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Background and Aims INTERASPIRE is an international study of coronary heart disease (CHD) patients, designed to measure if guideline standards for secondary prevention and cardiac rehabilitation are being achieved in a timely manner. Methods Between 2020 and 2023, adults hospitalized in the preceding 6–24 months with incident or recurrent CHD were sampled in 14 countries from all 6 World Health Organization regions and invited for a standardized interview and examination. Direct age and sex standardization was used for country-level prevalence estimation. Results Overall, 4548 (21.1% female) CHD patients were interviewed a median of 1.05 (interquartile range.76–1.45) years after index hospitalization. Among all participants, 24.6% were obese (40.7% centrally). Only 38.6% achieved a blood pressure (BP) < 130/80 mmHg and 16.6% a LDL cholesterol (LDL-C) of <1.4 mmol/L. Of those smoking at hospitalization, 48% persisted at interview. Of those with known diabetes, 55.2% achieved glycated haemoglobin (HbA1c) of <7.0%. A further 9.8% had undetected diabetes and 26.9% impaired glucose tolerance. Females were less likely to achieve the targets: BP (females 36.8%, males 38.9%), LDL-C (females 12.0%, males 17.9%), and HbA1c in diabetes (females 47.7%, males 57.5%). Overall, just 9.0% (inter-country range 3.8%–20.0%) reported attending cardiac rehabilitation and 1.0% (inter-country range.0%–2.4%) achieved the study definition of optimal guideline adherence. Conclusions INTERASPIRE demonstrates inadequate and heterogeneous international implementation of guideline standards for secondary prevention in the first year after CHD hospitalization, with geographic and sex disparity. Investment aimed at reducing between-country and between-individual variability in secondary prevention will promote equity in global efforts to reduce the burden of CHD. [ABSTRACT FROM AUTHOR]

Hyperferritinemia reflects iron accumulation in the body and has been associated with metabolic disturbances and alcohol use, and is also a common finding in individuals diagnosed with liver disease. The major genetic regulator of iron metabolism is the HFE gene. The aim of this this study was to investigate the association between serum ferritin and liver fibrosis using the enhanced liver fibrosis (ELF) test, and the association between ferritin and liver-related outcomes in a Finnish population-based cohort of 6194 individuals (45% male, mean [± standard deviation] age, 52.9 ± 14.9 years; body mass index 26.9 ± 4.7 kg/m2). The effects of HFE variants on these associations were also evaluated. Serum ferritin levels were significantly associated with liver fibrosis, as estimated by enhanced liver fibrosis (ELF) test in weighted linear regression analysis. Serum ferritin was significantly associated with both all liver-related outcomes (n = 92) and severe liver-related outcomes (n = 54) in weighted Cox regression analysis (hazard ratio [HR] per 1 SD, 1.11 [95% confidence interval (CI) 1.02–1.21]; p = 0.012 and HR 1.11 [95% CI 1.02–1.21]; p = 0.013, respectively). However, there was association neither between HFE risk variants and ELF test nor between HFE risk variants and liver-related outcomes. Serum ferritin levels were associated with liver fibrosis and incident liver disease, independent of HFE genotype in the general population. Furthermore, data demonstrated that metabolic disturbances and alcohol use were major risk factors for hyperferritinemia. [ABSTRACT FROM AUTHOR]

