HDL-cholesterol confers sensitivity of immunotherapy in nasopharyngeal carcinoma via remodeling tumor-associated macrophages towards the M1 phenotype.

BACKGROUND: The sustained effectiveness of anti-programmed cell death protein-1/programmed death-ligand 1 treatment is limited to a subgroup of patients with advanced nasopharyngeal carcinoma (NPC), and the specific biomarker determining the response to immunotherapy in NPC remains uncertain. METHODS: We assessed the associations between pre-immunotherapy and post-immunotherapy serum lipoproteins and survival in a training cohort (N=160) and corroborated these findings in a validation cohort (N=100). Animal studies were performed to explore the underlying mechanisms. Additionally, the relationship between high-density lipoprotein-cholesterol (HDL-C) levels and M1/M2-like macrophages, as well as activated CD8+T cells in tumor tissues from patients with NPC who received immunotherapy, was investigated. RESULTS: The lipoproteins cholesterol, HDL-C, low-density lipoprotein-cholesterol, triglycerides, apolipoprotein A-1 (ApoA1), and apolipoprotein B, were significantly altered after immunotherapy. Patients with higher baseline HDL-C or ApoA1, or those with increased HDL-C or ApoA1 after immunotherapy had longer progression-free survival, a finding verified in the validation cohort (p<0.05). Multivariate analysis revealed that baseline HDL-C and elevated HDL-C post-immunotherapy were independent predictors of superior PFS (p<0.05). Furthermore, we discovered that L-4F, an ApoA1 mimetic, could inhibit tumor growth in NPC xenografts. This effect was associated with L-4F's ability to polarize M2-like macrophages towards an M1-like phenotype via the activation of mitogen-activated protein kinase (MAPK) p38 and nuclear factor-κB (NF-κB) p65, thereby alleviating immunosuppression in the tumor microenvironment. Importantly, in patients with NPC with high plasma HDL-C levels, the number of M2-like macrophages was significantly decreased, while M1-like macrophages and activated CD8+T cells were notably increased in those with high HDL-C levels. CONCLUSION: Higher baseline HDL-C levels or an increase in HDL-C post-immunotherapy can enhance immunotherapeutic responses in patients with NPC by reprogramming M2-like macrophages towards the M1 phenotype. This suggests a potential role for prospectively exploring ApoA1 mimetics as adjuvant agents in combination with immunotherapy.

Increasing the complexity of lipoprotein characterization for cardiovascular risk in type 2 diabetes.

The burden of cardiovascular disease is particularly high among individuals with diabetes, even when LDL cholesterol is normal or within the therapeutic target. Despite this, cholesterol accumulates in their arteries, in part, due to persistent atherogenic dyslipidaemia characterized by elevated triglycerides, remnant cholesterol, smaller LDL particles and reduced HDL cholesterol. The causal link between dyslipidaemia and atherosclerosis in T2DM is complex, and our contention is that a deeper understanding of lipoprotein composition and functionality, the vehicle that delivers cholesterol to the artery, will provide insight for improving our understanding of the hidden cardiovascular risk of diabetes. This narrative review covers three levels of complexity in lipoprotein characterization: 1-the information provided by routine clinical biochemistry, 2-advanced nuclear magnetic resonance (NMR)-based lipoprotein profiling and 3-the identification of minor components or physical properties of lipoproteins that can help explain arterial accumulation in individuals with normal LDLc levels, which is typically the case in individuals with T2DM. This document highlights the importance of incorporating these three layers of lipoprotein-related information into population-based studies on ASCVD in T2DM. Such an attempt should inevitably run in parallel with biotechnological solutions that allow large-scale determination of these sets of methodologically diverse parameters.

CETP inhibition enhances monocyte activation and bacterial clearance and reduces streptococcus pneumonia-associated mortality in mice.

