Reverse Cholesterol Transport Research Articles

Bisphenol A attenuates testosterone synthesis via increasing apolipoprotein A1-mediated reverse cholesterol transport in mice

Bisphenol A (BPA), a widely used chemical compound in plastic manufacturing, has become ubiquitous in the environment. Previous studies have highlighted its adverse effects on reproductive function, as BPA exposure reduces testosterone levels. Cholesterol is involved in testosterone synthesis in Leydig cells. However, research on the mechanisms by which BPA affects testosterone synthesis from the perspective of reverse cholesterol transport (RCT) remains limited. This study aimed to investigate the effects of BPA on cholesterol levels, lipid droplet accumulation, and testosterone synthesis in TM3 cells and mice via Apolipoprotein A1 (APOA1)-mediated RCT. Adult male mice were treated by intraperitoneal injection of corn oil containing BPA (20 mg/kg) for 7 days. Testes were collected for protein extraction, RNA extraction, Oil red O staining or for Biochemical analysis. Serums were collected for detection of testosterone levels. flow cytometry, CCK8 assay, immunofluorescence or Filipin III staining was used to detect the effect of BPA on the TM3 cells. It was observed that serum and testicular testosterone levels were drastically reduced in BPA-treated mice. Moreover, lipid droplets accumulation and testicular total (TC) and free cholesterol (FC) levels were reduced in the mouse testes. Conversely, testicular high-density lipoprotein (HDL) content was partially elevated. Furthermore, BPA markedly enhanced Apoa1 mRNA and protein expression in the mouse model. Notably, BPA significantly upregulated Apoa1 mRNA and protein level, reduced cholesterol levels and lipid droplets accumulation, and attenuated testosterone synthesis in TM3 cells. In addition, exogenous supplement with 22-hydoxycholesterol promoted testosterone synthesis and alleviated the inhibitory effect of BPA on testosterone synthesis. Taken together, these results suggest that BPA upregulates APOA1 expression, enhances RCT, and ultimately reduces TC and FC levels in the testis. This cholesterol reduction likely led to testosterone synthesis disorders in the model, indicating that BPA inhibits testosterone synthesis in mice by disrupting cholesterol transport.

Overexpression of Apolipoprotein A-I Alleviates Insulin Resistance in MASLD Mice Through the PPARα Pathway

Insulin resistance (IR) is one of the important causes of metabolic dysfunction-associated steatotic liver disease (MASLD). Apolipoprotein A-I (apoA-I) is secreted primarily by hepatocytes and plays an essential role in reverse cholesterol transport. Our previous studies revealed that apoA-I can mitigate the progression of metabolic dysfunction-associated steatohepatitis (MASH). However, there is no clear evidence to explain the relationship between apoA-I and IR. Here, we investigated the effects of apoA-I overexpression on IR in both HepG2 cells and mice. In vitro experiment results revealed that apoA-I overexpression can promote cellular glucose uptake in oleic acid-induced IR in HepG2 cells. High-fat, high-cholesterol, and high-fructose diets were used to induce IR in mice. The results showed that apoA-I overexpression improved glucose tolerance, reduced serum insulin levels, and ameliorated IR in diet-induced MASLD mice. Moreover, apoA-I promoted the expression of peroxisome proliferator-activated receptor α (PPARα) in the nucleus both in vitro and in vivo. In conclusion, apoA-I could alleviate MASLD by reducing IR in mice and might exert this effect through the PPARα pathway.

Serum HDL and their subfractions are impaired in multisystem inflammatory syndrome in children (MIS-C)

