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A two‐sample Mendelian randomization (MR) analysis was utilized to assess the causal relationship between lipidomic profiles and the risk of intracranial aneurysms (IAs). Genetic variants related to lipidomic profiles (227 components) and IA [IA, aneurysmal subarachnoid hemorrhage (aSAH) only, unruptured IA (uIA) only] were obtained from published genome‐wide association studies (GWASs) or the IEU Open GWAS project and used as instrumental variables for MR analysis. The inverse‐variance weighted method was used in the primary analyses to derive causality estimates and was expressed as odds ratio (OR) with 95% confidence interval (CI). Of these 227 lipidomic profiles, only genetically predicted high levels of cholesterol to total lipids ratio in very small very‐low‐density lipoproteins (VLDL) [OR = 0.629 (95% CI, 0.504–0.786)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.637 (95% CI, 0.509–0.797)], ratio of docosahexaenoic acid to total fatty acids [OR = 0.691 (95% CI, 0.582–0.820)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.630 (95% CI, 0.522–0.760)] reduced the risk of aSAH, whereas genetically predicted high ratio of monounsaturated fatty acids to total fatty acids [OR = 1.471 (95% CI, 1.215–1.781)] increased the risk of aSAH. Moreover, genetically predicted high levels of cholesterol to total lipids ratio in very small VLDL [OR = 0.657 (95% CI, 0.542–0.798)], cholesteryl esters to total lipids ratio in very small VLDL [OR = 0.663 (95% CI, 0.548–0.803)], free cholesterol to total lipids ratio in small VLDL [OR = 0.682 (95% CI, 0.560–0.832)], phospholipids to total lipids ratio in small VLDL [OR = 0.674 (95% CI, 0.548–0.830)], and ratio of polyunsaturated fatty acids to monounsaturated fatty acids [OR = 0.678 (95% CI, 0.569–0.808)] reduced the risk of IA. The results of multivariable MR demonstrated that these causal associations persisted after adjusting for systolic blood pressure and cigarettes smoked per day. The effect of serum lipids on IA and aSAH may be mainly caused by subclasses of lipids such as VLDL. [ABSTRACT FROM AUTHOR]

The aim of this study was to evaluate the lipid‐lowering and plasma cholesteryl ester transfer protein(CETP) activity of Centranthus longiflorus(CL) and β‐Sitosterol(βS) following intraperitoneal administration of Triton‐WR 1339 (=Tyloxapol) (TWR) to male Wistar rats. Hyperlipidemia(HL) was developed by intraperitoneal injection of TWR. The animals were divided into main eight groups of six rats each. Rats were housed in separate cages and fed a standard diet for 7 days. After 7 days, ethanol extraction of CL plant, aqueous suspension of βS and anacetrapib was given to rats by oral gavage 1 h before the triton injection. Blood samples were collected and used for the biochemical parameters analysis. Histopathological studies were also performed on liver tissue. In hyperlipidemic rats(HR), CL extract and βS reduced total cholesterol similarly. βS lowered low‐density lipoprotein(LDL‐C) more than CL extract. Both CL extract and βS approximated impaired Alanine transaminase(ALT) and Aspartate transaminase(AST) levels in HR's to the level of control. CL extract provided better protection than βS against deterioration in liver tissue samples seen in hyperlipidemic rats. Finally, CL extract and βS inhibited CETP, at which point βS was more effective. These findings showed that CL extract and βS reduce plasma lipid concentration and may have a hypolipidemic effect due to their anti‐CETP properties. [ABSTRACT FROM AUTHOR]

Background: Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods: Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson's dementia. Results: MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson's dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4. Conclusions: These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers. [ABSTRACT FROM AUTHOR]

The article "Cause-specific death in adults with type 1 diabetes and type 2 diabetes: Insights from the UK Biobank" delves into the disparities in cause-specific mortality between individuals with type 1 and type 2 diabetes. It emphasizes the higher risk of death due to various causes in individuals with type 1 diabetes compared to those with type 2 diabetes, underscoring the necessity for tailored healthcare interventions for middle-aged and older adults with type 1 diabetes. The research also sheds light on the need for more inclusive trials and advancements in treatment strategies for individuals with type 1 diabetes, who have historically been underrepresented in research. [Extracted from the article]

Aim Methods Results Conclusions To investigate the associations of high‐density lipoprotein (HDL) subfractions and apolipoprotein A‐I (apo A‐I) with fat in the pancreas.A total of 170 individuals were studied. All participants underwent magnetic resonance imaging on a single 3.0‐Tesla scanner to determine the presence/absence of fatty pancreas. HDL subfractions were measured using a commercially available lipoprotein subfractions testing system and classed as large, intermediate and small HDL. Both unadjusted and adjusted (accounting for demographics, anthropometrics, insulin resistance and other covariates) logistic regression models were built.Individuals with fatty pancreas had significantly lower circulating levels of the large HDL class and apo A‐I. Every unit decrease in the large HDL class was associated with a 93% increase in the likelihood of fatty pancreas in the most adjusted model (P < .001). Every unit decrease in apo A‐I was associated with a 45% increase in the likelihood of fatty pancreas in the most adjusted model (P = .012). The intermediate and small HDL classes were not significantly associated with fatty pancreas.Fat in the pancreas is inversely associated with the circulating levels of large HDL particles and apo A‐I. Purposely designed studies are warranted to investigate the potential of fatty pancreas as an indicator of the risk of cardiovascular diseases. [ABSTRACT FROM AUTHOR]

Cardiovascular disease (CVD) is a leading cause of global mortality, with dyslipidemia being a significant modifiable risk factor. Dyslipidemia refers to all abnormalities in blood lipid levels. It plays a fundamental role in the development and progression of atherosclerosis. The reduction of low‐density lipoprotein (LDL) cholesterol has been shown to decrease cardiovascular risk. Cholesteryl ester transfer protein (CETP) plays a role in LDL metabolism, and its inhibition results in lower LDL levels. This study synthesizes and evaluates novel benzene sulfonamide derivatives as CETP inhibitors. Twenty compounds were synthesized and tested for their inhibitory activity using an in vitro bioassay. The results revealed that para‐methylated derivatives exhibited higher inhibitory activity compared to meta‐methylated derivatives, where compound 6n has an IC50 of 24.4 µM. Furthermore, electron withdrawing groups such as chlorine and nitro substitutions on the sulfanamido‐phenyl rings demonstrated superior inhibitory effects compared to electron donating groups. Positional isomerism of the substitutions also influenced inhibitory activity, with para substitutions being more effective. Nitro‐substituted compounds showed greater inhibition than chlorine‐substituted compounds, where compound 6t has an IC50 of 18.3 µM. Overall, this study provides valuable insights into the SAR of CETP inhibitors and identifies promising compounds for further investigation as potential therapeutics for CVD. [ABSTRACT FROM AUTHOR]

Background and purpose: While there is evidence that gut microbiota (GM) and blood metabolites are associated with ovarian cancer (OC), the precise mechanisms underlying this relationship are still unclear. This study used Mendelian randomization (MR) to elucidate the causal connections between GM, blood metabolite biomarkers, and OC. Methods: In this study, we leveraged summary data for GM (5,959 individuals with genotype-matched GM), blood metabolites (233 circulating metabolic traits with 136,016 participants), and OC (63,702 participants with 23,564 cases and 40,138 controls) from genome-wide association studies (GWASs). We performed MR analysis to explore the causal relationship between GM and OC. Further, we harnessed univariable MR (UVMR) analysis to evaluate the causal associations between GM and circulating metabolites. Finally, we employed a two-step approach based on multivariable MR (MVMR) to evaluate the total genetic prediction effect of metabolites mediating the GM on the risk of OC to discover a potential causal relationship. Results: In the MR analysis, 24 gut bacteria were causally associated with the pathogenesis of OC, including 10 gut bacteria (Dorea phocaeense, Succinivibrionaceae, Raoultella, Phascolarctobacterium sp003150755, Paenibacillus J, NK4A144, K10, UCG-010 sp003150215, Pseudomonas aeruginosa, and Planococcaceae) that were risk factors, and 14 gut bacteria (CAG-177 sp002438685, GCA-900066135 sp900066135, Enorma massiliensis, Odoribacter laneus, Ruminococcus E sp003521625, Streptococcus sanguinis, Turicibacter sp001543345, Bacillus velezensis, CAG-977, CyanobacteriaStaphylococcus A fleurettii, Caloranaerobacteraceae, RUG472 sp900319345, and CAG-269 sp001915995) that were protective factors. The UVMR analysis showed that these 24 positive gut bacteria were causally related to lipoproteins, lipids, and amino acids. According to the MVMR analysis, Enorma massiliensis could reduce the risk of OC by raising the total cholesterol to total lipids ratio in large low-density lipoprotein (LDL) and cholesteryl esters to total lipids ratio in intermediate-density lipoprotein (IDL). Turicibacter sp001543345, however, could reduce the risk of OC by lowering free cholesterol in small high-density lipoprotein (HDL) and increasing the ratios of saturated fatty acids to total fatty acids, total cholesterol to total lipids ratio in very small very-low-density lipoprotein (VLDL), and cholesteryl esters to total lipids ratio in very small VLDL. Conclusion: The current MR study provides evidence that genetically predicted blood metabolites can mediate relationships between GM and OC. [ABSTRACT FROM AUTHOR]