Sepsis is a leading cause of mortality worldwide, and pneumonia is the most common cause of sepsis in humans. Low levels of high-density lipoprotein cholesterol (HDL-C) levels are associated with an increased risk of death from sepsis, and increasing levels of HDL-C by inhibition of cholesteryl ester transfer protein (CETP) decreases mortality from intraabdominal polymicrobial sepsis in APOE*3-Leiden.CETP mice. Here, we show that treatment with the CETP inhibitor (CETPi) anacetrapib reduced mortality from Streptococcus pneumoniae-induced sepsis in APOE*3-Leiden.CETP and APOA1.CETP mice. Mechanistically, CETP inhibition reduced the host proinflammatory response via attenuation of proinflammatory cytokine transcription and release. This effect was dependent on the presence of HDL, leading to attenuation of immune-mediated organ damage. In addition, CETP inhibition promoted monocyte activation in the blood prior to the onset of sepsis, resulting in accelerated macrophage recruitment to the lung and liver. In vitro experiments demonstrated that CETP inhibition significantly promoted the activation of proinflammatory signaling in peripheral blood mononuclear cells and THP1 cells in the absence of HDL; this may represent a mechanism responsible for improved bacterial clearance during sepsis. These findings provide evidence that CETP inhibition represents a potential approach to reduce mortality from pneumosepsis.

Modulation of lipid profile by secretory phospholipase A2 group IIA: Verification with a transgenic mouse model.

We previously demonstrated a positive relation of secretory phospholipase A2 group IIA (sPLA2-IIA) with circulating high-density lipoprotein cholesterol (HDL-C) in patients with coronary artery disease, and sPLA2-IIA increased cholesterol efflux in THP-1 cells through peroxisome proliferator-activated receptor-γ (PPAR-γ)/liver X receptor α/ATP-binding cassette transporter A1 (ABCA1) signaling pathway. The aim of the present study was to examine the role of sPLA2-IIA over-expression on lipid profile in a transgenic mouse model. Fifteen apoE-/- and C57BL/7 female mice received bone marrow transplantation from transgenic SPLA2-IIA mice, and treated with specific PPAR-γ inhibitor GW9662. High fat diet was given after one week of bone marrow transplantation, and animals were sacrificed after twelve weeks. Immunohistochemical staining showed over-expression of sPLA2-IIA protein in the lung and spleen. The circulating level of HDL-C, but not that of low-density lipoprotein cholesterol (LDL-C), total cholesterol, or total triglyceride, was increased by sPLA2-IIA over-expression, and was subsequently reversed by GW9662 treatment. Over-expression of sPLA2-IIA resulted in augmented expression of cholesterol transporter ABCA1 at mRNA level in the aortas, and at protein level in macrophages, co-localized with macrophage specific antigen CD68. GW9662 exerted potent inhibitory effects on sPLA2-IIA-induced ABCA1 expression. Conclusively, we demonstrated the effects of sPLA2-IIA on circulating HDL-C level and the expression of ABCA1, possibly through regulation of PPAR-γ signaling in transgenic mouse model, that is in concert with the conditions in patients with coronary artery disease.

Endothelial lipase variant T111I does not alter inhibition by angiopoietin-like proteins.

High levels of HDL-C are correlated with a decreased risk of cardiovascular disease. HDL-C levels are modulated in part by the secreted phospholipase, endothelial lipase (EL), which hydrolyzes the phospholipids of HDL and decreases circulating HDL-C concentrations. A 584C/T polymorphism in LIPG, the gene which encodes EL, was first identified in individuals with increased HDL levels. This polymorphism results in a T111I point mutation the EL protein. The association between this variant, HDL levels, and the risk of coronary artery disease (CAD) in humans has been extensively studied, but the findings have been inconsistent. In this study, we took a biochemical approach, investigating how the T111I variant affected EL activity, structure, and stability. Moreover, we tested whether the T111I variant altered the inhibition of phospholipase activity by angiopoietin-like 3 (ANGPTL3) and angiopoietin-like 4 (ANGPTL4), two known EL inhibitors. We found that neither the stability nor enzymatic activity of EL was altered by the T111I variant. Moreover, we found no difference between wild-type and T111I EL in their ability to be inhibited by ANGPTL proteins. These data suggest that any effect this variant may have on HDL-C levels or cardiovascular disease are not mediated through alterations in these functions.

A regulatory element associated to NAFLD in the promoter of DIO1 controls LDL-C, HDL-C and triglycerides in hepatic cells.