BackgroundMultisystem inflammatory syndrome in children (MIS-C) is a severe post-COVID condition due to a delayed hyperimmune response to SARS-CoV-2. High-density lipoproteins (HDL) are pivotal players in inflammatory and immune modulation through the remodeling of their subfractions.MethodsThis study aimed to evaluate serum levels of cholesterol, HDL, and HDL subfractions (HDL-SUB) to define their role in the pathogenesis of MIS-C and their potential use as biomarkers of this condition. We analyzed serum cholesterol, HDL and HDL-SUB (by capillary electrophoresis) in relation to serum values of biomarkers of inflammation and endothelial damage (by microfluidic immunoassays) in 48 patients with MIS-C at hospital admission and in 48 age- and sex-matched healthy controls.ResultsSerum cholesterol, as well as HDL, were significantly lower in MIS-C patients than controls. Serum cholesterol was inversely correlated with all biomarkers of inflammation, confirming the impact of cytokines on reverse cholesterol transport, whereas HDL values were inversely correlated with serum biomarkers of endothelial damage, suggesting a role of HDL in endothelial damage in MIS-C patients. Furthermore, we found a remodeling of HDL-SUB with a more pronounced decrease in small HDL that have anti-inflammatory activity.ConclusionsThese data confirm the severe impairment of reverse cholesterol transport in MIS-C and indicate serum HDL and HDL-SUB as potential useful diagnostic biomarkers of MIS-C.

Floralozone attenuates atherosclerotic vascular injury by regulating AMPKα/SREBP-1c pathway and down-regulating miR-33-5p.

Severe disruption of lipid metabolism in vivo is one of the central mechanisms in the development of atherosclerotic vascular injury (AVI). Reverse cholesterol transport (RCT) plays a pivotal role in eliminating excess cholesterol, preventing lipid deposition in the aorta, and reducing plaque formation associated with AVI. Floralozone (FL) reduces endothelial cell injury in AVI rats by regulating sphingosine-1-phosphate (S1P) expression. However, FL's potential to prevent AVI by modulating cholesterol metabolism remains unknown. In this study, network pharmacology and molecular docking predicted FL's potential targets in AVI protection. AVI rats were induced with a high-sugar, high-fat diet and vitamin D3 injection. FL intervention's effects on aortic pathology and lipid levels were assessed. The expression levels of SREBP-1c, PPARγ, ABCA1, and ABCG1 were evaluated. Raw264.7 macrophages were induced to form foam cells with ox-LDL, and FL's effects on the AMPKα/SREBP-1c pathway and miR-33-5p were investigated. FL reduced lipid levels and SREBP-1c expression, increased HDL-C, promoted ABCA1- and ABCG1-mediated cholesterol efflux, and reduced aortic cholesterol accumulation. The AMPKα inhibitor dorsomorphin blocked FL's inhibition of intracellular cholesterol accumulation and SREBP1 down-regulation in foam cells. FL decreased miR-33-5p expression but up-regulated PPARγ, promoting ABCA1- and ABCG1-mediated cholesterol efflux. However, miR-33-5p mimic reduced FL-induced cholesterol efflux, while miR-33-5p inhibitor increased it. FL may promote foam cell cholesterol efflux by modifying the AMPKα/SREBP-1c pathway and down-regulating miR-33-5p, which targets cholesterol metabolism genes (PPARγ, ABCA1, and ABCG1). These findings provide a new insight into the protective effect of FL on AVI.

Cholesterol Metabolism in CNS Diseases: The Potential of SREBP2 and LXR as Therapeutic Targets.

The brain is the organ with the highest cholesterol content in the body. Cholesterol in the brain plays a crucial role in maintaining the integrity of synapses and myelin sheaths to ensure normal brain function. Disruptions in cholesterol metabolism are closely associated with various central nervous system (CNS) diseases, including Alzheimer's disease (AD), Huntington's disease (HD), and multiple sclerosis (MS). In this review, we explore the synthesis, regulation, transport, and functional roles of cholesterol in the CNS. We discuss in detail the associations between cholesterol homeostasis imbalance and CNS diseases including AD, HD, and MS, highlighting the significant role of cholesterol metabolism abnormalities in the development of these diseases. Sterol regulatory element binding protein-2 (SREBP2) and liver X receptor (LXR) are two critical transcription factors that play central roles in cholesterol synthesis and reverse transport, respectively. Their cooperative interaction finely tunes the balance of brain cholesterol metabolism, presenting potential therapeutic value for preventing and treating CNS diseases. We particularly emphasize the alterations in SREBP2 and LXR under pathological conditions and their impacts on disease progression. This review summarizes current therapeutic agents targeting these two pathways, with the hope of broadening the perspectives of CNS drug developers and encouraging further study into SREBP2 and LXR-related therapies for CNS diseases.