Introduction: Cholesteryl ester transfer protein (CETP) plays an important role in lipid metabolism. Early interest in the development of CETP inhibitors proved to be disappointing. Recent interest has focused on the potential for CETP inhibition to reduce cardiovascular risk by lowering levels of low-density lipoprotein cholesterol (LDL-C). Areas covered: The data suggesting that low CETP activity may associate with lower levels of cardiovascular risk and early experience with CETP inhibitors focused on raising HDL-C levels. More recent data that suggests that any potential to reduce cardiovascular risk by inhibition of CETP is more likely to result from lowering levels of atherogenic lipid parameters. The development of obicetrapib, a potent CETP inhibitor, with robust lowering of apoB and LDL-C, will be summarized as a potential approach to the prevention of cardiovascular disease. Expert opinion: Obicetrapib is a potent CETP inhibitor, with a demonstrated ability to lower levels of apoB and LDL-C as monotherapy and in addition to high intensity statin therapy. The ultimate impact of obicetrapib on cardiovascular events will be evaluated by ongoing clinical trials. [ABSTRACT FROM AUTHOR]

Aim Materials and Methods Results Conclusions To investigate the association between low‐density lipoprotein‐cholesterol (LDL‐C) levels and coronary artery disease (CAD) incidence based on combining high‐density lipoprotein‐cholesterol (HDL‐C) levels and glucose status.In this retrospective cohort study, we used data from a nationwide claims database (1,524,289 individuals without a history of CAD or familial hypercholesterolaemia; 2008–2019). Cox proportional hazards modelling identified the risk of incident CAD by a novel combination of four HDL‐C levels, seven LDL‐C levels and glucose status.During the follow‐up period (mean: 5.5 years), 8301 (0.99/1000 person‐years) events occurred. The risk of CAD increased from lower LDL‐C levels accompanied by lower HDL‐C levels regardless of the glucose status. Using the most favourable levels of HDL‐C and LDL‐C (i.e. 60–99 mg/dL and <80 mg/dL, respectively) as references, the hazard ratios (95% confidence interval) for the group with HDL‐C levels <40 mg/dL and LDL‐C levels <80 mg/dL were 2.74 (1.47–5.11), 2.52 (1.30–4.91) and 2.85 (1.68–4.84) for normoglycaemia, borderline glycaemia and diabetes, respectively. Comparison of the most favourable levels of HDL‐C and LDL‐C with their least favourable levels (i.e. <40 mg/dL and 180–199 mg/dL, respectively) revealed that the risk of new‐onset CAD exhibited a 19‐, nine‐ and seven‐fold increase in individuals with normoglycaemia, borderline glycaemia and diabetes, respectively.To prevent CAD, LDL‐C levels should be strictly controlled in patients with low HDL‐C levels regardless of glucose tolerance. Individualized treatment, which involves setting target LDL‐C levels based on glucose tolerance and HDL‐C values, is required. [ABSTRACT FROM AUTHOR]

Objective: This study aimed to investigate potential causal relationships between circulating metabolites and breast cancer risk using Mendelian randomization (MR) analysis. Materials and Methods: Summary-level genome-wide association study (GWAS) datasets for 249 circulating metabolites were obtained from the UK Biobank. GWAS datasets for estrogen receptor-positive (ER+) and estrogen receptornegative (ER-) breast cancer were acquired from previous studies based on the Combined Oncoarray. Instrumental variables (IVs) were selected from single nucleotide polymorphisms (SNPs) associated with circulating metabolites, and MR analyses were conducted using the inverse-variance weighted (IVW) method as the primary analysis, with additional sensitivity analyses using other MR methods. Odds ratios (OR) and 95% confidence interval (CI) were used to estimate the association of circulating metabolites with breast cancer risk. Results: The IVW analysis revealed significant causal relationships between 79 circulating metabolites and ER + breast cancer risk, and 10 metabolites were significantly associated with ER-breast cancer risk. Notably, acetate (OR = 1.12, P = 0.03), HDL cholesterol (OR = 1.09, P < 0.001), ration of omega-6 fatty acids to total fatty acids ratio (OR = 1.09, P = 0.01), and phospholipids in large LDL (OR = 1.09, P < 0.001) were linked to an increased risk of ER + breast cancer, while linoleic acid (OR = 0.91, P < 0.001) monounsaturated fatty acids (OR = 0.91, P < 0.001), and total lipids in LDL (OR = 0.91, P < 0.001) were associated with a decreased risk. In ER-breast cancer, glycine, citrate, HDL cholesterol, cholesteryl esters in HDL, cholesterol to total lipids ratio in very large HDL, and cholesterol in large LDL were associated with an increased risk, while the free cholesterol to total lipids in very large HDL was linked to a decreased risk. Conclusion: This MR approach underscores aberrant lipid metabolism as a key process in breast tumorigenesis, and may inform future prevention and treatment strategies. To further elucidate the underlying mechanisms and explore the potential clinical implications, additional research is warranted to validate the observed associations in this study. [ABSTRACT FROM AUTHOR]

The Sonic hedgehog (Shh) signaling pathway controls embryonic development and tissue homeostasis after birth. This requires regulated solubilization of dual-lipidated, firmly plasma membrane-associated Shh precursors from producing cells. Although it is firmly established that the resistance-nodulation-division transporter Dispatched (Disp) drives this process, it is less clear how lipidated Shh solubilization from the plasma membrane is achieved. We have previously shown that Disp promotes proteolytic solubilization of Shh from its lipidated terminal peptide anchors. This process, termed shedding, converts tightly membrane-associated hydrophobic Shh precursors into delipidated soluble proteins. We show here that Disp-mediated Shh shedding is modulated by a serum factor that we identify as high-density lipoprotein (HDL). In addition to serving as a soluble sink for free membrane cholesterol, HDLs also accept the cholesterol-modified Shh peptide from Disp. The cholesteroylated Shh peptide is necessary and sufficient for Disp-mediated transfer because artificially cholesteroylated mCherry associates with HDL in a Disp-dependent manner, whereas an N-palmitoylated Shh variant lacking C-cholesterol does not. Disp-mediated Shh transfer to HDL is completed by proteolytic processing of the palmitoylated N-terminal membrane anchor. In contrast to dual-processed soluble Shh with moderate bioactivity, HDL-associated N-processed Shh is highly bioactive. We propose that the purpose of generating different soluble forms of Shh from the dual-lipidated precursor is to tune cellular responses in a tissue-type and time-specific manner. [ABSTRACT FROM AUTHOR]

Background: Cardiovascular disease represents a significant risk factor for mortality in individuals with type 2 diabetes mellitus (T2DM). High-density lipoprotein (HDL) is believed to play a crucial role in maintaining cardiovascular health through its multifaceted atheroprotective effects and its capacity to enhance glycemic control. The impact of dietary interventions and intermittent fasting (IF) on HDL functionality remains uncertain. The objective of this study was to assess the effects of dietary interventions and IF as a strategy to safely improve glycemic control and reduce body weight on functional parameters of HDL in individuals with T2DM. Methods: Before the 12-week intervention, all participants (n = 41) of the INTERFAST-2 study were standardized to a uniform basal insulin regimen and randomized to an IF or non-IF group. Additionally, all participants were advised to adhere to dietary recommendations that promoted healthy eating patterns. The IF group (n = 19) followed an alternate-day fasting routine, reducing their calorie intake by 75% on fasting days. The participants' glucose levels were continuously monitored. Other parameters were measured following the intervention: Lipoprotein composition and subclass distribution were measured by nuclear magnetic resonance spectroscopy. HDL cholesterol efflux capacity, paraoxonase 1 (PON1) activity, lecithin cholesterol acyltransferase (LCAT) activity, and cholesterol ester transfer protein (CETP) activity were assessed using cell-based assays and commercially available kits. Apolipoprotein M (apoM) levels were determined by ELISA. Results: Following the 12-week intervention, the IF regimen significantly elevated serum apoM levels (p = 0.0144), whereas no increase was observed in the non-IF group (p = 0.9801). ApoM levels correlated with weight loss and fasting glucose levels in the IF group. Both groups exhibited a robust enhancement in HDL cholesterol efflux capacity (p < 0.0001, p = 0.0006) after 12 weeks. Notably, only the non-IF group exhibited significantly elevated activity of PON1 (p = 0.0455) and LCAT (p = 0.0117) following the 12-week intervention. In contrast, the changes observed in the IF group did not reach statistical significance. Conclusions: A balanced diet combined with meticulous insulin management improves multiple metrics of HDL function. While additional IF increases apoM levels, it does not further enhance other aspects of HDL functionality. Trial registration: The study was registered at the German Clinical Trial Register (DRKS) on 3 September 2019 under the number DRKS00018070. [ABSTRACT FROM AUTHOR]