BACKGROUND: Genome-wide association studies (GWAS) have identified genetic variants linked to fat metabolism and related traits, but rarely pinpoint causative variants. This limitation arises from GWAS not considering functional implications of noncoding variants that can affect transcription factor binding and potentially regulate gene expression. The aim of this study is to investigate a candidate noncoding functional variant within a genetic locus flagged by a GWAS SNP associated with non-alcoholic fatty liver disease (NAFLD), a condition characterized by liver fat accumulation in non-alcohol consumers. METHODS: CRISPR-Cas9 gene editing in HepG2 cells was used to modify the regulatory element containing the candidate functional variant linked to NAFLD. Global gene expression in mutant cells was assessed through RT-qPCR and targeted transcriptomics. A phenotypic assay measured lipid droplet accumulation in the CRISPR-Cas9 mutants. RESULTS: The candidate functional variant, rs2294510, closely linked to the NAFLD-associated GWAS SNP rs11206226, resided in a regulatory element within the DIO1 gene's promoter region. Altering this element resulted in changes in transcription factor binding sites and differential expression of candidate target genes like DIO1, TMEM59, DHCR24, and LDLRAD1, potentially influencing the NAFLD phenotype. Mutant HepG2 cells exhibited increased lipid accumulation, a hallmark of NAFLD, along with reduced LDL-C, HDL-C and elevated triglycerides. CONCLUSIONS: This comprehensive approach, that combines genome editing, transcriptomics, and phenotypic assays identified the DIO1 promoter region as a potential enhancer. Its activity could regulate multiple genes involved in the NAFLD phenotype or contribute to defining a polygenic risk score for enhanced risk assessment in NAFLD patients.

Potential association of genetically predicted lipid and lipid-modifying drugs with rheumatoid arthritis: A Mendelian randomization study.

BACKGROUND: Past studies have demonstrated that patients diagnosed with rheumatoid arthritis (RA) often exhibit abnormal levels of lipids. Furthermore, certain lipid-modifying medications have shown effectiveness in alleviating clinical symptoms associated with RA. However, the current understanding of the causal relationship between lipids, lipid-modifying medications, and the risk of developing RA remains inconclusive. This study employed Mendelian randomization (MR) to investigate the causal connection between lipids, lipid-modifying drugs, and the occurrence of RA. METHODS: We obtained genetic variation for lipid traits and drug targets related to lipid modification from three sources: the Global Lipids Genetics Consortium (GLGC), UK Biobank, and Nightingale Health 2020. The genetic data for RA were acquired from two comprehensive meta-analyses and the R8 of FINNGEN, respectively. These variants were employed in drug-target MR analyses to establish a causal relationship between genetically predicted lipid-modifying drug targets and the risk of RA. For suggestive lipid-modified drug targets, we conducted Summary-data-based Mendelian Randomization (SMR) analyses and using expression quantitative trait loci (eQTL) data in relevant tissues. In addition, we performed co-localization analyses to assess genetic confounders. RESULTS: Our analysis revealed no significant causal relationship between lipid and RA. We observed that the genetically predicted 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR) -mediated low density lipoprotein cholesterol (LDL-C) (OR 0.704; 95% CI 0.56, 0.89; P = 3.43×10-3), Apolipoprotein C-III (APOC3) -mediated triglyceride (TG) (OR 0.844; 95% CI 0.77, 0.92; P = 1.50×10-4) and low density lipoprotein receptor (LDLR) -mediated LDL-C (OR 0.835; 95% CI 0.73, 0.95; P = 8.81×10-3) were significantly associated with a lowered risk of RA. while Apolipoprotein B-100 (APOB) -mediated LDL-C (OR 1.212; 95%CI 1.05,1.40; P = 9.66×10-3) was significantly associated with an increased risk of RA. CONCLUSIONS: Our study did not find any supporting evidence to suggest that lipids are a risk factor for RA. However, we observed significant associations between HMGCR, APOC3, LDLR, and APOB with the risk of RA.

Association of Monocyte-to-HDL Cholesterol Ratio with Endothelial Dysfunction in Patients with Type 2 Diabetes.

