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This study aimed to evaluate the impact of combining high-intensity statins with CETP inhibitors on lipid levels, as well as to explore their potential clinical significance. We conducted a comprehensive search of relevant studies in the PubMed, Embase, Cochrane Library, and Web of Science databases. The Cochrane Risk of Bias Tool RoB 2.0 was employed to evaluate the quality of the included studies. Statistical analyses were carried out using STATA 15 software, with primary outcomes being high-density lipoprotein cholesterol (HDL-C) and low-density lipoprotein cholesterol (LDL-C). Out of 2,552 records, 7 studies were included in the final analysis. The findings revealed that the combination of high-intensity statins with CETP inhibitors significantly raised HDL-C levels (SMD 2.47 [1.77, 3.18], p < 0.001) and lowered LDL-C levels (SMD -1.75 [-2.19, -1.31], p < 0.001). Compared to statin monotherapy, the combination of high-intensity statins and CETP inhibitors resulted in a more pronounced increase in HDL-C and ApoAI, while reducing LDL-C, triglycerides (TG), and ApoB levels, without increasing the incidence of adverse events. Show less

Although conventional lipids (high density lipoprotein cholesterol (HDLC), low density lipoprotein cholesterol (LDLC), total cholesterol (TC) and triglycerides (TG)) are therapeutic targets to manage and prevent atherosclerotic cardiovascular disease (CVD), apolipoprotein (Apo) levels have sparked interest for their potential to improve CVD risk prediction. This study explored the relationships of traditional CVD risk factors with conventional lipids, as well as ApoA1, ApoB and its ratio (ApoB: ApoA1) in South African adults of African ancestry. This study included 1697 adults (aged 29 to 94) from the Prospective Urban Rural Epidemiology (PURE) study. The CVD risk markers included body mass index (BMI), physical activity index, tobacco use, dietary fat intake, γ-glutamyl transferase (γGT) and glycated haemoglobin (HbA1C). Conventional lipids were measured in serum samples using standard methodology, while ApoA1 and ApoB were measured using a multiplex magnetic bead immunoassay. Stratified into tertiles of conventional lipid and Apo levels, trends emerged across multiple CVD risk markers, including BMI, tobacco use, fat intake, γGT and HbA1C levels. Higher tertiles of LDLC, TC, TG, ApoB and ApoB: ApoA1, along with the lowest tertiles of HDLC and ApoA1 exhibited higher prevalence of Type II diabetes mellitus (all p ≤ 0.024) and overweight or obesity (all except for TC, p ≤ 0.024). HDLC was negatively associated and LDLC, TC, and TG were positively associated with BMI (all p < 0.001) and HbA1C (all except for TC, p ≤ 0.005). Similarly, ApoA1 associated negatively with BMI (β=-0.067 (-0.125; -0.010), p = 0.022) and HbA1C (β=-0.071 (-0.122; -0.020), p = 0.007), while ApoB associated positively with BMI (β = 0.168 (0.117; 0.218), p < 0.001). The ApoB: ApoA1 showed positive associations with BMI (β = 0.213 (0.163; 0.263), p < 0.001) and HbA1C (β = 0.123 (0.074; 0.172), p < 0.001). In South African adults of African ancestry, ApoA1, ApoB and ApoB: ApoA1 levels are associated with various established CVD risk markers and suggests that these apolipoproteins may provide additional mechanistic insights beyond the conventional lipids to understand the aetiology of early cardiometabolic disease development. Show less

Excess dietary sugar profoundly impacts organismal metabolism and health, yet it remains unclear how metabolic adaptations in adipose tissue influence other organs, including the brain. Here, we show that a high-sugar diet (HSD) in Drosophila reduces adipocyte glycolysis and mitochondrial pyruvate uptake, shifting metabolism toward fatty acid oxidation and ketogenesis. These metabolic changes trigger mitochondrial oxidation and elevate antioxidant responses. Adipocyte-specific manipulations of glycolysis, lipid metabolism, or mitochondrial dynamics non-autonomously modulate Draper expression in brain ensheathing glia, key cells responsible for neuronal debris clearance. Adipocyte-derived ApoB-containing lipoproteins maintain basal Draper levels in glia via LpR1, critical for effective glial phagocytic activity. Accordingly, reducing ApoB or LpR1 impairs glial clearance of degenerating neuronal debris after injury. Collectively, our findings demonstrate that dietary sugar-induced shifts in adipocyte metabolism substantially influence brain health by modulating glial phagocytosis, identifying adipocyte-derived ApoB lipoproteins as essential systemic mediators linking metabolic state with neuroprotective functions. Show less

