db mouse, to examine the effects of hApoA-I on the two main functional properties of HDL, i.e., macrophage-specific reverse cholesterol transport (m-RCT) in vivo and the antioxidant potential, as well as the phenotypic features of obesity. HApoA-I transgenic (hA-I) mice were bred with nonobese control (db/+) mice to generate hApoA-I-overexpressing db/+ offspring, which were subsequently bred to obtain hA-I-db/db mice. Overexpression of hApoA-I significantly increased weight gain and the incidence of fatty liver in db/db mice. Weight gain was mainly explained by the increased caloric intake of hA-I-db/db mice (>1.2-fold). Overexpression of hApoA-I also produced a mixed type of dyslipidemia in db/db mice. Despite these deleterious effects, the overexpression of hApoA-I partially restored m-RCT in db/db mice to levels similar to nonobese control mice. Moreover, HDL from hA-I-db/db mice also enhanced the protection against low-density lipoprotein (LDL) oxidation compared with HDL from db/db mice. In conclusion, overexpression of hApoA-I in db/db mice enhanced two main anti-atherogenic HDL properties while exacerbating weight gain and the fatty liver phenotype. These adverse metabolic side-effects were also observed in obese mice subjected to long-term HDL-based therapies in independent studies and might raise concerns regarding the use of hApoA-I-mediated therapy in obese humans.

Enhanced vascular permeability facilitates entry of plasma HDL and promotes macrophage-reverse cholesterol transport from skin in mice.

Reverse cholesterol transport (RCT) pathway from macrophage foam cells initiates when HDL particles cross the endothelium, enter the interstitial fluid, and induce cholesterol efflux from these cells. We injected [(3)H]cholesterol-loaded J774 macrophages into the dorsal skin of mice and measured the transfer of macrophage-derived [(3)H]cholesterol to feces [macrophage-RCT (m-RCT)]. Injection of histamine to the macrophage injection site increased locally vascular permeability, enhanced influx of intravenously administered HDL, and stimulated m-RCT from the histamine-treated site. The stimulatory effect of histamine on m-RCT was abolished by prior administration of histamine H1 receptor (H1R) antagonist pyrilamine, indicating that the histamine effect was H1R-dependent. Subcutaneous administration of two other vasoactive mediators, serotonin or bradykinin, and activation of skin mast cells to secrete histamine and other vasoactive compounds also stimulated m-RCT. None of the studied vasoactive mediators affected serum HDL levels or the cholesterol-releasing ability of J774 macrophages in culture, indicating that acceleration of m-RCT was solely due to increased availability of cholesterol acceptors in skin. We conclude that disruption of the endothelial barrier by vasoactive compounds enhances the passage of HDL into interstitial fluid and increases the rate of RCT from peripheral macrophage foam cells, which reveals a novel tissue cholesterol-regulating function of these compounds.

Reciprocal negative cross-talk between liver X receptors (LXRs) and STAT1: effects on IFN-γ-induced inflammatory responses and LXR-dependent gene expression.

Liver X receptors (LXRs) exert key functions in lipid homeostasis and in control of inflammation. In this study we have explored the impact of LXR activation on the macrophage response to the endogenous inflammatory cytokine IFN-γ. Transcriptional profiling studies demonstrate that ∼38% of the IFN-γ-induced transcriptional response is repressed by LXR activation in macrophages. LXRs also mediated inhibitory effects on selected IFN-γ-induced genes in primary microglia and in a model of IFN-γ-induced neuroinflammation in vivo. LXR activation resulted in reduced STAT1 recruitment to the promoters tested in this study without affecting STAT1 phosphorylation. A closer look into the mechanism revealed that SUMOylation of LXRs, but not the presence of nuclear receptor corepressor 1, was required for repression of the NO synthase 2 promoter. We have also analyzed whether IFN-γ signaling exerts reciprocal effects on LXR targets. Treatment with IFN-γ inhibited, in a STAT1-dependent manner, the LXR-dependent upregulation of selective targets, including ATP-binding cassette A1 (ABCA1) and sterol response element binding protein 1c. Downregulation of ABCA1 expression correlated with decreased cholesterol efflux to apolipoprotein A1 in macrophages stimulated with IFN-γ. The inhibitory effects of IFN-γ on LXR signaling did not involve reduced binding of LXR/retinoid X receptor heterodimers to target gene promoters. However, overexpression of the coactivator CREB-binding protein/p300 reduced the inhibitory actions of IFN-γ on the Abca1 promoter, suggesting that competition for CREB-binding protein may contribute to STAT1-dependent downregulation of LXR targets. The results from this study suggest an important level of bidirectional negative cross-talk between IFN-γ/STAT1 and LXRs with implications both in the control of IFN-γ-mediated immune responses and in the regulation of lipid metabolism.