Aims: To explore the relationship between monocyte-to-HDL cholesterol ratio (MHR) and endothelial function in patients with type 2 diabetes (T2DM). Methods: 243 patients diagnosed with T2DM were enrolled in this cross-sectional study. Patients were divided into two groups by flow-mediated dilation (FMD) quintile as nonendothelial dysfunction (FMD ≥ 6.4%) and endothelial dysfunction (FMD < 6.4%). The relationship between MHR and FMD was analyzed using Spearman's correlation, partial correlation, and multiple logistic regression analysis. ROC curve was fitted to evaluate the ability of MHR to predict endothelial dysfunction. Results: Endothelial dysfunction was present in 193 (79%) patients. Patients with endothelial dysfunction had higher MHR (p < 0.05) than those without endothelial dysfunction. Furthermore, MHR had a significantly positive correlation with endothelial dysfunction (r = 0.17, p < 0.05), and the positive association persisted even after controlling for confounding factors (r = 0.14, p < 0.05). Logistic regression showed that MHR was an independent contributor for endothelial dysfunction (OR: 1.35 (1.08, 1.70), p < 0.05) and the risk of endothelial dysfunction increases by 61% with each standard deviation increase in MHR (OR: 1.61 (1.12, 2.30), p < 0.05) (model 1). After adjusting for sex, age, BMI, disease course, hypertension, smoking, and drinking (model 2) as well as HbA1c, HOMA-IR, C-reactive protein, and TG (model 3), similar results were obtained. In ROC analysis, the area of under the ROC curve (AUC) for MHR was 0.60 (95% CI 0.52-0.69, p < 0.05). Conclusion: MHR was independently associated with endothelial dysfunction in T2DM patients. It could be a new biomarker for vascular endothelial function assessment.

HDL as a Treatment Target: Should We Abandon This Idea?

PURPOSE OF REVIEW: High-density lipoproteins (HDL) have long been regarded as an antiatherogenic lipoprotein species by virtue of their role in reverse cholesterol transport (RCT), as well as their established anti-inflammatory and antioxidant properties. For decades, HDL have been an extremely appealing therapeutic target to combat atherosclerotic cardiovascular diseases (ASCVD). RECENT FINDINGS: Unfortunately, neither increasing HDL with drugs nor direct infusions of reconstituted HDL have convincedly proven to be positive strategies for cardiovascular health, raising the question of whether we should abandon the idea of considering HDL as a treatment target. The results of two large clinical trials, one testing the latest CETP inhibitor Obicetrapib and the other testing the infusion of patients post-acute coronary events with reconstituted HDL, are still awaited. If they prove negative, these trials will seal the fate of HDL as a direct therapeutic target. However, using HDL as a therapeutic agent still holds promise if we manage to optimize their beneficial properties for not only ASCVD but also outside the cardiovascular field.

Identifying the natural products in the treatment of atherosclerosis by increasing HDL-C level based on bioinformatics analysis, molecular docking, and in vitro experiment.

BACKGROUND: Previous studies have demonstrated that high-density lipoprotein cholesterol (HDL-C) plays an anti-atherosclerosis role through reverse cholesterol transport. Several studies have validated the efficacy and safety of natural products in treating atherosclerosis (AS). However, the study of raising HDL-C levels through natural products to treat AS still needs to be explored. METHODS: The gene sets associated with AS were collected and identified by differential gene analysis and database query. By constructing a protein-protein interaction (PPI) network, the core submodules in the network are screened out. At the same time, by calculating node importance (Nim) in the PPI network of AS disease and combining it with Kyoto Encyclopedia of genes and genomes (KEGG) pathways enrichment analysis, the key target proteins of AS were obtained. Molecular docking is used to screen out small natural drug molecules with potential therapeutic effects. By constructing an in vitro foam cell model, the effects of small molecules on lipid metabolism and key target expression of foam cells were investigated. RESULTS: By differential gene analysis, 451 differential genes were obtained, and a total of 313 disease genes were obtained from 6 kind of databases, then 758 AS-related genes were obtained. The enrichment analysis of the KEGG pathway showed that the enhancement of HDL-C level against AS was related to Lipid and atherosclerosis, Cholesterol metabolism, Fluid shear stress and atherosclerosis, PPAR signaling pathway, and other pathways. Then we intersected 31 genes in the core module of the PPI network, the top 30 genes in Nims, and 32 genes in the cholesterol metabolism pathway, and finally found 3 genes. After the above analysis and literature collection, we focused on the following three related gene targets: APOA1, LIPC, and CETP. Molecular docking showed that Genistein has a good binding affinity for APOA1, CETP, and LIPC. In vitro, experiments showed that Genistein can up-regulated APOA1, LIPC, and CETP levels. CONCLUSIONS: Based on our research, Genistein may have the effects of regulating HDL-C and anti-atherosclerosis. Its mechanism of action may be related to the regulation of LIPC, CETP, and APOA1 to improve lipid metabolism.