High-density lipoprotein (HDL) cholesterol is traditionally viewed as protective against cardiovascular disease (CVD). However, emerging evidence reveals that dysfunctional HDL, characterized by impaired reverse cholesterol transport (RCT), reduced anti-inflammatory and antioxidant activities and increased endothelial dysfunction, which can contribute to coronary artery disease (CAD). Dysfunctional HDL, resulting from oxidative modifications of Apolipoprotein A-1 (Apo A-1) and enzyme inactivation, fails to effectively remove cholesterol from peripheral tissues and may promote inflammation and atherosclerosis. Genetic mutations affecting HDL metabolism further complicate its role in cardiovascular health. Studies have shown that conventional therapies aimed at raising HDL-C levels do not necessarily reduce cardiovascular events, highlighting the need for new approaches that improve HDL functionality. Therapeutic strategies such as Apo A-1 mimetic peptides, reconstituted HDL infusions, and drugs targeting specific HDL metabolic pathways are being explored. Additionally, weight loss, statin therapy, and niacin have shown potential in enhancing HDL function. The pathophysiology of dysfunctional HDL involves complex mechanisms, including oxidative stress, inflammation, and genetic mutations, which alter its structure and function, diminishing its cardioprotective effects. New functional assays, such as the cholesterol efflux capacity (CEC) and HDL inflammatory index, provide more accurate predictions of cardiovascular risk by assessing HDL quality rather than quantity. As research progresses, the focus is shifting towards therapeutic strategies that enhance HDL function and address the root causes of its dysfunction, offering a more effective approach to reducing cardiovascular risk and preventing CAD. [ABSTRACT FROM AUTHOR]

The cholesterogenic phenotype, encompassing de novo biosynthesis and accumulation of cholesterol, aids cancer cell proliferation and survival. Previously, the role of cholesteryl ester (CE) transfer protein (CETP) has been implicated in breast cancer aggressiveness, but the molecular basis of this observation is not clearly understood, which this study aims to elucidate. CETP knock‐down resulted in a >50% decrease in cell proliferation in both 'estrogen receptor‐positive' (ER+; Michigan Cancer Foundation‐7 (MCF7) breast cancer cells) and 'triple‐negative' breast cancer (TNBC; MDA‐MB‐231) cell lines. Intriguingly, the abrogation of CETP together with the combination treatment of tamoxifen (5 μM) and acetyl plumbagin (a cholesterol‐depleting agent) (5 μM) resulted in twofold to threefold increase in apoptosis in both cell lines. CETP knockdown also showed decreased intracellular CE levels, lipid raft and lipid droplets in both cell lines. In addition, RT2 Profiler PCR array (Qiagen, Germany)‐based gene expression analysis revealed an overall downregulation of genes associated in cholesterol biosynthesis, lipid signalling and drug resistance in MCF7 cells post‐CETP knock‐down. On the contrary, resistance in MDA‐MB‐231 cells was reduced through increased expression in cholesterol efflux genes and the expression of targetable surface receptors by endocrine therapy. The pilot xenograft mice study substantiated CETP's role as a cancer survival gene as knock‐down of CETP stunted the growth of TNBC tumour by 86%. The principal findings of this study potentiate CETP as a driver in breast cancer growth and aggressiveness and thus targeting CETP could limit drug resistance via the reduction in cholesterol accumulation in breast cancer cells, thereby reducing cancer aggressiveness. [ABSTRACT FROM AUTHOR]

Preterm birth is the leading cause of neonatal mortality worldwide, and dyslipidemia is associated with preterm birth in observational studies. We use Mendelian randomization (MR) analyses to uncover the causal association between blood lipid levels and preterm birth. We extracted uncorrelated (R2 < 0.001) single-nucleotide polymorphisms strongly associated (p < 5 × 10–8) with blood lipids from genome wide association studies of FinnGen database and UK Biobank participants. Inverse variance weighted method was the main MR analysis. Sensitivity analyses including genetic pleiotropy, heterogeneity, and directionality of causality were conducted. The study included 115,082 participants with lipid measurements, 8,507 patients with preterm birth. Increasing apolipoprotein B (odds ratio (OR), 1.12[95 % CI, 1.02–1.23]; p = 0.019), low-density lipoprotein cholesterol (OR, 1.11[95 % CI, 1.00–1.22]; p = 0.040), non-high-density lipoprotein cholesterol (OR, 1.12[95 % CI, 1.01–1.24]; p = 0.026), remnant cholesterol (OR, 1.11[95 % CI, 1.00–1.23]; p = 0.047) and total free cholesterol (OR, 1.11[95 % CI, 1.01–1.23]; p = 0.037) were associated with increased risk of preterm delivery. Moreover, triglycerides in low-density lipoprotein were causally associated with the risk of PTB. Our sensitivity analysis yielded robust results, uncovering no evidence of horizontal pleiotropy or reverse causal relationships. Our investigation unveils the adverse impact of dyslipidemia on preterm birth, with a particular emphasis on the detrimental effect of elevated low-density lipoprotein cholesterol. [ABSTRACT FROM AUTHOR]

[Display omitted] • A hamster model lacking both LCAT and LDL receptor (DKO) was successfully constructed in the present study. • A significant reduction in plasma LDL-C and HDL-C levels with increased triglyceride and free cholesterol levels was observed in DKO hamsters on a regular chow diet. • Dyslipidemia contributed to HFD-induced atherosclerosis and fatty liver independent on LDL levels in DKO hamsters. • Lipid metabolism was impaired in primary peritoneal macrophages from DKO hamsters. Lecithin cholesterol acyltransferase (LCAT) plays a crucial role in acyl-esterifying cholesterol in plasma, which is essential for reverse cholesterol transport (RCT). Previous studies indicated that its activity on both α and β lipoproteins interpret its effects on lipoproteins for many controversial investigations of atherosclerosis. To better understand the relationship between LCAT, diet-induced dyslipidemia and atherosclerosis, we developed a double knockout (LCAT−/−&LDLR−/−, DKO) hamster model to evaluate the specific role of LCAT independent of LDL clearance effects. Plasma triglyceride (TG), total cholesterol (TC), high-density lipoprotein-cholesterol (HDL-C), and free cholesterol (FC) levels were measured using biochemical reagent kits. FPLC was performed to analyze the components of lipoproteins. Apolipoprotein content was assessed using western blotting (WB). The hamsters were fed a high cholesterol/high fat diet (HCHFD) to induce atherosclerosis. Oil Red O staining was employed to detect plaque formation. Peritoneal macrophages were studied to investigate the effects of LCAT on cholesterol uptake and efflux. On HCHFD, DKO hamsters exhibited significantly elevated levels of TG and FC, while HDL-C was nearly undetectable without affecting TC levels, as compared to low-density lipoprotein receptor (LDLR)-deficient (LDLR−/−, LKO) hamsters. Lipoprotein profiling revealed a marked increase in plasma chylomicron/very low-density lipoprotein (CM/VLDL) fractions, along with an unexpected reduction in LDL fraction in DKO hamsters. Furthermore, DKO hamsters displayed aggravated atherosclerotic lesions in the aorta, aortic root, and coronary artery relative to LKO hamsters, attributed to a pro-atherogenic lipoprotein profile and impaired cholesterol efflux in macrophages. Our study demonstrates the beneficial role of LCAT in inhibiting atherosclerotic development and highlights the distinctive lipid metabolism characteristics in hamsters with familial hypercholesterolemia. [ABSTRACT FROM AUTHOR]