Existing evidence suggests that elevated 1-hour post-load plasma glucose (1-h PG ≥ 8.6 mmol/L) during an oral glucose tolerance test (OGTT) is associated with atherogenic lipid parameters which are linked to an increased risk of cardiovascular disease (CVD). However, it remains unclear whether normal glucose tolerance (NGT) individuals with elevated 1-h PG (NGT-1hPG-high) should still be considered low-risk. Therefore, this study aims to demonstrate comprehensive lipid characteristics in individuals with different glycemic status stratified by 1-h PG, with a particular focus on those with NGT-1hPG-high. This cross-sectional study included individuals aged 25-55 years with high-risk of diabetes from the Daqing Diabetes Prevention Study II (Daqing DPS-II). Individuals were categorized into different glycemic status based on the World Health Organization's 1999 criteria and the International Diabetes Federation's 2024 position statement on 1-h PG. Traditional (TC, TG, HDL-C, LDL-C) and non-traditional lipid parameters [ApoA-1, ApoB, sdLDL-C, Lp(a), non-HDL-C, remnant cholesterol (RC), ApoB/ApoA-1, LDL-C/ApoB] were measured. Dyslipidemia was defined according to the 2023 Chinese Guidelines for Lipid Management. The China-PAR equation was used to estimate 10-year CVD risk. Spearman's correlation coefficients were calculated to evaluate the correlation between lipid parameters and 10-year CVD risk. Logistic and multiple linear regression models were performed to assess the association between 1-h PG and dyslipidemia as well as lipid parameters adjusting for covariates. Among 2 469 individuals, 22.7% had NGT with normal 1-h PG (NGT-1hPG-normal), 19.9% had NGT-1hPG-high, 2.6% had prediabetes with normal 1-h PG (PDM-1hPG-normal), 34.2% had prediabetes with elevated 1-h PG (PDM-1hPG-high), and 20.6% had newly diagnosed diabetes. The prevalence of dyslipidemia did not significantly differ between NGT-1hPG-high and PDM-1hPG-high (OR = 1.13, 95%CI: 0.88-1.44, P > 0.05). Higher 1-h PG levels were consistently associated with an atherogenic lipid profile, characterized by increased TC, TG, LDL-C, ApoB, sdLDL-C, non-HDL-C, RC and ApoB/ApoA-1, along with decreased ApoA-1, HDL-C and LDL-C/ApoB (all P < 0.05). Among lipid parameters, TG, sdLDL-C, RC, ApoB/ApoA-1, LDL-C/ApoB and HDL-C showed the strongest correlation with 10-year CVD risk, with Spearman's correlation coefficients of 0.41, 0.38, 0.35, 0.31, - 0.37 and - 0.36, respectively. In the NGT-1hPG-high, TG, sdLDL-C, and ApoB/ApoA-1 levels were significantly higher, while HDL-C and LDL-C/ApoB levels were significantly lower compared to counterparts with NGT-1hPG-normal (all P < 0.05). Moreover, except for TG and RC (both P < 0.01), the majority of lipid parameter levels in NGT-1hPG-high did not significantly differ from those in PDM (all P > 0.05). NGT-1hPG-high exhibited a similar atherogenic lipid profile to that observed in PDM. 1-h PG could serve as a potential indicator for the early identification of at-risk individuals who may otherwise go undetected among NGT population. Show less

Diabetes mellitus is associated with morphological and functional impairment of the heart primarily due to lipid toxicity caused by increased fatty acid metabolism. Extracellular signal-regulated protein kinases 1 and 2 (ERK1/2) have been implicated in the metabolism of fatty acids in the liver and skeletal muscles. However, their role in the heart in diabetes remains unclear. In this study, we tested our hypothesis that pharmacological inhibition of ERK1/2 alleviates cardiac remodeling in diabetic mice through a reduction in fatty acid metabolism. ERK1/2 phosphorylation in diabetes was determined both ERK1/2 phosphorylation was significantly increased in diabetic conditions. Inhibition of ERK1/2 by U0126 in both streptozotocin-induced diabetic mice and ERK1/2 are potential therapeutic targets for diabetic cardiomyopathy by modulating fatty acid metabolism in the heart. Show less

Chronic hepatitis C virus (HCV) infection is associated with hypolipidemia. HCV eradication may, therefore, result in hyperlipidemia and increase cardiovascular disease (CVD) risk. We investigated the impact of HCV eradication on serum lipid and lipoprotein profiles and CVD risk during and following direct-acting antiviral (DAA) therapy. We retrospectively analysed stored sera and plasma from 60 DAA-naïve patients, genotypes 1-4, treated with 12 weeks of sofosbuvir-velpatasvir. Serum lipids, apolipoproteins (apo), and a systemic inflammatory marker, GlycA, were measured serially beginning early on treatment and off treatment. Additionally, NMR LipoProfile analysis was performed on plasma samples. Expression of genes regulating lipid metabolism was assessed from paired liver biopsies obtained before and on treatment. Linear mixed models were used to examine changes in lipid and inflammatory markers; Framingham and ASCVD CVD risk scores were assessed before and after treatment. Decline in HCV viremia was associated with a rapid, significant increase in TChol, HDL-C, LDL-C, ApoA-1 and ApoB, and GlycA, improvement in ALT, hepatic inflammation, and steatosis but no change in glycemic control (HOMA-IR and HbA1c). Increase in TChol, LDL-C, and ApoB was associated with an increased SREBP1expression. Both ASCVD and Framingham risk scores were significantly increased at week 24 post treatment after adjusting for age (p < 0.0001). Serum lipids and lipoproteins rapidly increase with inhibition of viral replication during DAA therapy, an effect that may be mediated by genes affecting hepatic de novo lipogenesis. Based on lipid changes, HCV eradication may increase CVD risk, but this needs to be investigated prospectively. Show less