Comparison of cholesterol transport capacity of peptide- and polymer-based lipid Nanodiscs.

Apolipoprotein-based, synthetic high-density lipoprotein (sHDL) nanodiscs have been extensively studied as a potential therapeutic agent for cardiovascular disease due to their ability to promote reverse cholesterol transport. Recently, polymer-based nanodiscs have been made possible with the development of novel polymeric materials such as styrene-maleic anhydride copolymer (SMA). While the polymer-based nanodiscs resemble the discoidal structure of sHDLs, their functional similarity with sHDL has not been investigated. In the present study, we compared the SMA-based and peptide-based sHDL nanodiscs focusing on their cholesterol mobilization effects. Results showed that SMA-based nanoparticles presented similar particle size and in vitro cholesterol efflux effect to those of sHDL nanodiscs. However, SMA nanodiscs induced less cholesterol mobilization in vivo, possibly due to insufficient cholesterol esterification by lecithin:cholesterol acyltransferase.

Trimethylamine N-oxide in cardiovascular disease: Pathophysiology and the potential role of statins.

Cardiovascular diseases are one of the leading causes of mortality and morbidity worldwide, with the total number of cases increasing to 523 million in 2019. Despite the advent of new drugs, cardiovascular mortality has increased at an alarming rate of 53.7% from 12.1 million deaths in 1990. Recently, the role of gut microbiome metabolites, such as Trimethylamine N-Oxide (TMAO), in the pathogenesis of cardiovascular disease (CVD) has attracted significant attention. The gut microbiome is critical in various physiological processes including metabolism, immune function, and inflammation. Elevated TMAO levels are associated with atherosclerosis, heart failure, arrhythmia, and atrial fibrillation. TMAO accelerates atherosclerosis by promoting vascular inflammation and reducing reverse cholesterol transport, which leads to lipid accumulation and vessel narrowing. Previous research has indicated that a Mediterranean diet rich in fiber and phytochemicals can reduce TMAO levels by limiting precursors and fostering beneficial gut microbiota. Prebiotics and probiotics also decrease TMAO, while drugs such as meldonium, aspirin, and antibiotics have shown promise. However, recent studies have demonstrated major potential for the use of statins in reducing TMAO levels. Statin therapy can significantly reduce TMAO levels independent of their cholesterol-lowering effects. This reduction may involve direct interactions with the gut microbiome, changes in cholesterol metabolism, and changes in bile acid composition. This review aims to comprehensively evaluate the therapeutic potential of statins in reducing TMAO levels to improve CV outcomes.

Research Progress of Targeted Therapy in Atherosclerosis Based on the ApoA- I

The chronic inflammatory disease atherosclerosis, is caused by the buildup of plaque within the arteries. This may result in the narrowing and stiffening of the lumen. Current studies have shifted towards innovative treatments that target specific proteins central to atherosclerosis development. The subject of focus in this article is ApoA-I, a crucial component in the mechanism of reverse cholesterol transportation. ApoA-I’s high effectiveness in interacting with ABCA1 and ABCG1 receptors on membranes facilitates the extraction of phospholipids and cholesterol from foam cells. In vivo experiments suggest that ApoA-I could serve as a novel therapeutic target for coronary atherosclerosis, but its extended effects require further investigation. The last step in the advancements of ApoA-I research would be clinical and human-based trials. As of currently, no human treatment experiments have been carried out, and the effect loss caused by a rejection reaction cannot be ruled out, and more research must be done before it is medically used.

Effects of Cynara scolymus L. Bract Extract on Lipid Metabolism Disorders Through Modulation of HMG-CoA Reductase, Apo A-1, PCSK-9, p-AMPK, SREBP-2, and CYP2E1 Expression.