ApolipoproteinC1 (apoC1) is the main physiological inhibitor of the cholesterol ester transfer protein (CETP). Increased CETP activity is associated with macrovascular complications in patients with type 1 diabetes (T1D). ApoC1 has lost its ability to inhibit CETP in patients with T1D, and in vitro glycation of apoC1 increases CETP activity, suggesting that hyperglycemia could be a factor implicated in the loss of the inhibitory effect of apoC1 on CETP. Thus, we aimed to see whether improvement of glycemic control might restore apoC1 inhibitory effect on CETP. We studied 98 patients with T1D and HbA1c > 9% at baseline and 3 months after improvement of glycemic control by a medical intervention (insulin introduction or changes in multi-injection therapy or pump therapy introduction/therapeutic education for all patients). CETP activity was assessed by a radioactive method and plasma apoC1 levels were measured by ELISA. The different isoforms of apoC1 were determined by mass spectrometry. CETP activity was not significantly modified after improvement of glycemic control, despite a significant reduction in mean HbA1c (8.7 ± 1.7 vs. 10.8 ± 2, p < 0.0001). No association between plasma apoC1 and CETP activity was observed in patients with T1D at baseline, nor at 3 months, even in the subgroup of patients with optimal control (3-month HbA1c < 7%). We did not find any glycated form of apoC1 using mass spectrometry in people with T1D. Hyperglycemia in vivo does not seem to be a major factor implicated in the loss of apoC1 ability to inhibit CETP activity observed in T1D. Other factors, such as qualitative abnormalities of lipoproteins, could be involved. Our data emphasize the fact that hyperglycemia is not the only factor involved in lipid abnormalities and macrovascular complications in T1D. Clinical trial reg. no. NCT02816099 ClinicalTrials.gov. [ABSTRACT FROM AUTHOR]

Abstract Background Elevated concentrations of low-density lipoprotein cholesterol (LDL-C) are linked to dementia risk, and conversely, increased plasma concentrations of high-density lipoprotein cholesterol (HDL-C) and apolipoprotein-A1 (Apo-A1) associate with decreased dementia risk. Inhibition of cholesteryl ester transfer protein (CETP) meaningfully affects the concentrations of these blood lipids and may therefore provide an opportunity to treat dementia. Methods Drug target Mendelian randomization (MR) was employed to anticipate the on-target effects of lower CETP concentration (μg/mL) on plasma lipids, cardiovascular disease outcomes, autopsy confirmed Lewy body dementia (LBD), as well as Parkinson’s dementia. Results MR analysis of lower CETP concentration recapitulated the blood lipid effects observed in clinical trials of CETP-inhibitors, as well as protective effects on coronary heart disease (odds ratio (OR) 0.92, 95% confidence interval (CI) 0.89; 0.96), heart failure, abdominal aortic aneurysm, any stroke, ischemic stroke, and small vessel stroke (0.90, 95%CI 0.85; 0.96). Consideration of dementia related traits indicated that lower CETP concentrations were associated higher total brain volume (0.04 per standard deviation, 95%CI 0.02; 0.06), lower risk of LBD (OR 0.81, 95%CI 0.74; 0.89) and Parkinson’s dementia risk (OR 0.26, 95%CI 0.14; 0.48). APOE4 stratified analyses suggested the LBD effect was most pronounced in APOE-ε4 + participants (OR 0.61 95%CI 0.51; 0.73), compared to APOE-ε4- (OR 0.89 95%CI 0.79; 1.01); interaction p-value 5.81 × 10− 4. Conclusions These results suggest that inhibition of CETP may be a viable strategy to treat dementia, with a more pronounced effect expected in APOE-ε4 carriers.

Background: Aberrant lipid metabolism is intricately linked to the development of endometrial cancer, and statin lipid-lowering medications are regarded as promising adjunctive therapies for future management of this malignancy. This study employed Mendelian randomization (MR) to explore the causal association between lipid traits and endometrial cancer while assessing the potential impact of drug targets on lower lipids on endometrial cancer. Method: Two-sample Mendelian randomization was employed to probe the causal association between lipid traits and endometrial carcinoma. Drug-target Mendelian randomization was also utilized to identify potential drug-target genes for managing endometrial carcinoma. In instances where lipid-mediated effects through particular drug targets were notable, the impacts of these drug targets on endometrial carcinoma risk factors were investigated to bolster the findings. Result: No causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC was found in two-sample Mendelian randomization. In drug target Mendelian randomization, genetic modeling of apolipoprotein B (APOB) (OR [95%CI]=0.31, [0.16-0.60]; p=4.73e-04) and cholesteryl ester transfer protein (CETP) (OR [95%CI]=1.83, [1.38-2.43]; p=2.91e-05) genetic mimicry was associated with non-endometrioid carcinoma. Conclusion: The results of our MR study revealed no causal association between genetically predicted lipid traits (LDL-C, TG, TC, and HDL-C) and EC. Among the six lipid-lowering drug targets, we observed a significant association between lower predicted APOB levels and higher CETP levels with an increased risk of endometrioid carcinoma. These findings provide novel insights into the importance of lipid regulation in individuals with endometrial carcinoma, warranting further clinical validation and mechanistic investigations. [ABSTRACT FROM AUTHOR]

Obicetrapib is a selective cholesteryl ester transfer protein (CETP) inhibitor. Previous research has demonstrated similar pharmacokinetic (PK) responses to single doses of obicetrapib between Japanese and White males, but the PK responses have not been established in Chinese individuals. The purpose of this randomized, parallel, open‐label trial was to characterize the PK and pharmacodynamic (PD; CETP activity and plasma lipids) responses and safety of single doses (5, 10, or 25 mg; N = 36) and multiple doses (10 mg for 14 days; N = 12) of obicetrapib in healthy Chinese individuals. The maximum concentration and area under the drug concentration‐time curve of obicetrapib from 0 h to infinity increased with dose after all single doses of obicetrapib. After 7 consecutive days of dosing, low‐density lipoprotein cholesterol and high‐density lipoprotein cholesterol reached their minimum and maximum changes of 42% reduction and 108% increase, respectively. Primary PK and PD parameters after single‐ and multiple‐dose administration of obicetrapib were similar to those in healthy white participants in previous studies. One participant in the 5 mg dose group experienced a treatment‐emergent adverse event of decreased white blood cell and neutrophil counts, which resolved without intervention. In conclusion, these findings support the inclusion of Chinese individuals in the ongoing phase 3 clinical development program of obicetrapib. [ABSTRACT FROM AUTHOR]

Polymorphisms in the cholesteryl ester transfer protein (CETP) gene are known to be strongly associated with increased cardiovascular risk, primarily through their effects on the lipid profile and consequently on atherosclerotic risk. The acute heart rate response (AHRR) to physical activity is closely related to individual cardiovascular health. This study aimed to investigate the effect of CETP gene polymorphisms on AHRR. Our analysis examines the association of five single nucleotide polymorphisms (SNPs; rs1532624, rs5882, rs708272, rs7499892, and rs9989419) and their haplotypes (H) in the CETP gene with AHRR in 607 people from the Hungarian population. Individual AHRR in the present study was assessed using the YMCA 3-min step test and was estimated as the difference between resting and post-exercise heart rate, i.e., delta heart rate (ΔHR). To exclude the direct confounding effect of the CETP gene on the lipid profile, adjustments for TG and HDL-C levels, next to conventional risk factors, were applied in the statistical analyses. Among the examined five SNPs, two showed a significant association with lower ΔHR (rs1532624—Cdominant: B = −8.41, p < 0.001; rs708272—Gdominant: B = −8.33, p < 0.001) and reduced the risk of adverse AHRR (rs1532624—Cdominant: OR = 0.44, p = 0.004; rs708272—Gdominant: OR = 0.43, p = 0.003). Among the ten haplotypes, two showed significant association with lower ΔHR (H3—CAGCA: B = −6.81, p = 0.003; H9—CGGCG: B = −14.64, p = 0.015) and lower risk of adverse AHRR (H3—CAGCA: OR = 0.58, p = 0.040; H9—CGGCG: OR = 0.05, p = 0.009) compared to the reference haplotype (H1—AGACG). Our study is the first to report a significant association between CETP gene polymorphisms and AHRR. It also confirms that the association of the CETP gene with cardiovascular risk is mediated by changes in heart rate in response to physical activity, in addition to its effect on lipid profile. [ABSTRACT FROM AUTHOR]