Background and Aims: Effective and feasible population screening strategies are needed for the early detection of individuals at high risk of future severe liver‐related outcomes. We evaluated the predictive performance of the combination of liver fibrosis assessment, phenotype profile, and genetic risk. Methods: Data from 5795 adults attending the Finnish Health 2000 Survey were linked with healthcare registers for liver‐related outcomes (hospitalization, hepatocellular cancer, and death). Fibrosis was assessed using the enhanced liver fibrosis (ELF) test, phenotype profile by the chronic liver disease (CLivD) risk score, and genetic risk by a validated Polygenic Risk Score (PRS‐5). Predictive performance was assessed by competing‐risk analyses. Results: During a median 13‐year follow‐up, 64 liver‐related outcome events were recorded. ELF, CLivD score, and PRS‐5 were independently associated with liver‐related outcomes. The absolute 10‐year risk of liver‐related outcomes at an ELF value of 11.3 ranged from 0.3% to 33% depending on the CLivD score. The CLivD score added 51% of new predictive information to the ELF test and improved areas under the curve (AUCs) from 0.91, 0.81, and 0.71 for ELF alone to 0.95, 0.85, and 0.80, respectively, for ELF combined with the CLivD score at 1, 5, and 10 years. The greatest improvement was for 10‐year predictions (delta‐AUC 0.097, p <.0001). Adding PRS‐5 did not significantly increase predictive performance. Findings were consistent in individuals with obesity, diabetes, or alcohol risk use, and regardless of whether gamma‐glutamyltransferase was used in the CLivD score. Conclusion: A combination of ELF and CLivD score predicts liver‐related outcomes significantly better than the ELF test alone. [ABSTRACT FROM AUTHOR]

Objective: The optimal screening strategy for dysglycemia (including type 2 diabetes and impaired glucose tolerance) in patients with coronary artery disease (CAD) is debated. We tested the hypothesis that measures of insulin resistance by HOMA indexes may constitute good screening methods.Research Design and Methods: Insulin, C-peptide, glycated hemoglobin A1c, and an oral glucose tolerance test (OGTT) were centrally assessed in 3,534 patients with CAD without known dysglycemia from the fifth European Survey of Cardiovascular Disease Prevention and Diabetes (EUROASPIRE V). Three different HOMA indexes were calculated: HOMA of insulin resistance (HOMA-IR), HOMA2 based on insulin (HOMA2-ins), and HOMA2 based on C-peptide (HOMA2-Cpep). Dysglycemia was diagnosed based on the 2-h postload glucose value obtained from the OGTT. Information on study participants was obtained by standardized interviews. The optimal thresholds of the three HOMA indexes for dysglycemia diagnosis were obtained by the maximum value of Youden's J statistic on receiver operator characteristic curves. Their correlation with clinical parameters was assessed by Spearman coefficients.Results: Of 3,534 patients with CAD (mean age 63 years; 25% women), 41% had dysglycemia. Mean insulin, C-peptide, and HOMA indexes were significantly higher in patients with versus without newly detected dysglycemia (all P < 0.0001). Sensitivity and specificity of the three HOMA indexes for the diagnosis of dysglycemia were low, but their correlation with BMI and waist circumference was strong.Conclusions: Screening for dysglycemia in patients with CAD by HOMA-IR, HOMA2-ins, and HOMA2-Cpep had insufficient diagnostic performance to detect dysglycemia with reference to the yield of an OGTT, which should still be prioritized despite its practical drawbacks. [ABSTRACT FROM AUTHOR]

Hepatocyte‐like cells (HLCs) differentiated from human‐induced pluripotent stem cells offer an alternative platform to primary human hepatocytes (PHHs) for studying the lipid metabolism of the liver. However, despite their great potential, the lipid profile of HLCs has not yet been characterized. Here, we comprehensively studied the lipid profile and fatty acid (FA) metabolism of HLCs and compared them with the current standard hepatocyte models: HepG2 cells and PHHs. We differentiated HLCs by five commonly used methods from three cell lines and thoroughly characterized them by gene and protein expression. HLCs generated by each method were assessed for their functionality and the ability to synthesize, elongate, and desaturate FAs. In addition, lipid and FA profiles of HLCs were investigated by both mass spectrometry and gas chromatography and then compared with the profiles of PHHs and HepG2 cells. HLCs resembled PHHs by expressing hepatic markers: secreting albumin, lipoprotein particles, and urea, and demonstrating similarities in their lipid and FA profile. Unlike HepG2 cells, HLCs contained low levels of lysophospholipids similar to the content of PHHs. Furthermore, HLCs were able to efficiently use the exogenous FAs available in their medium and simultaneously modify simple lipids into more complex ones to fulfill their needs. In addition, we propose that increasing the polyunsaturated FA supply of the culture medium may positively affect the lipid profile and functionality of HLCs. In conclusion, our data showed that HLCs provide a functional and relevant model to investigate human lipid homeostasis at both molecular and cellular levels. Hepatocyte‐like cells (HLCs) offer an alternative platform to primary human hepatocytes (PHHs) for studying lipid metabolism of the liver; however, their lipid profile has not yet been characterized. We demonstrate that HLCs resemble PHHs by their functionality and showing similarities in their lipid and fatty acid (FA) profile. Unlike HepG2 cells, HLCs contained low levels of lysophospholipids, similar to the content of PHHs. Here, we propose that HLCs provide a functional and relevant model to investigate human lipid homeostasis at both molecular and cellular levels. [ABSTRACT FROM AUTHOR]