Proteomic Determinants of Variation in Cholesterol Efflux: Observations from the Dallas Heart Study.

High-density lipoproteins (HDLs) are promising targets for predicting and treating atherosclerotic cardiovascular disease (ASCVD), as they mediate removal of excess cholesterol from lipid-laden macrophages that accumulate in the vasculature. This functional property of HDLs, termed cholesterol efflux capacity (CEC), is inversely associated with ASCVD. HDLs are compositionally diverse, associating with >250 different proteins, but their relative contribution to CEC remains poorly understood. Our goal was to identify and define key HDL-associated proteins that modulate CEC in humans. The proteomic signature of plasma HDL was quantified in 36 individuals in the multi-ethnic population-based Dallas Heart Study (DHS) cohort that exhibited persistent extremely high (>=90th%) or extremely low CEC (<=10th%) over 15 years. Levels of apolipoprotein (Apo)A-I associated ApoC-II, ApoC-III, and ApoA-IV were differentially correlated with CEC in high (r = 0.49, 0.41, and -0.21 respectively) and low (r = -0.46, -0.41, and 0.66 respectively) CEC groups (p for heterogeneity (pHet) = 0.03, 0.04, and 0.003 respectively). Further, we observed that levels of ApoA-I with ApoC-III, complement C3 (CO3), ApoE, and plasminogen (PLMG) were inversely associated with CEC in individuals within the low CEC group (r = -0.11 to -0.25 for subspecies with these proteins vs. r = 0.58 to 0.65 for subspecies lacking these proteins; p < 0.05 for heterogeneity). These findings suggest that enrichment of specific proteins on HDLs and, thus, different subspecies of HDLs, differentially modulate the removal of cholesterol from the vasculature.

Genetic scores associated with favourable and unfavourable adiposity have consistent effect on metabolic profile and disease risk across diverse ethnic groups.

AIM: This study aims to investigate the associations between genetic risk scores (GRS) for favourable and unfavourable adiposity and a wide range of adiposity-related outcomes across diverse populations. METHODS: We utilised previously identified variants associated with favourable (36 variants) and unfavourable (38 variants) adiposity to create GRS for each adiposity phenotype. We used summary statistics from 39 outcomes generated by the Pan-UKB genome-wide association studies Version 0.3, incorporating covariates such as age, sex and principal components in six populations: European (n = 420,531), African (6636), American (980), Central/South Asian (8876), East Asian (2709) and Middle Eastern (1599). RESULTS: The favourable adiposity GRS was associated with a healthy metabolic profile, including lower risk of type 2 diabetes, lower liver enzyme levels, lower blood pressure, higher HDL-cholesterol, lower triglycerides, higher apolipoprotein A, lower apolipoprotein B, higher testosterone, lower calcium and lower insulin-like growth factor 1 generally consistently across all the populations. In contrast, the unfavourable adiposity GRS was associated with an adverse metabolic profile, including higher risk of type 2 diabetes, higher random glucose levels, higher HbA1c, lower HDL-cholesterol, higher triglycerides, higher liver enzyme levels, lower testosterone, and higher C-reactive protein generally consistently across all the populations. CONCLUSION: The study provides evidence that the genetic scores associated with favourable and unfavourable adiposity have consistent effects on metabolic profiles and disease risk across diverse ethnic groups. These findings deepen our understanding of distinct adiposity subtypes and their impact on metabolic health.

Cholesterol Metabolic Profiling of HDL in Women with Late-Onset Preeclampsia.