Background: Dysferlin-deficient limb-girdle muscular dystrophy type 2B (Dysf) mice are notorious for their mild phenotype. Raising plasma total cholesterol (CHOL) via apolipoprotein E (ApoE) knockout (KO) drastically exacerbates muscle wasting in Dysf mice. However, dysferlinopathic patients have abnormally reduced plasma high-density lipoprotein cholesterol (HDL-C) levels. The current study aimed to determine whether HDL-C lowering can exacerbate the mild phenotype of dysferlin-null mice. Methods: Human cholesteryl ester transfer protein (CETP), a plasma lipid transfer protein not found in mice that reduces HDL-C, and/or its optimal adapter protein human apolipoprotein B (ApoB), were overexpressed in Dysf mice. Mice received a 2% cholesterol diet from 2 months of age and characterized through ambulatory and hanging functional tests, plasma analyses, and muscle histology. Results: CETP/ApoB expression in Dysf mice caused reduced HDL-C (54.5%) and elevated ratio of CHOL/HDL-C (181.3%) compared to control Dysf mice in plasma, but without raising CHOL. Compared to the severe muscle pathology found in high CHOL Dysf/ApoE double knockout mice, Dysf/CETP/ApoB mice did not show significant changes in ambulation, hanging capacity, increases in damaged area, collagen deposition, or decreases in cross-sectional area and healthy myofibre coverage. Conclusions: CETP/ApoB over-expression in Dysf mice decreases HDL-C without increasing CHOL or exacerbating muscle pathology. High CHOL or nonHDL-C caused by ApoE KO, rather than low HDL-C, likely lead to rodent muscular dystrophy phenotype humanization. [ABSTRACT FROM AUTHOR]

This article discusses the challenges of accurately measuring the incidence and mortality of sepsis, a global health priority. The U.S. Centers for Disease Control and Prevention (CDC) developed the "Adult Sepsis Event" (ASE) definition in 2018, which uses clinical data from electronic health records (EHR) to identify sepsis. This study in South Korea validates the feasibility and benefits of using the ASE definition to measure sepsis incidence and outcomes outside of the U.S. The study also highlights the limitations of using International Classification of Diseases (ICD) codes for tracking sepsis. The findings suggest that ASE surveillance could facilitate standardized international comparisons of sepsis rates and mortality. The study identifies areas for improvement, such as incorporating additional criteria and improving the match between electronic and traditional assessment methods. However, the study's limitations include its focus on a single hospital and a single year during the COVID-19 pandemic. The authors emphasize the importance of conducting sepsis surveillance in low- and middle-income settings and the potential for ASE surveillance to provide reliable global data on sepsis epidemiology. [Extracted from the article]

The article discusses the importance of cholesterol in cardiovascular diseases (CVDs) and the role of high-density lipoprotein (HDL) in protecting against CVDs. It highlights the challenges in measuring cholesterol efflux capacity (CEC) and the limitations of focusing solely on HDL cholesterol (HDL-C) levels. The article also presents the results of the AEGIS-II trial, which tested the efficacy of CSL112, a form of Apolipoprotein A-I (ApoA-I), in reducing cardiovascular events after acute myocardial infarction (AMI). The trial found no significant difference in the primary endpoint between the CSL112 and placebo groups, suggesting the need for further research and a reevaluation of the HDL hypothesis. [Extracted from the article]

The association between high-density lipoprotein cholesterol (HDL-C) and cardiovascular disease (CVD) is controversial. HDL-C is one content type of high-density lipoprotein (HDL). HDL consists of diverse proteins and lipids and can be classified into different subclasses based on size, shape, charge, and density, and can change dynamically in disease states. Therefore, HDL-C levels alone cannot represent HDLs' cardioprotective role. In this review, we summarized the methods for separating HDL subclasses, the studies on the association between HDL subclasses and cardiovascular risk (CVR), and the impact of lipid-modifying medications and nonpharmacological approaches (exercise training, dietary omega fatty acids, and low-density lipoprotein apheresis) on HDL subclasses. As HDL is a natural nanoplatform, recombinant HDLs (rHDLs) have been used as a delivery system in vivo by loading small interfering RNA, drugs, contrast agents, etc. Therefore, we further reviewed the HDL subclasses used in rHDLs and their advantages and disadvantages. This review would provide recommendations and guidance for future studies on HDL subclasses' cardioprotective roles. [ABSTRACT FROM AUTHOR]

Seminal plasma contains a heterogeneous population of extracellular vesicles (sEVs) that remains poorly characterized. This study aimed to characterize the lipidomic profile of two subsets of differently sized sEVs, small (S-) and large (L-), isolated from porcine seminal plasma by size-exclusion chromatography and characterized by an orthogonal approach. High-performance liquid chromatography–high-resolution mass spectrometry was used for lipidomic analysis. A total of 157 lipid species from 14 lipid classes of 4 major categories (sphingolipids, glycerophospholipids, glycerolipids, and sterols) were identified. Qualitative differences were limited to two cholesteryl ester species present only in S-sEVs. L-sEVs had higher levels of all quantified lipid classes due to their larger membrane surface area. The distribution pattern was different, especially for sphingomyelins (more in S-sEVs) and ceramides (more in L-sEVs). In conclusion, this study reveals differences in the lipidomic profile of two subsets of porcine sEVs, suggesting that they differ in biogenesis and functionality. [ABSTRACT FROM AUTHOR]

Statins, also known as HMG-CoA reductase inhibitors, are widely prescribed drugs for the prevention and treatment of cardiovascular diseases. In addition to their lipid-lowering effects, these compounds have been found to possess immune-modulating properties. Macrophages, which are crucial phagocytic cells in the body, can be divided into two main subsets: M1 (proinflammatory) and M2 (anti-inflammatory). While there is evidence suggesting that statins exert an anti-inflammatory action on macrophages and promote their polarization towards the M2 subset, recent studies have identified the proinflammatory impact of statins on macrophages, leading to polarization towards the M1 subset. For example, statins have been shown to inhibit NF-κB activation to promote anti-inflammatory responses. On the other hand, statins can induce NFκB/AP-1 activation and increase IL-1β secretion in macrophages to promote pro-inflammatory responses. This review aims to provide a comprehensive overview of both in vivo and in vitro studies that have investigated the effects of statins on macrophage polarization and inflammatory responses in various diseases. Furthermore, this review seeks to evaluate the underlying mechanisms involved in these effects. By summarizing the existing evidence, this review contributes to our understanding of the complex interactions between statins and macrophages in different disease contexts. [ABSTRACT FROM AUTHOR]

The present study aimed to evaluate antidiarrheal potential of prickly pear cladode and its hepatoprotective role in different groups of diarrhea‐induced mice. Mice received cefixime (4 mg/kg of bw) and different concentrations of aqueous cladode extract (250 mg/kg of bw, 500 mg/kg of bw and 1000 mg/kg of bw). Feces Salmonella typhi ATCC 19430 was used to assess antidiarrheal potential and hematological, biochemical parameters, and histopathological analyses were carried out for 17 days. The results showed that administration of Salmonella typhi ATCC 19430 in mice produced liver injuries with histological damage, whereas 1000 mg/kg of bw cladode extract reduced the Salmonella typhi ATCC 19430 load of feces earlier as compared to the other groups during 17 days. Hematological parameters, like red blood cells (RBCs) (6.19 ± 1.85 × 106/mm3) and hemoglobin (Hb) (10.06 ± 2.03 g/dL), of negative control group decreased, while white blood cells (WBCs) (13.46 × 106/mm3) increased from reference values. In lipid profile, low‐density lipoprotein (LDL) (9.0 ± 2.41 mg/dL), high‐density lipoprotein (HDL) (6.07 ± 2.45 mg/dL) and total cholesterol (TC) (35.22 ± 8.29 mg/dL) of negative control group decreased, while triglycerides (TG) (168.35 ± 71.75 mg/dL) increased from reference values. Alanine transferase (ALT) (60.30 ± 20.33 IU/L), alkaline phosphatase (ALP) (359.9 ± 100.05 IU/L) and aspartate transferase (AST) (168.77 ± 66.61 IU/L) of negative control group increased from reference values. Urea (27.36 ± 10.54 mmol/L) and creatinine (35.29 ± 12.15 mmol/L) of the negative control group increased. Cefixime also ameliorated injuries due to the administration of Salmonella typhi ATCC 19430. Conclusively, these findings indicated that pure aqueous extract of cladode showed more promising results regarding antidiarrheal potential. Hence, cladode might be used in food and supplement formulations as a functional ingredient. [ABSTRACT FROM AUTHOR]