Aims Low-density lipoprotein (LDL) particles cause atherosclerotic cardiovascular disease (ASCVD) through their retention, modification, and accumulation within the arterial intima. High plasma concentrations of LDL drive this disease, but LDL quality may also contribute. Here, we focused on the intrinsic propensity of LDL to aggregate upon modification. We examined whether inter-individual differences in this quality are linked with LDL lipid composition and coronary artery disease (CAD) death, and basic mechanisms for plaque growth and destabilization. Methods and results We developed a novel, reproducible method to assess the susceptibility of LDL particles to aggregate during lipolysis induced ex vivo by human recombinant secretory sphingomyelinase. Among patients with an established CAD, we found that the presence of aggregation-prone LDL was predictive of future cardiovascular deaths, independently of conventional risk factors. Aggregation-prone LDL contained more sphingolipids and less phosphatidylcholines than did aggregation-resistant LDL. Three interventions in animal models to rationally alter LDL composition lowered its susceptibility to aggregate and slowed atherosclerosis. Similar compositional changes induced in humans by PCSK9 inhibition or healthy diet also lowered LDL aggregation susceptibility. Aggregated LDL in vitro activated macrophages and T cells, two key cell types involved in plaque progression and rupture. Conclusion Our results identify the susceptibility of LDL to aggregate as a novel measurable and modifiable factor in the progression of human ASCVD. View large Download slide View large Download slide [ABSTRACT FROM AUTHOR]

Smoking is a major risk factor for several diseases including chronic obstructive pulmonary disease (COPD). To better understand the systemic effects of cigarette smoke exposure and mild to moderate COPD-and to support future biomarker development-we profiled the serum lipidomes of healthy smokers, smokers with mild to moderate COPD (GOLD stages 1 and 2), former smokers, and never-smokers (n = 40 per group) (ClinicalTrials.gov registration: NCT01780298). Serum lipidome profiling was conducted with untargeted and targeted mass spectrometry-based lipidomics. Guided by weighted lipid co-expression network analysis, we identified three main trends comparing smokers, especially those with COPD, with non-smokers: a general increase in glycero(phospho)lipids, including triglycerols; changes in fatty acid desaturation (decrease in ω-3 polyunsaturated fatty acids, and an increase in monounsaturated fatty acids); and an imbalance in eicosanoids (increase in 11,12- and 14,15-DHETs (dihydroxyeicosatrienoic acids), and a decrease in 9- and 13-HODEs (hydroxyoctadecadienoic acids)). The lipidome profiles supported classification of study subjects as smokers or non-smokers, but were not sufficient to distinguish between smokers with and without COPD. Overall, our study yielded further insights into the complex interplay between smoke exposure, lung disease, and systemic alterations in serum lipid profiles. [ABSTRACT FROM AUTHOR]