Evaluation of the relationship between effervescent paracetamol and blood pressure: clinical trial.

BACKGROUND: Paracetamol's solubility is achieved by adding to the excipient sodium salts, either as bicarbonate, carbonate or citrate. As the relationship between salt and hypertension is well known, due to the sodium content it has raised a hypothesis that may interfere with the control of that risk factor. Therefore, the objective of this study is to evaluate the effect on blood pressure of effervescent paracetamol compared to non-effervescent, in hypertensive patients. METHODS/DESIGN: This is the protocol of a phase IV multicenter clinical trial, randomized, controlled, crossover, open, which will compare the effect of two different formulations of paracetamol (effervescent or non-effervescent) in the blood pressure of hypertensive patients, with a seven weeks follow up. 49 controlled hypertensive patients will be included (clinical BP lower than 150 and 95 mmHg, and lower than 135 mmHg and 85 mmHg in patients with diabetes or a history of cardiovascular event, and daytime ambulatory measurements lower than 140 and 90 mmHg) and mild to moderate pain (Visual Analog Scale between 1 and 4). The study was approved by the ethics committee of the Fundació Jordi Gol i Gurina and following standards of good clinical practice. The primary endpoint will be the variations in systolic BP in 24 h Ambulatory Blood Pressure Monitoring, considering significant differences 2 or more mmHg among those treated with non-effervescent and effervescent formulations. Intention-to-treat and per-protocol analysis will be held. DISCUSSION: Despite the broad recommendation not to use effervescent drugs in patients with hypertension, there are relatively little studies that show exactly this pressor effect due to sodium in salt that gives the effervescence of the product. This is the first clinical trial designed to study the effect of effervescence compared to the non-effervescent, in well-controlled hypertensive patients with mild to moderate pain, performed in routine clinical practice. TRIAL REGISTRATION: NCT 02514538.

HDL and lifestyle interventions.

The main lifestyle interventions to modify serum HDL cholesterol include physical exercise, weight loss with either caloric restriction or specific dietary approaches, and smoking cessation. Moderate alcohol consumption can be permitted in some cases. However, as these interventions exert multiple effects, it is often difficult to discern which is responsible for improvement in HDL outcomes. It is particularly noteworthy that recent data questions the use of HDL cholesterol as a risk factor and therapeutic target since randomised interventions and Mendelian randomisation studies failed to provide evidence for such an approach. Therefore, these current data should be considered when reading and interpreting this review. Further studies are needed to document the effect of lifestyle changes on HDL structure-function and health.

Hepatic lipase- and endothelial lipase-deficiency in mice promotes macrophage-to-feces RCT and HDL antioxidant properties.

Hepatic lipase (HL) and endothelial lipase (EL) are negative regulators of plasma HDL cholesterol (HDLc) levels and presumably could affect two main HDL atheroprotective functions, macrophage-to-feces reverse cholesterol transport (RCT) and HDL antioxidant properties. In this study, we assessed the effects of both HL and EL deficiency on macrophage-specific RCT process and HDL ability to protect against LDL oxidation. HL- and EL-deficient and wild-type mice were injected intraperitoneally with [(3)H]cholesterol-labeled mouse macrophages, after which the appearance of [(3)H]cholesterol in plasma, liver, and feces was determined. The degree of HDL oxidation and the protection of oxidative modification of LDL co-incubated with HDL were evaluated by measuring conjugated diene kinetics. Plasma levels of HDLc, HDL phospholipids, apoA-I, and platelet-activated factor acetyl-hydrolase were increased in both HL- and EL-deficient mice. These genetically modified mice displayed increased levels of radiolabeled, HDL-bound [(3)H]cholesterol 48h after the label injection. The magnitude of macrophage-derived [(3)H]cholesterol in feces was also increased in both the HL- and EL-deficient mice. HDL from the HL- and EL-deficient mice was less prone to oxidation and had a higher ability to protect LDL from oxidation, compared with the HDL derived from the wild-type mice. These changes were correlated with plasma apoA-I and apoA-I/HDL total protein levels. In conclusion, targeted inactivation of both HL and EL in mice promoted macrophage-to-feces RCT and enhanced HDL antioxidant properties.

Sitosterolemia: diagnosis, investigation, and management.