Crystals or stones within the gallbladder wall in patients with gallbladder stones (GBS) have been occasionally reported, but their clinical features and aetiology remain unclear. This retrospective study analysed 323 consecutive patients with GBS who underwent rigid choledochoscopic gallbladder-preserving cholecystolithotomy to determine the detection rate, clinical features, and potential risk factors of gallbladder intramural stones (IS). IS were found in 24.1% (78/323) of patients, characterised by distinct cholangioscopic findings, including stone shadows, yellow floating bands, or a combination of both within the gallbladder wall. Compared to patients without IS, those with IS had a higher prevalence of Clonorchis sinensis (C. sinensis) eggs (60.3% vs. 40.8%, P < 0.05) and elevated serum cholesterol, LDL cholesterol, and Apo-B levels (P < 0.05). However, stone composition and C. sinensis egg detection rates did not differ between intraluminal stones and IS within the same patient (P > 0.05). Logistic regression analysis revealed that IS were associated with C. sinensis infection and elevated Apo-B levels. In conclusion, IS share homology with intraluminal stones in the same patient with GBS and exhibit unique appearances in rigid choledochoscopy. For patients with GBS and IS, elevated serum Apo-B levels and C. sinensis infection were independent risk factors. Show less

We have designed the first antigen-less pro-vaccine, named 8206, for treating autoimmune diseases. Composed of dexamethasone, rapamycin, and R848 at a mass ratio of 8:20:6, 8206 is a complete tolerogenic adjuvant that acts systemically to form an active vaccine in situ with endogenous pathogenic autoantigens. This active vaccine suppresses autoimmunity by expanding antigen-specific Treg cells in affected tissues. In a mouse model of atherosclerosis, 8206 successfully targeted all three analyzed pathogenic autoantigens (ApoB, HSP60, and HMGB1) and inhibited disease progression. These findings suggest that 8206 can potentially serve as a universal treatment vaccine for autoimmune diseases by eliminating the need for exogenous immunogens, with implications for broad applications in immunotherapy. Show less

Aromatase, encoded by Cyp19a1, is the rate limiting enzyme in biosynthesis of estrogens, and excessive aromatase can reduce the semen quality in roosters. Seminal plasma extracellular vesicles (SPEV) are nanoscale vesicles that carry and transmit signaling molecules, thereby affecting semen quality. Currently it is still unclear whether SPEV are involved in the process of that aromatase affects the quality semen in chicken. To clarify this issue, lentivirus carrying Cyp19a1 (LV-CYP19A1) for over-expression of aromatase was constructed and injected to testis of 35-week-old roosters. Semen quality and seminal plasma hormone were measured, and SPEV were also extracted and proteome sequencing was performed after treatment of LV-CYP19A1. The results indicated that semen volume, fertility, sperm motility, testosterone (T) levels were significantly decreased, and estradiol (E Our results reveal that aromatase can down-regulate the protein expression related to regulation of ATP synthesis and metabolism, and sperm motility in SPEV, thereby reducing semen quality in roosters. Show less

Chylomicron biosynthesis plays a vital role in supplying essential lipids and lipid soluble vitamins to peripheral tissues for various functions. Despite this, the intracellular synthesis, trafficking, and secretion of chylomicrons remains only partly understood. The purpose of this review is to summarize the role of established proteins in this process and bring attention to recently identified proteins to provide an up-to-date model of chylomicron biosynthesis. Recently, several proteins have been shown to play a role in the initial formation and lipidation of chylomicrons at the endoplasmic reticulum (ER), which include: TM6SF2, PLA2G12B, PRAP1, and SURF4. In addition, mitochondria have been implicated in chylomicron metabolism, but mechanistic insight is missing. The trafficking of chylomicrons from the ER to the Golgi, and the subsequent trafficking from the Golgi to the basolateral side of enterocytes, however, remains a mystery. Progress in the chylomicron biosynthesis field is largely associated with findings in VLDL biosynthesis. In addition, increased insight in events after prechylomicrons leave the ER is needed. Given the important role of chylomicron biosynthesis in whole-body lipid metabolism, further research into the molecular mechanisms is warranted. Show less