A specific feature of dyslipidemia in pregnancy is increased high-density lipoprotein (HDL) cholesterol concentration, which is probably associated with maternal endothelium protection. However, preeclampsia is most often associated with low HDL cholesterol, and the mechanisms behind this change are scarcely explored. We aimed to investigate changes in HDL metabolism in risky pregnancies and those complicated by late-onset preeclampsia. We analyze cholesterol synthesis (cholesterol precursors: desmosterol, 7-dehydrocholesterol, and lathosterol) and absorption markers (phytosterols: campesterol and ß-sitosterol) within HDL particles (NCSHDL), the activities of principal modulators of HDL cholesterol's content, and major HDL functional proteins levels in mid and late pregnancy. On the basis of the pregnancy outcome, participants were classified into the risk group (RG) (70 women) and the preeclampsia group (PG) (20 women). HDL cholesterol was lower in PG in the second trimester compared to RG (p < 0.05) and followed by lower levels of cholesterol absorption markers (p < 0.001 for campesterolHDL and p < 0.05 for ß-sitosterolHDL). Lowering of HDL cholesterol between trimesters in RG (p < 0.05) was accompanied by a decrease in HDL phytosterol content (p < 0.001), apolipoprotein A-I (apoA-I) concentration (p < 0.05), and paraoxonase 1 (PON1) (p < 0.001), lecithin-cholesterol acyltransferase (LCAT) (p < 0.05), and cholesterol ester transfer protein (CETP) activities (p < 0.05). These longitudinal changes were absent in PG. Development of late-onset preeclampsia is preceded by the appearance of lower HDL cholesterol and NCSHDL in the second trimester. We propose that reduced capacity for intestinal HDL synthesis, decreased LCAT activity, and impaired capacity for HDL-mediated cholesterol efflux could be the contributing mechanisms resulting in lower HDL cholesterol.

Association of CETP Gene Polymorphisms and Haplotypes with Cardiovascular Risk.

Cholesteryl ester transfer protein (CETP) is known to influence HDL-C levels, potentially altering the profile of HDL subfractions and consequently cardiovascular risk (CVR). This study aimed to investigate the effect of five single-nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene on 10-year CVR estimated by the Systematic Coronary Risk Evaluation (SCORE), the Framingham Risk Score for Coronary Heart Disease (FRSCHD) and Cardiovascular Disease (FRSCVD) algorithms. Adjusted linear and logistic regression analyses were used to investigate the association of SNPs and 10 haplotypes (H1-H10) on 368 samples from the Hungarian general and Roma populations. The T allele of rs7499892 showed a significant association with increased CVR estimated by FRS. H5, H7, and H8 showed a significant association with increased CVR based on at least one of the algorithms. The impact of H5 was due to its effect on TG and HDL-C levels, while H7 showed a significant association with FRSCHD and H8 with FRSCVD mediated by a mechanism affecting neither TG nor HDL-C levels. Our results suggest that polymorphisms in the CETP gene may have a significant effect on CVR and that this is not mediated exclusively by their effect on TG and HDL-C levels but also by presently unknown mechanisms.

A commentary on the paper, 'Development and validation of a novel automatable assay for cholesterol efflux capacity'.

The determination of functionality or quality of high-density lipoproteins (HDL) is assuming a central stage in the prediction of cardiovascular diseases (CVD). To assess HDL quality, several attempts have been made to develop an automated, cost-effective cholesterol efflux capacity (CEC) system with few operational steps that might be used in clinical settings for large throughput testing. The work of Dr. Ohkawa and co-workers seems to address this issue and provide a solution for the same (Bioscience Reports (2023), 43 BSR20221519, https://doi.org/10.1042/BSR20221519). Earlier work from the author's lab utilized a radioisotope and cell-free CEC assay known as the immobilized liposome-bound gel beads (ILGs) method. However, this assay required a centrifugation step to separate the cells and was not suitable for automation. To overcome these limitations, two very important changes were made: (i) magnetic beads were used instead of gel beads that allowed them to avoid the centrifugation process that would allow ease of setting up an autonomous analyzer; (ii) porous magnetic beads were coated with liposomes containing fluorescently tagged cholesterol instead radiolabeled cholesterol. These two changes can be considered not only significant but also novel as they were highly suitable for CEC testing. The authors reported the successful development of a simple immobilized liposome-based magnetic beads (ILMs) automated system to measure CEC, which provided both consistent performance and satisfactory correlation with the other methods. Thus, we feel the present study will open newer avenues for measuring the quality of HDL in addition to the quantity of HDL-cholesterol in clinical settings in a more robust way.