Aims The aim was to study the prognostic value of plasma ceramides (Cer) as cardiovascular death (CV death) markers in three independent coronary artery disease (CAD) cohorts. Methods and results Corogene study is a prospective Finnish cohort including stable CAD patients (n = 160). Multiple lipid biomarkers and C-reactive protein were measured in addition to plasma Cer(d18:1/16:0), Cer(d18:1/18:0), Cer(d18:1/24:0), and Cer(d18:1/24:1). Subsequently, the association between high-risk ceramides and CV mortality was investigated in the prospective Special Program University Medicine--Inflammation in Acute Coronary Syndromes (SPUM-ACS) cohort (n = 1637), conducted in four Swiss university hospitals. Finally, the results were validated in Bergen Coronary Angiography Cohort (BECAC), a prospective Norwegian cohort study of stable CAD patients. Ceramides, especially when used in ratios, were significantly associated with CV death in all studies, independent of other lipid markers and C-reactive protein. Adjusted odds ratios per standard deviation for the Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio were 4.49 (95% CI, 2.24-8.98), 1.64 (1.29-2.08), and 1.77 (1.41-2.23) in the Corogene, SPUM-ACS, and BECAC studies, respectively. The Cer(d18:1/16:0)/Cer(d18:1/24:0) ratio improved the predictive value of the GRACE score (net reclassification improvement, NRI = 0.17 and ΔAUC = 0.09) in ACS and the predictive value of the Marschner score in stable CAD (NRI = 0.15 and ΔAUC = 0.02). Conclusions Distinct plasma ceramide ratios are significant predictors of CV death both in patients with stable CAD and ACS, over and above currently used lipid markers. This may improve the identification of high-risk patients in need of more aggressive therapeutic interventions. [ABSTRACT FROM AUTHOR]

The impact of cigarette smoke (CS), a major cause of lung diseases, on the composition and metabolism of lung lipids is incompletely understood. Here, we integrated quantitative lipidomics and proteomics to investigate exposure effects on lung lipid metabolismin a C57BL/6 and an Apolipoprotein E-deficient (Apoe-/-) mouse study. In these studies, mice were exposed to high concentrations of 3R4F reference CS, aerosol from potential modified risk tobacco products (MRTPs) or filtered air (Sham) for up to 8 months. The 2 assessed MRTPs, the prototypical MRTP for C57BL/6 mice and the Tobacco Heating System 2.2 for Apoe-/- mice, utilize"heat-not-burn" technologies and were each matched in nicotine concentrations to the 3R4F CS. After 2 months of CS exposure, some groups were either switched to the MRTP or underwent cessation. In both mouse strains, CS strongly affected several categories of lung lipids and lipid-related proteins. Candidate surfactant lipids, surfactant proteins, and surfactant metabolizing proteins were increased. Inflammatory eicosanoids, their metabolic enzymes, and several ceramide classes were elevated. Overall, CS induced a coordinated lipid response controlled by transcription regulators such as SREBP proteins and supported by other metabolic adaptations. In contrast, most of these changes were absent in the mice exposed to the potential MRTPs, in the cessation group, and the switching group. Our findings demonstrate the complex biological response of the lungs to CS exposure and support the benefits of cessation or switching to a heat-not-burn product using a design such as those employed in this study. [ABSTRACT FROM AUTHOR]

Summary Cold exposure greatly alters brown adipose tissue (BAT) gene expression and metabolism to increase thermogenic capacity. Here, we used RNA sequencing and mass-spectrometry-based lipidomics to provide a comprehensive resource describing the molecular signature of cold adaptation at the level of the transcriptome and lipidome. We show that short-term (3-day) cold exposure leads to a robust increase in expression of several brown adipocyte genes related to thermogenesis as well as the gene encoding the hormone irisin. However, pathway analysis shows that the most significantly induced genes are those involved in glycerophospholipid synthesis and fatty acid elongation. This is accompanied by significant changes in the acyl chain composition of triacylglycerols (TAGs) as well as subspecies-selective changes of acyl chains in glycerophospholipids. These results indicate that cold adaptation of BAT is associated with significant and highly species-selective remodeling of both TAGs and glycerophospholipids. [ABSTRACT FROM AUTHOR]