Purpose: The etiology of alopecia areata (AA) in relation to serum lipids remains unclear, thereby prompting our intention to do Mendelian study on this subject. Design: Two‐sample Mendelian randomization (MR) analysis was performed in the study. The inverse variance‐weighted method was used as the primary method. Methods: In our study, we integrated a set of 123 single‐nucleotide polymorphisms (SNPs) into our analysis. These SNPs have been extensively studied and are known to exhibit associations with serum lipids. We sourced these SNPs from a variety of relevant studies and consortia that specifically focus on lipid‐related research, such as the MRC Integrative Epidemiology Unit. These carefully curated SNPs were then utilized as instrumental variables in our analysis, allowing us to explore and evaluate the causal relationships between these genetic variants and serum lipids. By incorporating this comprehensive set of SNPs, we aimed to enhance the precision and robustness of our findings, shedding light on the intricate interplay between genetics and serum lipids. Results: In the MR analysis, a higher total lipid concentration in large low‐density lipoprotein (LDL) particles (odds ratio [OR] = 1.502; 95% confidence interval [CI] = 1.086–1.953; p = 0.006), a greater ratio of cholesteryl esters to total lipids in chylomicrons and extremely large very LDL (VLDL) particles (OR = 2.174; 95% CI = 1.300–2.500; p = 0.010), and a greater ratio of cholesterol to total lipids in chylomicrons and extremely large VLDL particles (OR = 2.363;95% CI = 1.556–4.438; p = 0.004), were genetically predicted to be causally associated with an increased risk of AA, while patients with a higher triglyceride to total lipids ratio in chylomicrons and extremely large VLDL particles had a lower risk of AA (OR = 0.481; 95% CI = 0.191–1.270; p = 0.002). Conclusion: This study found that serum lipids may be causally implicated in AA. [ABSTRACT FROM AUTHOR]

Introduction: Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. Methods: We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. Results: The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. Discussion: The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair. [ABSTRACT FROM AUTHOR]

Introduction: Cholesteryl ester transfer protein (CETP) inhibitors, initially developed for treating hyperlipidemia, have shown promise in reducing the risk of new-onset diabetes during clinical trials. This positions CETP inhibitors as potential candidates for repurposing in metabolic disease treatment. Given their oral administration, they could complement existing oral medications like sodium-glucose cotransporter 2 (SGLT2) inhibitors, potentially delaying the need for injectable therapies such as insulin. Methods: We conducted a 2x2 factorial Mendelian Randomization analysis involving 233,765 participants from the UK Biobank. This study aimed to evaluate whether simultaneous genetic inhibition of CETP and SGLT2 enhances glycemic control compared to inhibiting each separately. Results: Our findings indicate that dual genetic inhibition of CETP and SGLT2 significantly reduces glycated hemoglobin levels compared to controls and single-agent inhibition. Additionally, the combined inhibition is linked to a lower incidence of diabetes compared to both the control group and SGLT2 inhibition alone. Discussion: These results suggest that combining CETP and SGLT2 inhibitor therapies may offer superior glycemic control over SGLT2 inhibitors alone. Future clinical trials should investigate the potential of repurposing CETP inhibitors for metabolic disease treatment, providing an oral therapeutic option that could benefit high-risk patients before they require injectable therapies like insulin or glucagon-like peptide-1 (GLP-1) receptor agonists. [ABSTRACT FROM AUTHOR]

Context Among children, evidence on long-term longitudinal associations of accelerometer-measured sedentary time, light physical activity (LPA), and moderate to vigorous PA (MVPA) with lipid indices are few. The mediating role of body composition and other metabolic indices in these associations remains unclear and whether poor movement behavior precedes altered lipid levels is unknown. Objective This study examined the associations of sedentary time, LPA, and MVPA from childhood through young adulthood with increased lipids, the mediating role of body composition, and whether temporal interrelations exist. Methods Data from 792 children (58% female; mean [SD] age at baseline, 11.7 [0.2] years), drawn from the Avon Longitudinal Study of Parents and Children (ALSPAC) UK birth cohort, who had at least 2 time-point measures of accelerometer-based sedentary time, LPA, and MVPA during clinic visits at ages 11, 15, and 24 years and complete fasting plasma high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, triglyceride, and total cholesterol measured during follow-up visits at ages 15, 17, and 24 years were analyzed. Results Total fat mass partly mediated the inverse associations of LPA with low-density lipoprotein cholesterol by 13%, triglyceride by 28%, and total cholesterol by 6%. Total fat mass mediated the inverse associations of MVPA with low-density lipoprotein cholesterol by 37% and total cholesterol by 48%, attenuating the effect on total cholesterol to nonsignificance (P =.077). In the temporal path analyses, higher MVPA at age 15 years was associated with lower low-density lipoprotein cholesterol at 24 years (β = −0.08, SE, 0.01, P =.022) but not vice versa. Conclusion Sedentary time worsens lipid indices, but increased LPA had a 5- to 8-fold total cholesterol-lowering effect and was more resistant to the attenuating effect of fat mass than MVPA. [ABSTRACT FROM AUTHOR]

Background Chronic inflammation has been connected by epidemiological evidence to coronary artery disease (CAD) along with myocardial infarction (MI). Nevertheless, it is still unclear whether reverse causality or confounders account for these connections. Our objectives are to examine the causality between inflammatory cytokines and CAD/MI as well as the potential mediating influence of lipid characteristics. Methods We acquired instrumental variables through genome-wide association studies meta-analyses of 41 inflammatory cytokines (8293 individuals). Genetic associations with CAD (122 733 cases and 424 528 controls), MI (~61 505 cases and 577 716 controls) and five candidate lipid mediators were obtained from the corresponding genome-wide association studies. A two-step, two-sample Mendelian randomization analysis was applied, followed with comprehensive sensitivity analyses. Results Genetically determined growth regulated oncogene-α was causally linked to a decreased incidence of CAD [odds ratio (OR), 0.97; 95% confidence interval (CI), 0.95-0.99; P  = .007] and MI (OR, 0.95; 95% CI, 0.92-0.98; P  = .002). There is suggestive evidence indicating a causal impact of macrophage inflammatory protein-1β upon CAD (OR, 1.04; 95% CI, 1.01–1.07; P  = .010) and MI (OR, 1.07; 95% CI, 1.02–1.11; P  = .002). Furthermore, we discovered suggestive causal connections between tumor necrosis factor-related apoptosis-inducing ligand and CAD (OR, 0.97; 95% CI, 0.95–1.00; P  = .020). Two-step Mendelian randomization analysis revealed that triglycerides partially mediate the effect of growth regulated oncogene-α on CAD (proportion-mediated: 13.28%) and MI (8.05%). Conclusions We provided novel genetic evidence supporting the causality of inflammatory cytokines on CAD/MI and elucidate the mediating effect of triglycerides in the causal pathways linking inflammatory cytokines and CAD/MI. What is already known on this topic Observational studies have linked inflammatory cytokines to coronary artery disease (CAD) and myocardial infarction (MI); however, the associations are still controversial due to confounding factors and reverse causation bias. Furthermore, the role of lipid traits in mediating the causal effects of inflammatory cytokines on CAD/MI remains unknown. What this study adds This Mendelian randomization study provides novel genetic evidence that supports the causal impact of specific inflammatory cytokines on CAD/MI and elucidates the mediating role of triglycerides in the causal pathways linking inflammatory cytokines to CAD/MI. How this study might affect research, practice, or policy Our findings demonstrate that monitoring levels of inflammatory cytokines and managing dyslipidemia are clinically applicable strategies for preventing CAD/MI. [ABSTRACT FROM AUTHOR]

On average, LDL particles are the most populous lipoprotein in serum under fasting conditions. For many reasons, it has been the primary target of lipid-lowering guidelines around the world. In the past 30 years, we have witnessed remarkable changes in each iteration of dyslipidaemia guidelines, with LDL-cholesterol (LDL-C) targets becoming lower and lower among patients at high and very high risk for atherosclerotic cardiovascular disease (ASCVD). The world over, goal attainment rates are low, and hence, ASCVD prevalence remains unacceptably high. Inadequate LDL-C lowering is a major issue in contemporary cardiovascular (CV) medicine. Another issue that vexes even the most astute clinician is that of 'residual risk', meaning the excess risk that remains even after LDL-C is appropriately reduced. In recent years, an important new component of residual risk has emerged: triglyceride-enriched lipoproteins or remnant lipoproteins. These precursors to LDL particles can assume outsized importance among patients with derangements in triglyceride metabolism (e.g. genetic variants, insulin resistance, and diabetes mellitus) and may be more atherogenic than LDL species. Consequently, to reduce total risk for acute CV events, the time has come to include the entire spectrum of apoB-containing lipoproteins in approaches to both risk evaluation and treatment. [ABSTRACT FROM AUTHOR]

Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein–ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein–ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development. [ABSTRACT FROM AUTHOR]

CETP inhibitors are a class of lipid-lowering drugs in development for treatment of coronary heart disease (CHD). Genetic studies in East Asian ancestry have interpreted the lack of CETP signal with low-density lipoprotein cholesterol (LDL-C) and lack of drug target Mendelian randomization (MR) effect on CHD as evidence that CETP inhibitors might not be effective in East Asian participants. Capitalizing on recent increases in sample size of East Asian genetic studies, we conducted a drug target MR analysis, scaled to a standard deviation increase in high-density lipoprotein cholesterol. Despite finding evidence for possible neutral effects of lower CETP levels on LDL-C, systolic blood pressure and pulse pressure in East Asians (interaction p-values < 1.6 × 10−3), effects on cardiovascular outcomes were similarly protective in both ancestry groups. In conclusion, on-target inhibition of CETP is anticipated to decrease cardiovascular disease in individuals of both European and East Asian ancestries. CETP inhibitors are being developed for treatment of coronary heart disease. Here, the authors show that the anticipated beneficial effects of lower plasma levels of CETP are shared among individuals of European and East Asian ancestry. [ABSTRACT FROM AUTHOR]