Proprotein convertase subtilisin/kexin type 9 (PCSK9) increases circulating LDL levels and cardiovascular disease (CVD) risk; its levels may be related to the dysregulation of glycemic control and may be affected by estrogens. The aim of this study was to assess factors related to PCSK9 levels, and to evaluate the correlation between PCSK9 levels and CV parameters in post-menopausal diabetic women in primary prevention. Generalized linear models (GLM) were adopted to evaluate predictors of PCSK9 levels as well as factors related to CV outcomes, such as pulse wave velocity (PWV), pulse pressure (PP), and augmentation index (AI). A total of 135 post-menopausal diabetic women, with a median (Q1-Q3) serum PCSK9 levels of 370.3 (344.0-409.4) ng/ml were enrolled. Apolipoprotein B values resulted an independent predictor of PCSK9 levels ( ApoB and LDL may influence PCSK9 levels and PCSK9 directly influence PWV in post-menopausal diabetic women in primary prevention. Therefore, the relationship between PCSK9 and primary prevention cannot be excluded, thus highlighting its role as biomarker of CV risk. Show less

Genome-wide association studies have revealed numerous loci associated with coronary artery disease (CAD). However, some potential causal/risk genes remain unidentified, and causal therapies are lacking. We integrated multi-omics data from gene methylation, expression, and protein levels using summary data-based Mendelian randomization and colocalization analysis. Candidate genes were prioritized based on protein-level associations, colocalization probability, and links to methylation and expression. Single-cell RNA sequencing data were used to assess differential expression in the coronary arteries of patients with CAD. Our findings provide multi-omics evidence suggesting that Show less

Previous studies have reported that 40 Hz visual stimulation (acute white light exposure) reduced Aβ levels in Alzheimer's disease (AD) mouse model. However, whether different light colors distinctly regulate AD pathologies has not been well characterized. In the present study, an optimized organic light-emitting diode (OLED)-based visual stimulation platform was developed to provide uniform illumination without blind spots, and the color-dependent effects on cognitive function and amyloid-β (Aβ) pathology were investigated in 5xFAD mice, an Aβ-overexpressing AD model. Acute exposure to white or red OLED light (1 h/day for 2 days) significantly improved cognitive function, reduced hippocampal Aβ plaque accumulation via increasing ADAM17 activity, and downregulated proinflammatory cytokine IL-1β levels in 3-month-old 5xFAD mice, whereas green or blue OLED light did not produce these effects. In addition, chronic white and red OLED stimulation (1 h/day for 2 weeks) was shown to enhance recognition memory; however, only red light further diminished Aβ plaque deposition by upregulating ADAM17 activity and suppressing BACE-1 activity without altering neuroinflammation in 6-month-old 5xFAD mice. Moreover, acute white and red OLED exposure (1 h, single session) was observed to enhance c-fos expression, which is associated with neural activation along the visual pathway, thereby suggesting a mechanistic link between light stimulation and cognitive enhancement. Taken together, these findings demonstrate that color-dependent visual stimulation may serve as a promising electroceutical strategy for AD, with red light uniquely combining memory enhancement, Aβ reduction via ADAM17 upregulation and BACE1 suppression, and anti-inflammatory effects. Show less

Lipoprotein(a) [Lp(a)] is underutilized in short-term atherosclerotic cardiovascular disease (ASCVD) risk prediction. This study investigates Lp(a) contribution to short-term ASCVD event prediction using contemporary real-world data and machine learning (ML). A cohort of 731,983 individuals from a claims database was used to investigate the association of Lp(a) with incident ASCVD and all-cause mortality using Cox proportional hazards models. Novel ML models were developed to predict incident ASCVD events at 1, 2, and 3 years after Lp(a) testing. The models were validated in an independent cohort of 53,930 patients. An increase of 50 nmol/L in Lp(a) was independently associated with incident ASCVD events (HR: 1.072; 95% CI: 1.059-1.084) and all-cause mortality (HR: 1.041; 95% CI: 1.015-1.068) after adjustment for age, sex, and race/ethnicity. Novel ML models featuring Lp(a) predicted incident ASCVD events at 1, 2, and 3 years with robust discrimination (C-statistic: 0.83-0.84) in both the derivation and validation cohorts. Modest underestimation of risk was observed in the validation cohort for the 1-year model (calibration slope 1.25). Lp(a) contributed more to 1-year ASCVD prediction than smoking, diabetes, and other lipid parameters. Inclusion of Lp(a) in the 1-year model led to an integrated discrimination improvement of 0.03 and an optimal net reclassification improvement of 10% at a risk threshold of 26%. Lp(a) is a significant predictor of short-term ASCVD risk. Assessing Lp(a) and imminent ASCVD risk may assist in identifying patients who may benefit from escalation of preventative therapies. Show less