Background: Marine food is an important source of omega-3 fatty acids with beneficial health effects. Oils from marine organisms have different fatty acid composition and differ in their molecular composition. Fish oil (FO) has a high content of eicosapentaenoic and docosahexaenoic acids mainly esterified to triacylglycerols, while in krill oil (KO) these fatty acids are mainly esterified to phospholipids. The aim was to study the effects of these oils on the lipid content and fatty acid distribution in the various lipid classes in liver and brain of mice. Methods: Mice were fed either a high-fat diet (HF), a HF diet supplemented with FO or with KO (n = 6). After six weeks of feeding, liver and brain lipid extracts were analysed using a shotgun and TAG lipidomics approach. Student t-test was performed after log-transformation to compare differences between study groups. Results: Six weeks of feeding resulted in significant changes in the relative abundance of many lipid classes compared to control mice. In both FO and KO fed mice, the triacylglycerol content in the liver was more than doubled. The fatty acid distribution was affected by the oils in both liver and brain with a decrease in the abundance of 18:2 and 20:4, and an increase in 20:5 and 22:6 in both study groups. 18:2 decreased in all lipid classes in the FO group but with only minor changes in the KO group. Differences between the feeding groups were particularly evident in some of the minor lipid classes that are associated with inflammation and insulin resistance. Ceramides and diacylglycerols were decreased and cholesteryl esters increased in the liver of the KO group, while plasmalogens were decreased in the FO group. In the brain, diacylglycerols were decreased, more by KO than FO, while ceramides and lactosylceramides were increased, more by FO than KO. Conclusion: The changes in the hepatic sphingolipids and 20:4 fatty acid levels were greater in the KO compared to the FO fed mice, and are consistent with a hypothesis that krill oil will have a stronger anti-inflammatory action and enhances insulin sensitivity more potently than fish oil. [ABSTRACT FROM AUTHOR]

Abstract: Oxysterol-binding protein homologs (ORPs) are implicated in lipid metabolism, vesicle transport and cell signaling. In this study we generated RAW264.7 cells with ORP1L, ORP3, or ORP8 silenced using shRNA lentiviruses. The lipidome of the cells under basal serum-free culture conditions or as treated with oxidized LDL (oxLDL), enzymatically modified LDL (E-LDL), or lipopolysaccharide (LPS) was analyzed by mass spectrometry. Reduction in each ORP resulted in distinct and complex effects on macrophage lipidome. Under basal conditions, ORP1L silencing had strongest effects on phosphatidylinositols (PI, increase), free cholesterol (FC, increase), and cholesteryl esters (CE, increase). ORP3 silencing affected most the glucosyl ceramides (GluCer, decrease) and PE-plasmalogens (PE-pl, decrease), while ORP8 silencing increased FC and CE, and decreased GluCer and PE-pl. Upon LPS treatment, the ORP effects were modified: under these conditions ORP1L silencing caused increase of Cer, ORP3 silencing decrease of PI, and ORP8 silencing decrease of PI and increase of PE, not detectable under basal conditions. The lipid species data were subjected to multivariate statistical analysis of principal components, revealing numerous specific alterations upon ORP silencing. The cells cultured in basal conditions or treated with LPS showed qualitatively different responses. However, in LPS-stimulated cells silencing of any of the three ORPs decreased the relative amount of arachidonic acid-containing PI species, increased the corresponding PE species, and favored 16-carbon sphingomyelin (SM) species at the expense of the 24-carbon ones. As a conclusion, the present study reveals the distinct and sophisticated roles of different ORP proteins as regulators of macrophage lipid composition, with implications for inflammatory signaling. [Copyright &y& Elsevier]

Cytoplasmic oxysterol-binding protein homologues, designated OSBP-like (OSBPL) or OSBP-related (ORP) proteins, constitute a family of lipid binding/transfer proteins present in a wide spectrum of eukaryotes. In mammals these proteins are encoded by 12 genes expressed ubiquitously but at different quantities in different tissue and cell types. Their unifying feature is a β-barrel-like ligand-binding domain that has been shown to accommodate sterol ligands: oxysterols, cholesterol, or both, while a recent report shows that also phospholipid can be bound. Certain family members have the capacity to mediate or facilitate intracellular sterol transport or lipid exchange, while others are implicated as sterol sensors involved in cell regulation: lipid homeostatic control, signal transduction, organelle motility, or vesicle transport. Several ORPs have been localized to membrane contact sites, at which endoplasmic reticulum membranes are closely apposed with other organelles-indicating functions in the non-vesicular transport of ions or small molecules, or in regulation of enzymatic components active at the contact sites. OSBPL gene polymorphisms are associated with cardiovascular risk factors, and altered ORP expression levels occur in certain cancers, providing the first indications of ORP involvement in human disease. In this review we summarize and analyze the latest findings concerning the function of OSBPL/ORP proteins. [ABSTRACT FROM AUTHOR]