Hepatic Cdkal1 deletion regulates HDL catabolism and promotes reverse cholesterol transport.

BACKGROUND AND AIMS: Associations between CDKAL1 variants and cholesterol efflux capacity (CEC) have been reported. This study aimed to investigate the effects of Cdkal1 deficiency on high-density lipoprotein (HDL) metabolism, atherosclerosis, and related pathways. METHODS: Lipid and glucose metabolic profiles, CEC, and in vivo reverse cholesterol transport (RCT) were compared in liver-specific Alb-Cre:Cdkal1fl/fl and Cdkal1fl/fl mice. Aortic atherosclerosis was compared in Apoe-/-Alb-Cre:Cdkal1fl/fl and Apoe-/- mice fed high-fat diets. HDL subclasses and mediators of HDL metabolism from Alb-Cre:Cdkal1fl/fl mice were examined. RESULTS: HDL-cholesterol level tended to be higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.050). Glucose and other lipid profiles were similar in the two groups of mice, irrespective of diet. The mean CEC was 27% higher (p = 0.007) in the Alb-Cre:Cdkal1fl/fl mice, as were the radioactivities of bile acids (mean difference 17%; p = 0.035) and cholesterol (mean difference 42%; p = 0.036) from faeces. The radioactivity tendency was largely similar in mice fed a high-fat diet. Atherosclerotic lesion area tended to be smaller in the Apoe-/-Alb-Cre:Cdkal1fl/fl mice than in the Apoe-/- mice (p = 0.067). Cholesterol concentrations in large HDLs were higher in the Alb-Cre:Cdkal1fl/fl mice (p = 0.024), whereas in small HDLs, they were lower (p = 0.024). Endothelial lipase (mean difference 39%; p = 0.002) and hepatic lipase expression levels (mean difference 34%; p < 0.001) were reduced in the Alb-Cre:Cdkal1fl/fl mice, whereas SR-B1 expression was elevated (mean difference 35%; p = 0.007). CONCLUSIONS: The promotion of CEC and RCT in Alb-Cre:Cdkal1fl/fl mice verified the effect of CDKAL1 seen in human genetic data. These phenotypes were related to regulation of HDL catabolism. This study suggests that CDKAL1 and associated molecules could be targets for improving RCT and vascular pathology.

[Moxibustion of 45 ℃ at "Zusanli" (ST36) improves vascular endothelial oxidative stress in hyperlipidemia rats].

OBJECTIVE: To explore the antioxidant effect of moxibustion on vascular endothelial function and the under-lying mechanism. METHODS: Forty male SD rats were randomly divided into blank, model, moxibustion and endothelial nitric oxide synthase (eNOS) inhibitor groups, with 10 rats in each group. Hyperlipidemia rat model was established by high fat diet for 8 weeks. Rats in the moxibustion group received 45 ℃ moxibustion at "Zusanli" (ST36) for 10 min once daily for consecutive 4 weeks. Rats in the eNOS inhibitor group received intraperitoneal injection of eNOS inhibitor L-NAME (1 mg/100 g) at the same time of moxibustion intervention. The morphology of abdominal aorta endothelium was observed by HE staining. Lipid deposition in abdominal aorta was observed by oil red O staining. The contents of total cholesterol (TC), triglyceride (TG), high density lipoprotein cholesterol (HDL-C), low density lipoprotein cholesterol (LDL-C) in serum and reactive oxygen species (ROS), nitric oxide (NO), superoxide dismutase (SOD), oxidized LDL lipoprotein (ox-LDL), endothelin-1 (ET-1), eNOS, malondialdehyde (MDA) in serum and abdominal aorta were determined by ELISA. The expression of eNOS in abdominal aorta was detected by immunofluorescence. RESULTS: HE staining of the abdominal aorta showed no significant pathological abnormality in the blank group; the endovascular cortex was rough, and the inner, media and outer membrane were rough in the model group; the nucleus and surrounding tissue structure were clear and the vascular wall was smooth in the moxibustion group; abdominal aorta texture was rough in the eNOS inhibitor group. Compared with the blank group, the area of oil red O staining in abdominal aorta increased (P<0.05); the contents of serum TC, TG and LDL-C increased (P<0.01, P<0.05) while HDL-C decreased (P<0.05); the contents of ET-1 in serum and abdominal aorta were increased (P<0.01, P<0.05) while the contents of NO and eNOS were decreased (P<0.05, P<0.001); the contents of ROS, ox-LDL and MDA in serum and abdominal aorta were increased (P<0.001, P<0.01, P<0.000 1) while the content of SOD in abdominal aorta was decreased (P<0.000 1); the expression level of eNOS in abdominal aorta was decreased (P<0.05) in the model group. Compared with the model group, the area of oil red O staining in abdominal aorta decreased (P<0.05); the contents of TC, TG and LDL-C in serum decreased (P<0.05) while HDL-C increased (P<0.05); the contents of ET-1 in serum and abdominal aorta were decreased (P<0.01, P<0.05) while the contents of NO and eNOS in abdominal aorta were increased (P<0.001, P<0.01); the contents of ROS and MDA in serum and abdominal aorta were decreased (P<0.001, P<0.01, P<0.05), the content of ox-LDL was decreased (P<0.01) and the content of SOD was increased (P<0.000 1) in abdominal aorta; the expression level of eNOS in abdominal aorta was increased (P<0.05) in the moxibustion group. Compared with the moxibustion group, the contents of serum TC, LDL-C and MDA in the eNOS inhibitor group were increased (P<0.05); the contents of ET-1, ROS, ox-LDL and MDA in abdominal aorta were increased (P<0.05), the contents of NO, eNOS and SOD were decreased (P<0.05); the expression level of eNOS in abdominal aorta was decreased (P<0.05). CONCLUSION: 45 ℃ moxibustion at ST36 can protect and repair vascular endothelial injury in abdominal aorta of hyperlipidemia rats and improve the oxidative stress of vascular endothelium.