Background: Osteoporosis and atherosclerosis frequently afflict older adults, and recent insights suggest a deeper connection between these conditions that surpasses mere aging effects. The ratio of non-high-density to high-density lipoprotein cholesterol (NHHR) has emerged as a novel lipid marker for evaluating the risk of cardiovascular diseases. Nonetheless, investigations into the correlation of the NHHR with the risk of developing osteoporosis remain unexplored. Methods: We collected NHHR and bone mineral density (BMD) data from 11,024 National Health and Nutrition Examination Survey (NHANES) participants between 2011 and 2018. Multivariate linear regression was employed to examine the correlation between BMD and NHHR. Smooth curves were employed to deal with the nonlinearity. To further account for the nonlinear link, we used a two-part linear regression model. The threshold effects were estimated using two components of a linear regression model. Subgroup and sensitivity analyses were carried out to ascertain the stability of the findings. Results: We discovered a negative relationship between the NHHR and lumbar spine BMD in all three models. An L-shaped curvilinear association existed between the NHHR and lumbar spine BMD, with a key inflection point of 6.91. The fully adjusted model showed that the BMD of the lumbar spine fell by 0.03 g/cm2 in those who were in the fourth quartile as opposed to the lowest quartile. The sensitivity analysis using unweighted logistic analysis verified the stability of the results. In addition, BMD in the nondiabetic group was more significantly affected by the negative effect of the NHHR in the subgroup analysis. Conclusions: According to this research, there appears to be a negative correlation between BMD and NHHR in US Adults. To clarify the precise physiological mechanisms by which the NHHR contributes to the onset of osteoporosis, more research is necessary. [ABSTRACT FROM AUTHOR]

Objective: High low-density-lipoprotein (LDL) cholesterol has been associated with an increased risk of coronary artery diseases (CAD) including acute myocardial infarction (AMI). However, whether lipids lowering drug treatment is causally associated with decreased risk of AMI remains largely unknown. We used Mendelian randomization (MR) to evaluate the influence of genetic variation affecting the function of lipid-lowering drug targets on AMI. Methods: Single-nucleotide polymorphisms (SNPs) associated with lipids as instruments were extracted from the Global Lipids Genetics Consortium (GLGC). The genome-wide association study (GWAS) data for AMI were obtained from UK Biobank. Two sample MR analysis was used to study the associations between high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides (TG) with AMI (n = 3,927). Genetic variants associated with LDL cholesterol at or near drug target gene were used to mimic drug effects on the AMI events in drug target MR. Results: Genetically predicted higher LDL-C (per one SD increase in LDL-C of 38.67 mg/dL, OR 1.006, 95% CI 1.004–1.007) and TG (per one SD increase in TG of 90.72 mg/dL, 1.004, 1.002–1.006) was associated with increased risk of AMI, but decreased risk for higher HDL-C (per one SD increase in HDL-C of 15.51 mg/dL, 0.997, 0.995–0.999) in univariable MR. Association remained significant for LDL-C, but attenuated toward the null for HDL-C and TG in multivariable MR. Genetically proxied lower LDL-C with genetic variants at or near the PCSK9 region (drug target of evolocumab) and NPC1L1 (drug target of ezetimibe) were associated with decreased risk of AMI (0.997, 0.994–0.999 and 0.986, 0.975–0.998, respectively), whereas genetic variants at HMGCR region (drug target of statin) showed marginal association with AMI (0.995, 0.990-1.000). After excluding drug target-related SNPs, LDL-C related SNPs outside the drug target region remained a causal effect on AMI (0.994, 0.993–0.996). Conclusions: The findings suggest that genetically predicted LDL-C may play a predominant role in the development of AMI. The drug MR results imply that ezetimibe and evolocumab may decrease the risk of AMI due to their LDL-C lowering effect, and there are other non-drug related lipid lowering pathways that may be causally linked to AMI. [ABSTRACT FROM AUTHOR]

Purpose: To investigate ocular and systemic factors associated with the retinal arterial wall‐to‐lumen ratio (WLR) and to determine the relative contribution of genetic and environmental variation to WLR in healthy adults. Methods: This cross‐sectional twin study included 78 monozygotic and 67 dizygotic same‐sex twin pairs aged 58.4 ± 9.8 (mean ± SD) years. Lumen diameter (LD) and outer diameter (OD) of a superotemporal retinal artery were measured using adaptive optics fundus photography, and the WLR was calculated. Linear mixed model regression analysis of associations with WLR comprised the descriptive variables ocular axial length (AL), intraocular pressure (IOP), height, weight, body mass index (BMI), smoking, blood pressure, high density (HDL), low density (LDL) and very low density (VLDL) lipoproteins, total cholesterol and triglycerides. The relative influence of genes and environment on WLR was calculated through polygenetic modelling. Results: Increasing age and arterial blood pressure were associated with a higher WLR, while increasing retinal artery OD and ocular AL were associated with a lower WLR. Sex, smoking status, BMI, IOP, cholesterol levels or triglycerides had no detectable impact on the WLR. Broad‐sense heritability of WLR was 21% (95% CI: 1–41%), while environmental factors accounted for the remaining 79% of the interindividual variance (95% CI: 59–99%). Conclusion: Retinal artery wall thickness was closely linked to increasing age and higher arterial blood pressure, the latter being mediated by the environment over genes. [ABSTRACT FROM AUTHOR]

Recent studies have suggested the use of insects to enhance various bioactivities in the treatment of many diseases or as alternative sources of nutrients. White‐spotted flower chafer (Protaetia brevitarsis seulensis; PBS) extract, which is used for medicinal purposes, appears to be effective in improving blood circulation. However, few studies have investigated the efficacy of PBS extract in improving blood circulation. Here, we investigated the effects of PBS extract on serum cholesterol metabolites (total cholesterol, high‐density lipoprotein cholesterol, and low‐density lipoprotein cholesterol) and anticoagulant activities (prothrombin time [PT], activated partial thromboplastin time [aPTT], and fibrinogen [Fib]) in very‐high‐fat diet (VHFD)‐induced hyperlipidemic rats. The experimental groups comprised a control group that was not treated with PBS and five PBS treatment groups (50, 100, 150, 200, and 250 mg/kg) in a randomized complete block design. In the efficacy evaluation for health functionality to reduce cholesterol levels, no beneficial effects on serum cholesterol metabolites were observed in the control and PBS treatment groups. In addition, the cholesterol data indicated that the effect of the PBS extract was not related to antioxidant activity. Moreover, the PT, aPPT, and Fib values were prolonged by increasing the PBS extract concentration, and PBS extract concentrations of 150–250 mg/kg were recommended for the VHFD model based on the anticoagulant activity. In conclusion, the PBS extract can be used in a potential therapeutic strategy for improving anticoagulant activity rather than improving the serum cholesterol profile. [ABSTRACT FROM AUTHOR]

OBJECTIVE: Whether genetic susceptibility to disease and dietary cholesterol (DC) absorption contribute to inconsistent associations of DC consumption with diabetes and cardiovascular disease (CVD) remains unclear. RESEARCH DESIGN AND METHODS: DC consumption was assessed by repeated 24-h dietary recalls in the UK Biobank. A polygenetic risk score (PRS) for DC absorption was constructed using genetic variants in the Niemann-Pick C1-Like 1 and ATP Binding Cassettes G5 and G8 genes. PRSs for diabetes, coronary artery disease, and stroke were also created. The associations of DC consumption with incident diabetes (n = 96,826) and CVD (n = 94,536) in the overall sample and by PRS subgroups were evaluated using adjusted Cox models. RESULTS: Each additional 300 mg/day of DC consumption was associated with incident diabetes (hazard ratio [HR], 1.17 [95% CI, 1.07–1.27]) and CVD (HR, 1.09 [95% CI, 1.03–1.17]), but further adjusting for BMI nullified these associations (HR for diabetes, 0.99 [95% CI, 0.90–1.09]; HR for CVD, 1.04 [95% CI, 0.98–1.12]). Genetic susceptibility to the diseases did not modify these associations (P for interaction ≥0.06). The DC-CVD association appeared to be stronger in people with greater genetic susceptibility to cholesterol absorption assessed by the non-high-density lipoprotein cholesterol-related PRS (P for interaction = 0.04), but the stratum-level association estimates were not statistically significant. CONCLUSIONS: DC consumption was not associated with incident diabetes and CVD, after adjusting for BMI, in the overall sample and in subgroups stratified by genetic predisposition to cholesterol absorption and the diseases. Nevertheless, whether genetic predisposition to cholesterol absorption modifies the DC-CVD association requires further investigation. [ABSTRACT FROM AUTHOR]