Patients with diabetic nephropathy (DN) often present with lipid profile abnormalities. While associations between these parameters and DN have been suggested, confounding factors obscure causal relationships. This study employed bidirectional Mendelian randomization (MR) to explore these links. Using genome-wide association study (GWAS) data, the primary analysis used the inverse-variance weighted (IVW) method, which was supported by MR-Egger regression and a weighted median estimator (WME). Sensitivity analyses, including heterogeneity, pleiotropy tests, leave-one-out, and reverse causality analyses, were conducted. The IVW model revealed the following: (1) causal relationships between triglycerides (TG) (OR: 1.5807, 95% CI: 1.2578-1.9865, P = 0.0001), high-density lipoprotein cholesterol (HDL-C) (OR: 0.7342, 95% CI: 0.5729-0.9409, P = 0.0146), and apolipoprotein A1 (ApoA1) (OR: 0.6506, 95% CI: 0.5190-0.8156, P = 0.0002) and DN; (2) causal relationships between TG (OR: 1.0607, 95% CI: 1.0143-1.1093, P = 0.0098), HDL-C (OR: 0.9453, 95% CI: 0.9053-1.9871, P = 0.0109), and apolipoprotein B (ApoB) (OR: 1.0672, 95% CI: 0.0070-1.1310, P = 0.0280) and the urinary albumin-creatinine ratio (UACR); (3) no causal relationship between total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), ApoB and DN, or between TC, LDL-C, ApoA1 and UACR; (4) none of the results showed reverse causality. TG is a risk factor for DN and UACR; HDL-C is protective for both; ApoA1 protects against DN; and ApoB is a risk factor for UACR. To further explore the underlying mechanisms between TG, HDL-C, ApoA1, ApoB, and their associations with DN and UACR, and to provide reference for the selection of lipid management and treatment strategies for clinical DN patients. This study demonstrated that causal relationships between TG, HDL-C, and ApoA1 with DN and between TG, HDL-C, and ApoB with the UACR. Show less

The objective was to assess the clinical efficacy of long non-coding RNA (lncRNA) alpha-2-macroglobulin-antisense 1 (A2M-AS1) in acute myocardial infarction (AMI). One hundred patients with AMI and eighty patients with chest pain were recruited in the case-control study. A2M-AS1 expression was examined by quantitative real-time polymerase chain reaction (qRT-PCR). Receiver operating characteristic (ROC) analysis was utilized for evaluating the diagnostic value. Pearson's correlation analysis was used to analyze the correlation between A2M-AS1 and conventional AMI biomarkers. AMI-associated risk indicators were identified using logistic regression analysis. A significant reduction of serum A2M-AS1 was measured in AMI patients relative to chest pain patients. A2M-AS1 had an area under the curve (AUC) of 0.927 to distinguish AMI patients from those with chest pain. Pearson's correlation analysis showed that A2M-AS1 was adversely correlated with white blood cell (WBC) (r=-0.6682, P < 0.001), low density lipoprotein cholesterol (LDL-C) (r=-0.5795, P < 0.001), creatine kinase MB (CK-MB) (r=-0.6022, P < 0.001) and cTnl (r=-0.5473; P < 0.001), while positively correlated with high density lipoprotein cholesterol (HDL-C) (r = 0.6445, P < 0.001). Relative to non-Major Adverse Cardiovascular Events (non-MACE) group, serum A2M-AS1 was obviously declined in the MACE group of AMI patients with high capacity to distinguish the MACE group from the non-MACE patients (AUC = 0.802). Additionally, A2M-AS1 (P = 0.013; OR = 0.268; 95%CI = 0.095-0.760) was a risk indicator for predicting MACE with AMI patients, as well as age (P = 0.014; OR = 3.478; 95%CI = 1.285-9.414). A reduction in A2M-AS1 expression was observed in AMI patients, suggesting its potential as an underlying indicator for AMI diagnosis. Show less