The monocyte-to-high-density lipoprotein ratio is associated with the occurrence of atrial fibrillation among NAFLD patients: A propensity-matched analysis.

Background: Accumulating evidence suggests that patients with nonalcoholic fatty liver disease (NAFLD) have a significantly high risk of incident atrial fibrillation (AF). Systemic inflammation, metabolic disorders and oxidative stress could be the potential mechanisms by which NAFLD drives AF. Monocyte-to- high-density lipoprotein ratio (MHR) has emerged as a novel biomarker of inflammation and oxidative stress that has not been studied in AF with NAFLD patients. We aimed to investigate the relationship between MHR and the risk of AF among NAFLD patients. Methods: A retrospective analysis was performed for the clinical data of the patients with NAFLD in the Second Hospital of Shanxi Medical University from January 2019 to October 2022, among whom 204 patients with AF were enrolled as NAFLD+AF group and 613 patients without AF were enrolled as NAFLD control, and 152 patients were selected from each group based on propensity score matching (PSM) at a ratio of 1:1 to balance the covariates between groups. The t-test or the Mann-Whitney U test was used for comparison of continuous data between two groups; the chi-square test or the Fisher's exact test was used for comparison of categorical data between two groups. Logistic regression analysis was performed to identify the independent predictor for occurrence of AF among NAFLD patients. Trend chi-square test to analyze the prevalence of AF among MHR tertiles, and then the correlation between MHR and the risk of AF confirmed by restricted cubic splines (RCS). The receiver operating characteristic (ROC) curve analysis was used to determine the optimum MHR cutoff value to predict AF. Results: Univariate analysis showed that AF patients had higher MHR than non-AF patients (P < 0.001). Meanwhile, compared with pure NAFLD patients, multivariate logistic regression analysis showed that MHR remained to be an independent risk factor for AF after adjusting for confounding risk factors (OR = 10.67, 95% CI 2.17-52.37, P = 0.004). TC、HDL-C were also independent risk factors for AF. Among them, TC and HDL-C are protective factors for AF. The trend chi-square test showed that the risk of AF increased with an increase in MHR (P < 0.05). However, the RCS showed a nonlinear and J-shaped relationship between MHR and the risk of AF (P for non-linearity = 0.023). The occurrence of AF increased with increasing MHR only when MHR > 0.44. The ROC curve showed that MHR combined with traditional risk factors can improve the ability to predict AF. Conclusion: MHR is an independently associated with incident AF in patients with NAFLD and show a certain predictive value.