This document is an editorial from the International Journal of Molecular Sciences titled "Apolipoproteins and Lipoproteins in Health and Disease 2.0." It discusses the role of apolipoproteins and lipoproteins in various biological processes and disease pathways, beyond their traditional association with cardiovascular diseases. The editorial highlights several studies that investigate the impact of diet, supplementation, and drug therapies on lipoprotein structure and function, as well as their potential cardiovascular benefits. It also explores the use of biomarkers and genetic analysis in understanding diseases such as familial hypercholesterolemia and neuropsychiatric disorders. The document concludes by emphasizing the importance of these studies in providing new data and resources for researchers in the field. [Extracted from the article]

During the past half-century, although numerous interventions for obesity have arisen, the condition’s prevalence has relentlessly escalated annually. Obesity represents a substantial public health challenge, especially due to its robust correlation with co-morbidities, such as colorectal cancer (CRC), which often thrives in an inflammatory tumor milieu. Of note, individuals with obesity commonly present with calcium and vitamin D insufficiencies. Transient receptor potential canonical (TRPC) channels, a subclass within the broader TRP family, function as critical calcium transporters in calcium-mediated signaling pathways. However, the exact role of TRPC channels in both obesity and CRC pathogenesis remains poorly understood. This study set out to elucidate the part played by TRPC channels in obesity and CRC development using a mouse model lacking all seven TRPC proteins (TRPC HeptaKO mice). Relative to wildtype counterparts, TRPC HeptaKO mice manifested severe obesity, evidenced by significantly heightened body weights, augmented weights of epididymal white adipose tissue (eWAT) and inguinal white adipose tissue (iWAT), increased hepatic lipid deposition, and raised serum levels of total cholesterol (T-CHO) and lowdensity lipoprotein cholesterol (LDL-C). Moreover, TRPC deficiency was accompanied by an decrease in thermogenic molecules like PGC1-α and UCP1, alongside a upsurge in inflammatory factors within adipose tissue. Mechanistically, it was revealed that pro-inflammatory factors originating from inflammatory macrophages in adipose tissue triggered lipid accumulation and exacerbated obesity-related phenotypes. Intriguingly, considering the wellestablished connection between obesity and disrupted gut microbiota balance, substantial changes in the gut microbiota composition were detected in TRPC HeptaKO mice, contributing to CRC development. This study provides valuable insights into the role and underlying mechanisms of TRPC deficiency in obesity and its related complication, CRC. Our findings offer a theoretical foundation for the prevention of adverse effects associated with TRPC inhibitors, potentially leading to new therapeutic strategies for obesity and CRC prevention. [ABSTRACT FROM AUTHOR]

N-linked glycosylation is an essential and highly conserved co- and post-translational protein modification in all domains of life. In humans, genetic defects in N-linked glycosylation pathways result in metabolic diseases collectively called Congenital Disorders of Glycosylation. In this modification reaction, a mannose rich oligosaccharide is transferred from a lipid-linked donor substrate to a specific asparagine side-chain within the -N-X-T/S- sequence (where X ≠ Proline) of the nascent protein. Oligosaccharyltransferase (OST), a multi-subunit membrane embedded enzyme catalyzes this glycosylation reaction in eukaryotes. In yeast, Ost4 is the smallest of nine subunits and bridges the interaction of the catalytic subunit, Stt3, with Ost3 (or its homolog, Ost6). Mutations of any C-terminal hydrophobic residues in Ost4 to a charged residue destabilizes the enzyme and negatively impacts its function. Specifically, the V23D mutation results in a temperature-sensitive phenotype in yeast. Here, we report the reconstitution of both purified recombinant Ost4 and Ost4V23D each in a POPC/POPE lipid bilayer and their resonance assignments using heteronuclear 2D and 3D solid-state NMR with magic-angle spinning. The chemical shifts of Ost4 changed significantly upon the V23D mutation, suggesting a dramatic change in its chemical environment. [ABSTRACT FROM AUTHOR]

The APOA1/C3/A4/A5 cluster is an essential component in regulating lipoprotein metabolism and maintaining plasma lipid homeostasis. A genome-wide association analysis and Mendelian randomization have revealed potential associations between genetic variants within this cluster and lipid metabolism disorders, including hyperlipidemia and cardiovascular events. An enhanced understanding of the complexity of gene regulation has led to growing recognition regarding the role of epigenetic variation in modulating APOA1/C3/A4/A5 gene expression. Intensive research into the epigenetic regulatory patterns of the APOA1/C3/A4/A5 cluster will help increase our understanding of the pathogenesis of lipid metabolism disorders and facilitate the development of new therapeutic approaches. This review discusses the biology of how the APOA1/C3/A4/A5 cluster affects circulating lipoproteins and the current progress in the epigenetic regulation of the APOA1/C3/A4/A5 cluster. [ABSTRACT FROM AUTHOR]

The article discusses the results of the ApoA-I Event Reducing in Ischemic Syndromes II (AEGIS-II) study, which aimed to determine the efficacy and safety of CSL112, a human plasma-derived apolipoprotein A1, in reducing the risk of major adverse cardiovascular events (MACEs) in the 90-day high-risk period after an acute myocardial infarction (AMI). The study involved 18,226 patients from 49 countries and found no significant difference in MACEs between the CSL112 group and the placebo group at 90, 180, or 365 days of follow-up. The article raises questions about the strategy of using HDL-boosting therapies to reduce cardiovascular risk and suggests that further research is needed to determine the appropriate dose and treatment duration for stabilizing atherosclerotic plaques. [Extracted from the article]

Purpose of reviewCholesteryl ester transfer proteins (CETP) regulate plasma cholesterol levels by transferring cholesteryl esters (CEs) among lipoproteins. Lipoprotein cholesterol levels correlate with the risk factors for atherosclerotic cardiovascular disease (ASCVD). This article reviews recent research on CETP structure, lipid transfer mechanism, and its inhibition.Recent findingsGenetic deficiency in CETP is associated with a low plasma level of low-density lipoprotein cholesterol (LDL-C) and a profoundly elevated plasma level of high-density lipoprotein cholesterol (HDL-C), which correlates with a lower risk of atherosclerotic cardiovascular disease (ASCVD). However, a very high concentration of HDL-C also correlates with increased ASCVD mortality. Considering that the elevated CETP activity is a major determinant of the atherogenic dyslipidemia, i.e., pro-atherogenic reductions in HDL and LDL particle size, inhibition of CETP emerged as a promising pharmacological target during the past two decades. CETP inhibitors, including torcetrapib, dalcetrapib, evacetrapib, anacetrapib and obicetrapib, were designed and evaluated in phase III clinical trials for the treatment of ASCVD or dyslipidemia. Although these inhibitors increase in plasma HDL-C levels and/or reduce LDL-C levels, the poor efficacy against ASCVD ended interest in CETP as an anti-ASCVD target. Nevertheless, interest in CETP and the molecular mechanism by which it inhibits CE transfer among lipoproteins persisted. Insights into the structural-based CETP-lipoprotein interactions can unravel CETP inhibition machinery, which can hopefully guide the design of more effective CETP inhibitors that combat ASCVD. Individual-molecule 3D structures of CETP bound to lipoproteins provide a model for understanding the mechanism by which CETP mediates lipid transfer and which in turn, guide the rational design of new anti-ASCVD therapeutics.

Abstract Cholesteryl ester transfer protein (CETP) is a promising therapeutic target for cardiovascular diseases. It effectively lowers the low-density lipoprotein cholesterol levels and increases the high-density lipoprotein cholesterol levels in the human plasma. This study identified novel and highly potent CETP inhibitors using virtual screening techniques. Molecular docking and molecular dynamics (MD) simulations revealed the binding patterns of these inhibitors, with the top 50 compounds selected according to their predicted binding affinity. Protein–ligand interaction analyses were performed, leading to the selection of 26 compounds for further evaluation. A CETP inhibition assay confirmed the inhibitory activities of the selected compounds. The results of the MD simulations revealed the structural stability of the protein–ligand complexes, with the binding site remaining significantly unchanged, indicating that the five compounds (AK-968/40709303, AG-690/11820117, AO-081/41378586, AK-968/12713193, and AN-465/14952302) identified have the potential as active CETP inhibitors and are promising leads for drug development. Graphical Abstract