Small and dense LDL cholesterol (sdLDL-C) and apolipoprotein B (ApoB) have important roles in promoting the development of atherosclerosis and are highly correlated with the degree of atherosclerosis. Several studies have found differences in anterior and posterior circulation strokes and in the mechanisms of their atherosclerosis, but little research has been done on the relationship of sdLDL-C and ApoB to atherosclerotic stenosis in anterior and posterior circulation strokes. We analyzed the correlation between sdLDL-C and ApoB and the degree of arterial stenosis in patients with posterior circulation stroke. We included 230 anterior circulation stroke (ACS) patients and 170 posterior circulation stroke (PCS) patients. Blood specimens were collected at admission, serum ApoB and sdLDL-C concentrations were measured, and the degree of arterial stenosis was determined on the basis of vascular imaging. We analyzed the predictive value of ApoB and sdLDL-C for the degree of cerebral artery stenosis in patients with PCS. For patients with nonmild stenosis, sdLDL-C and ApoB levels were higher in the PCS group than in the ACS group (P < 0.05). SdLDL-C (P < 0.001) and ApoB (P < 0.05) were independent risk factors for increased intracranial artery stenosis in the posterior circulation group. Binary logistic regression analysis showed that sdLDL-C (P < 0.05) and ApoB (P < 0.05) were independent risk factors for non-mild stenosis of the intracranial arteries in patients with PCS after correction for confounders. In the posterior circulation group, there was an interaction between the effects of sdLDL and ApoB on intracranial artery stenosis, P < 0.05. Plotting the ROC curve showed that the AUC of the combined detection of sdLDL-C and ApoB was 0.791, which was better than that of the single index. We built nomogram model, the DCA curves, calibration curves, NRI index, and IDI index of both the modeling and validation groups indicated that the diagnostic efficacy and clinical benefit of the combined sdLDL-C and ApoB assay were greater than those of single-indicator assays for cerebral artery stenosis in posterior circulation stroke. Risk factors contributing to the increased degree of intracranial arterial stenosis in ACS and PCS vary somewhat. SdLDL-C and ApoB may be of value in clinical decision making as predictors of cerebral arterial stenosis in patients with PCS. Show less

Genome-wide association studies (GWAS) have identified common variants associated with metabolic dysfunction-associated steatotic liver disease (MASLD). However, rare coding variant studies have been limited by phenotyping challenges and small sample sizes. We test associations of rare and ultra-rare coding variants with proton density fat fraction (PDFF) and MASLD case-control status in 736,010 participants of diverse ancestries from the UK Biobank, All of Us, and BioMe and performed a trans-ancestral meta-analysis. We then developed models to accurately predict PDFF and MASLD status in the UK Biobank and tested associations with these predicted phenotypes to increase statistical power. The trans-ancestral meta-analysis with PDFF and MASLD case-control status identifies two single variants and two gene-level associations in APOB, CDH5, MYCBP2, and XAB2. Association testing with predicted phenotypes, which replicates more known genetic variants from GWAS than true phenotypes, identifies 16 single variants and 11 gene-level associations implicating 23 additional genes. Two variants were polymorphic only among African ancestry participants and several associations showed significant heterogeneity in ancestry and sex-stratified analyses. In total, we identified 27 genes, of which 3 are monogenic causes of steatosis (APOB, G6PC1, PPARG), 4 were previously associated with MASLD (APOB, APOC3, INSR, PPARG), and 23 had supporting clinical, experimental, and/or genetic evidence. Our results suggest that trans-ancestral association analyses can identify ancestry-specific rare and ultra-rare coding variants in MASLD pathogenesis. Furthermore, we demonstrate the utility of machine learning in genetic investigations of difficult-to-phenotype diseases in trans-ancestral biobanks. Show less

Previous studies have investigated the role of metabolic factors in risk of hematological malignancies with contradicting findings. Existing studies are generally limited by potential concern of reverse causality and confounding by inflammation. Therefore, we aimed to investigate the associations of glucose, lipid, and apolipoprotein biomarkers with the risk of hematological malignancy. We performed a study of over 560,000 individuals of the Swedish AMORIS cohort, with measurements of biomarkers for carbohydrate, lipid, and apolipoprotein metabolism during 1985-1996 and follow-up until 2020. We conducted a prospective cohort study and used Cox models to investigate the association of nine different metabolic biomarkers (glucose, total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), LDL-C/HDL-C, triglyceride (TG), apolipoprotein B (ApoB), apolipoprotein A-I (ApoA I), and ApoB/ApoA-I) with risk of hematological malignancy, after excluding the first five years of follow-up and adjustment for inflammatory biomarkers. We observed a decreased risk of hematological malignancy associated with one SD increase of TC (HR 0.93; 95% CI 0.91-0.96), LDL-C (HR 0.94; 95% CI 0.91-0.97), HDL-C (HR 0.92; 95% CI 0.86-0.99), and ApoA-I (HR 0.96; 95% CI 0.93-0.996). Our study highlights a decreased risk of hematological malignancy associated with a higher level of TC, LDL-C, HDL-C, and ApoA-I. Show less