Sitosterolemia is a rare autosomal recessively inherited disease caused by mutations affecting ABCG5 or ABCG8, which are located on human chromosome band 2p21. Around 100 cases have been reported in the literature. Sitosterolemic patients typically exhibit a 30-fold to 100-fold increase in plasma concentrations of plant sterols. The clinical manifestations include xanthomas, premature atherosclerosis, hemolytic anemia, and macrothrombocytopenia. It is noteworthy that abnormal hematological parameters may be the only clinical feature of sitosterolemic patients, suggesting that sitosterolemia may be more frequent than previously thought. Severe accumulation of plant sterols in mouse models of sitosterolemia induced complex cardiac lesions, anemia, and macrothrombocytopenia, disrupted adrenal and liver cholesterol homeostasis, and caused infertility and hypertriglyceridemia. It remains unclear whether all disease traits are present in sitosterolemic patients. The drug ezetimibe appears to be effective in reducing plasma plant sterol levels, promotes xanthoma regression, and improves the cardiovascular and hematological signs in sitosterolemic patients.

Acute psychological stress accelerates reverse cholesterol transport via corticosterone-dependent inhibition of intestinal cholesterol absorption.

RATIONALE: Psychological stress is associated with an increased risk of cardiovascular diseases. However, the connecting mechanisms of the stress-inducing activation of the hypothalamic-pituitary-adrenal axis with atherosclerosis are not well-understood. OBJECTIVE: To study the effect of acute psychological stress on reverse cholesterol transport (RCT), which transfers peripheral cholesterol to the liver for its ultimate fecal excretion. METHODS AND RESULTS: C57Bl/6J mice were exposed to restraint stress for 3 hours to induce acute psychological stress. RCT in vivo was quantified by measuring the transfer of [(3)H]cholesterol from intraperitoneally injected mouse macrophages to the lumen of the small intestine within the stress period. Surprisingly, stress markedly increased the contents of macrophage-derived [(3)H]cholesterol in the intestinal lumen. In the stressed mice, intestinal absorption of [(14)C]cholesterol was significantly impaired, the intestinal mRNA expression level of peroxisome proliferator-activated receptor-α increased, and that of the sterol influx transporter Niemann-Pick C1-like 1 decreased. The stress-dependent effects on RCT rate and peroxisome proliferator-activated receptor-α gene expression were fully mimicked by administration of the stress hormone corticosterone (CORT) to nonstressed mice, and they were blocked by the inhibition of CORT synthesis in stressed mice. Moreover, the intestinal expression of Niemann-Pick C1-like 1 protein decreased when circulating levels of CORT increased. Of note, when either peroxisome proliferator-activated receptor α or liver X receptor α knockout mice were exposed to stress, the RCT rate remained unchanged, although plasma CORT increased. This indicates that activities of both transcription factors were required for the RCT-accelerating effect of stress. CONCLUSIONS: Acute psychological stress accelerated RCT by compromising intestinal cholesterol absorption. The present results uncover a novel functional connection between the hypothalamic-pituitary-adrenal axis and RCT that can be triggered by a stress-induced increase in circulating CORT.

The Lipidomic Profile Is Associated with the Dietary Pattern in Subjects with and without Diabetes Mellitus from a Mediterranean Area.

Lipid functions can be influenced by genetics, age, disease states, and lifestyle factors, particularly dietary patterns, which are crucial in diabetes management. Lipidomics is an expanding field involving the comprehensive exploration of lipids from biological samples. In this cross-sectional study, 396 participants from a Mediterranean region, including individuals with type 1 diabetes (T1D), type 2 diabetes (T2D), and non-diabetic individuals, underwent lipidomic profiling and dietary assessment. Participants completed validated food frequency questionnaires, and lipid analysis was conducted using ultra-high-performance liquid chromatography coupled with mass spectrometry (UHPLC/MS). Multiple linear regression models were used to determine the association between lipid features and dietary patterns. Across all subjects, acylcarnitines (AcCa) and triglycerides (TG) displayed negative associations with the alternate Healthy Eating Index (aHEI), indicating a link between lipidomic profiles and dietary habits. Various lipid species (LS) showed positive and negative associations with dietary carbohydrates, fats, and proteins. Notably, in the interaction analysis between diabetes and the aHEI, we found some lysophosphatidylcholines (LPC) that showed a similar direction with respect to aHEI in non-diabetic individuals and T2D subjects, while an opposite direction was observed in T1D subjects. The study highlights the significant association between lipidomic profiles and dietary habits in people with and without diabetes, particularly emphasizing the role of healthy dietary choices, as reflected by the aHEI, in modulating lipid concentrations. These findings underscore the importance of dietary interventions to improve metabolic health outcomes, especially in the context of diabetes management.