Abstract: Families of oxysterol-binding protein (ORP) homologues are present in eukaryotes from yeast to man. Their hallmark feature is a characteristic ligand binding domain that, for several family members, has been shown to accommodate different oxysterols and/or cholesterol. ORPs of the “long” subtype contain targeting determinants for the endoplasmic reticulum and to other organelle membranes, the most prominent of which are phosphoinositide-binding pleckstrin homology domains, while “short” ORPs comprise a ligand binding domain with little additional sequences. There is increasing evidence that both long and short ORPs can be enriched at membrane contact sites, junctions of the endoplasmic reticulum with other organelles, where they are suggested to execute regulatory or sterol transfer functions. In this review we discuss the current evidence for putative roles of ORPs as sterol sensors or transporters. [Copyright &y& Elsevier]

We earlier identified OSBP-related protein 8 (ORP8) as an endoplasmic reticulum oxysterol-binding protein implicated in cellular lipid homeostasis. We now investigated its action in hepatic cells in vivo and in vitro. Adenoviral overexpression of ORP8 in mouse liver induced a decrease of cholesterol, phospholipids, and triglycerides in serum (234%, 226%, 237%, respectively) and liver tissue (240%, 212%, 224%), coinciding with reduction of nuclear (n)SREBP-1 and -2 and mRNA levels of their target genes. Consistently, excess ORP8 reduced nSREBPs in HuH7 cells, and ORP8 overexpression or silencing by RNA interference moderately suppressed or induced the expression of SREBP-1 and SREBP-2 target genes, respectively. In accordance, cholesterol biosynthesis was reduced by ORP8 overexpression and enhanced by ORP8 silencing in [3H]acetate pulse-labeling experiments. ORP8, previously shown to bind 25-hydroxycholesterol, was now shown to bind also cholesterol in vitro. Yeast two-hybrid, bimolecular fluorescence complementation (BiFC), and co-immunoprecipitation analyses revealed the nuclear pore component Nup62 as an interaction partner of ORP8. Co-localization of ORP8 and Nup62 at the nuclear envelope was demonstrated by BiFC and confocal immunofluorescence microscopy. Furthermore, the impact of overexpressed ORP8 on nSREBPs and their target mRNAs was inhibited in cells depleted of Nup62. Our results reveal that ORP8 has the capacity to modulate lipid homeostasis and SREBP activity, probably through an indirect mechanism, and provide clues of an entirely new mode of ORP action. [ABSTRACT FROM AUTHOR]

Abstract: Insulin resistance is a major feature of pathological states such as obesity and diabetes. A consequence of insulin resistance is enhanced lipolysis, which causes excessive release of free fatty acids and deregulates fatty acid homeostasis. The transcription factor FOXO1 has a central role in the regulation of glucose levels by insulin: reduced insulin signaling causes FOXO1 activation, which increases hepatic glucose production by activating transcription of phosphoenolpyruvate carboxykinase and glucose-6-phosphatase mRNAs. Our results suggest an additional role for FOXO transcription factors: the regulation of lipid homeostasis by insulin. Here, we show that in flies, dFOXO regulates lipase 4 (dLip4), a Drosophila homologue of human acid lipases. dFOXO binds and activates the dLip4 promoter, in vitro and in vivo, and regulates dLip4 expression. In addition, dLip4 mRNA expression in flies is dependent on dFOXO. Our results support a model where dFOXO acts as a key modulator of lipid metabolism by insulin signaling and integrates insulin responses to glucose and lipid homeostasis. [Copyright &y& Elsevier]