Atrial fibrillation (AF) has become the most common arrhythmia of clinical importance. A well-established and recommended therapeutic option for AF is the balloon-based cryoablation (CBA) method. There are still no sensitive biomarkers for AF prediction and cryoablation effectiveness assessment, therefore in our prospective study, we examined the plasma content of apolipoproteins (Apo) and sphingolipids, as well as the distribution of selected sphingolipids among lipoprotein fractions. The study included 33 patients with AF on admission and 24 h after cryoablation therapy, while 20 healthy volunteers were recruited to the control group. Plasma Apo concentrations were determined using a multiplex assay kit measuring fluorescence signal, whereas the high-performance liquid chromatography (HPLC) method was applied to assess the total plasma sphingolipid levels as well as their content in isolated lipoprotein fractions. Our results showed that cryoballoon ablation in AF patients markedly reduced the level of almost all Apo compared to the individuals from the control and Pre-CBA groups (Apo-A1: -25.9% and -20.0%, Apo-A2: -19.9% and -17.3%, Apo-B: -26.8% and -14.4%, Apo-C1: -20.3% and -13.4%, Apo-D: -15.9% and -22.2%, Apo-E: -18.3% and -14.3%, and Apo-J: -36.4% and -21.5%, p < 0.05, respectively). Importantly, the area under the curve of Apo-J (AUC 0.81; 95% CI, 0.71-0.92) indicates that it might be a useful biomarker of cryotherapy success in AF patients. Moreover, we also observed a pronounced increase in sphinganine (Sa; +33.5%), sphingosine (So; +24.6%), sphinganine-1-phosphate (Sa1P; +34.3%), and sphingosine-1-phosphate (So1P; +22.3%) concentrations in the Pre-CBA group in comparison with controls. This is the first study that evaluates such a broad panel of Apo and sphingolipids in patients with AF undergoing the CBA procedure, however, to confirm whether any of these parameters could be a clinically useful biomarker for predicting AF or assessing the effectiveness of treatment, further research will be necessary due to limitations of the study. Show less

Studies have shown that essential oils not only increase cell viability but also affect lipid metabolism in mammals. However, the extent to which these effects are realized in goose liver has not yet been fully elucidated. The object of research is to investigate the effects of four essential oil mixtures (juniper oil, mint oil, thyme oil, rosemary oil) on lipid metabolic gene expressions in goose. We measured mRNA levels of metabolic genes (ACSBG2, ELOVL1, ELOVL2, CYP2Cl9, CYP2K1), antioxidative gene (SOD1) and very low-density lipoprotein triglyceride (VLDL) synthesis genes (APOB, FOXO1, MTTP), in goose (Anser anser) liver. Search groups were formed as C (control; no additives), EK1 (0.4 mL/L essential oil mixture supplemented) and EK2 (0.8 mL/L essential oil mixture supplemented). The relative expression levels of genes in the liver were measured using RT-qPCR. β-Actin was used as reference gene control for normalization of qPCR data. As a result, essential oil supplementation downregulated metabolic genes compared to the control group. APOB gene among VLDL genes was significantly downregulated. Antioxidative effect gene was downregulated in parallel with the others. This indicates that essential oil intake with drinking water downregulates the genes involved in lipid metabolism in goose liver. Our data show that essential oils have a significant effect on the regulation of genes and pathways involved in hepatic lipid metabolism. Show less

The heat shock response (HSR) is a conserved cellular mechanism critical for adaptation to environmental and physiological stressors, with broad implications for cell survival, immune responses, and cancer biology. While the HSR has been extensively studied at the proteomic and transcriptomic levels, the role of lipid metabolism and membrane reorganization remains underexplored. Here, we integrate mass spectrometry-based lipidomics with RNA sequencing to characterize global lipidomic and transcriptomic changes in HeLa cells exposed to three conditions: control, heat shock (HS), and HS with eight hours of recovery. Heat shock-induced extensive lipid remodeling, including significant increases in fatty acids, glycerophospholipids, and sphingolipids, with partial normalization during recovery. Transcriptomic analysis identified over 2,700 upregulated and 2,300 downregulated genes under heat shock, with GO enrichment suggesting potential transcriptional contributions to lipid metabolism. However, transcriptional changes alone did not fully explain the observed lipidomic shifts, suggesting additional layers of regulation. Joint pathway analysis revealed enrichment in glycerophospholipid and sphingolipid metabolism, while network analysis identified lipid transport regulators (STAB2, APOB), stress-linked metabolic nodes (KNG1), and persistent sphingolipid enrichment during recovery. These findings provide a comprehensive framework for understanding lipid-mediated mechanisms of the HSR and highlight the importance of multi-omics integration in stress adaptation and disease biology. Show less

Heterozygous familial hypobetalipoproteinemia (FHBL) is a semi-autosomal disorder that is caused mainly by an A 12-year-old boy was referred to our hospital after prolonged elevation of liver enzymes was observed during health checkups in Kagawa Prefecture. Abdominal ultrasound showed a bright liver, and laboratory investigations revealed low low-density lipoprotein cholesterol and apolipoprotein B protein levels. His family history included fatty liver and hypolipidemia in his father, which led to a clinical diagnosis of FHBL. A liver biopsy was performed on suspicion of liver fibrosis based on biomarkers. The liver tissue showed fatty steatosis, inflammation, hepatocyte ballooning, and fibrosis, indicating NASH. Genetic testing detected the It is important to assess family history and liver dysfunction severity in non-obese patients with hypolipidemia and fatty liver. Show less

Studies using machine learning to identify the target characteristics and develop predictive models for coronary artery disease severity in patients with premature myocardial infarction (PMI) are limited. In this observational study, 1111 PMI patients (≤55 years) at Tianjin Chest Hospital from 2017 to 2022 were selected and divided according to their SYNTAX scores into a low-risk group (≤22) and medium-high-risk group (>22). These groups were further randomly assigned to a training or test set in a ratio of 7:3. Lasso-logistic was initially used to screen out target factors. Subsequently, Lasso-logistic, random forest (RF), k-nearest neighbor (KNN), support vector machine (SVM), and eXtreme Gradient Boosting (XGBoost) were used to establish prediction models based on the training set. After comparing prediction performance, the best model was chosen to build a prediction system for coronary artery severity in PMI patients. Glycosylated hemoglobin (HbA1c), angina, apolipoprotein B (ApoB), total bile acid (TBA), B-type natriuretic peptide (BNP), D-dimer, and fibrinogen (Fg) were associated with the severity of lesions. In the test set, the area under the curve (AUC) of Lasso-logistic, RF, KNN, SVM, and XGBoost were 0.792, 0.775, 0.739, 0.656, and 0.800, respectively. XGBoost showed the best prediction performance according to the AUC, accuracy, F1 score, and Brier score. In addition, we used decision curve analysis (DCA) to assess the clinical validity of the XGBoost prediction model. Finally, an online calculator based on the XGBoost was established to measure the severity of coronary artery lesions in PMI patients. In summary, we established a novel and convenient prediction system for the severity of lesions in PMI patients. This system can swiftly identify PMI patients who also have severe coronary artery lesions before the coronary intervention, thus offering valuable guidance for clinical decision-making. Show less

The therapeutic value of lipid-lowering drugs in pulmonary vascular disease remains uncertain due to insufficient studies and evidence. This study aims to investigate the causal effects of lipid-lowering drugs (specifically, inhibitors of APOB, CETP, HMGCR, NPC1L1, and PCSK9) on pulmonary vascular diseases using a Mendelian randomization (MR) approach. We utilized summary-level statistics from genome-wide association studies (GWAS) to simulate the exposure to low-density lipoprotein cholesterol (LDL-C) and its outcomes on pulmonary arterial hypertension (PAH), pulmonary embolism (PE), and pulmonary heart disease (PHD). Single-nucleotide polymorphisms (SNPs) within or near drug target-associated LDL-C loci were selected as proxies for the lipid-lowering drugs. Data from the FinnGen cohort and UK Biobank (UKB) were incorporated to enhance the robustness and generalizability of the findings. The inverse variance weighted (IVW) and MR-Egger methods were employed to estimate MR effects. Our MR analysis indicated that LDL-C mediated by NPC1L1 (odds ratio [OR] = 104.76, 95% confidence interval [CI] = 2.01-5457.01, Show less

This study aims to evaluate the relationship between apolipoproteins (ApoA1, ApoB, and the ApoB/A1 ratio) and the incidence of major adverse cardiovascular events (MACE) in patients with coronary artery disease (CAD) and impaired kidney function, assessing their potential role in secondary prevention. A prospective cohort of 1,640 patients with impaired kidney function who underwent percutaneous coronary intervention in China was analyzed. Patients were categorized based on the measurements of ApoA1, ApoB, and ApoB/A1 ratio. MACE, defined as a composite of all-cause mortality, cardiovascular death, nonfatal myocardial infarctions, strokes, and unplanned revascularizations, was tracked post-procedure, with statistical analyses including Kaplan-Meier survival curves and Cox regression models to identify associations with apolipoproteins. Subgroup analyses according to kidney function were conducted. During a median follow-up of 3.1 years, 324 MACE events were observed. Multivariable Cox regression analyses illustrated higher levels of ApoB and the ApoB/A1 ratio were significantly associated with increased MACE incidence (adjusted HR [95%CI] 1.668[1.044-2.666]; adjusted HR [95%CI] 2.231[1.409-3.533], respectively), while lower ApoA1 levels correlated with a higher risk (adjusted HR [95%CI] 0.505[0.326-0.782]). ROC curve analyses indicated comparable predictive performances to traditional risk factors like LDL cholesterol. Subgroup analysis revealed that the above association was not statistically significant in the moderate-to-severe renal impairment CAD patients (eGFR < 45 mL/min/1.73 m Our findings illustrate that apolipoproteins, specifically ApoA1 and ApoB, along with their ratio, are significant predictors of major adverse cardiovascular events in CAD patients with impaired kidney function. These results emphasize the need for incorporating apolipoprotein measurements in secondary prevention strategies for this high-risk population. Show less