Background/Objectives: Hyperlipidemia is a major contributor to metabolic complications and tissue damage, leading to conditions such as liver steatosis, atherosclerosis, and obesity. This study aimed to investigate the effects of aqueous artichoke bract extract (AE) on lipid metabolism, liver antioxidative defense, and liver steatosis in mice fed a high-fat, high-sucrose diet while elucidating the underlying mechanisms. Methods: An 8-week study used hyperlipidemic mice treated with AE at daily doses of 100 and 200 mg/kg bw, compared to fenofibrate. Plasma, liver, fecal, and biliary lipids, as well as blood glucose, were analyzed enzymatically. The liver antioxidative defense was assessed by measuring reduced glutathione, malondialdehyde (MDA), and antioxidant enzyme activities, while liver steatosis was evaluated through transaminase and alkaline phosphatase activities and histological monitoring of lipid droplets. Polyphenol profiling and quantification were performed using HPLC-DAD, and potential mechanisms were predicted by molecular docking and confirmed in HepG2 cells. Results: At 200 mg/kg, AE significantly improved plasma lipid profiles by reducing total cholesterol, triglycerides, and LDL-cholesterol while increasing HDL-cholesterol. It facilitated cholesterol reduction in the liver and its excretion, indicating activation of reverse cholesterol transport, which led to reduced body weight and liver steatosis. AE lowered MDA levels and enhanced antioxidant enzyme activities. AE was found to be safe (LD50 > 5000 mg/kg) and modulated gene expression in HepG2 cells. Conclusions: Based on our results, the artichoke bract extract could be considered a natural resource of bioactive compounds to treat hyperlipidemia and related cardiometabolic diseases.

Insulin resistance in childhood obesity: The role of dietary habits and their association with novel markers of cardiovascular disease

Background Childhood obesity presents numerous comorbidities such as insulin resistance (IR) and dyslipidemia, and could be associated with alterations in novel markers of cardiovascular (CV) risk like: (1) the activities of associated enzymes such as lipoprotein associated phospholipase A2 (Lp-PLA2) and paraoxonase 1 (PON 1), (2) reverse cholesterol transport (RCT), which comprises cellular cholesterol efflux (CCE), in addition to lecithin:cholesterol acyltransferase (LCAT) and cholesteryl ester transfer protein (CETP) activities, and (3) high density lipoprotein (HDL) antioxidant capacity. Moreover, IR could worsen these cardiometabolic alterations. The objective of the present study was to characterize the effect of IR on novel CV markers in a pediatric population with obesity. Methods Twenty-five obese children and adolescents with IR, and 25 without IR took part in the study. Anthropometric parameters, Tanner stage and dietary habits were registered. Glucose, insulin, non-esterified fatty acid (NEFA), lipid, and high sensitivity C reactive protein (hsCRP) levels, plus Lp-PLA2, LCAT, CETP and PON 1 activities, as well as CCE and HDL antioxidant capacity were measured. A cutoff point of 3.16 in Homeostatic Model Assessment for Insulin Resistance (HOMA-IR) determined the presence of IR. Results No differences were observed in age, sex and Tanner stage. Expectedly, the group with IR displayed higher insulin and NEFA levels (p < 0.05). They also presented increased Lp-PLA2 and decreased PON activities (p < 0.05). Importantly, these differences were associated with dietary habits (p < 0.05). Conclusion IR present in pediatric obesity associated with vascular specific inflammation and reduced PON 1 activity, in addition to alterations in glucose metabolism, thus increasing CV risk in adulthood. These proatherogenic disturbances were conditioned by dietary habits.

Ajuga iva extract lowers plasma cholesterol and improves lipoprotein profile and lecithin: cholesterol acyltransferase (LCAT) activity in rats fed high cholesterol diet

The purpose of the study was to investigate the therapeutic and preventive effects of Ajuga iva (L) Schreber (Labiatae) (Ai) extract on hypercholesterolemic model rats. For this aim, male Wistar rats were fed a high‑cholesterol (1%) diet to establish a hypercholesterolemia model supplemented or not with aqueous extract of Ajuga Iva (Ai) (5 g/kg diet) for 4 weeks. Ai lowered plasma total cholesterol (TC) (18%) with a reduction in cholesteryl esters (CE) (29%). Low VLDL-TC and high HDL2-TC were observed in Ai group. TC/HDL’s -C ratio was 1.64-fold lower, whereas HDL’s-C/ LDL-HDL1-C was 1.82-fold higher in Ai treated rats. Triacylglycerols (TG) were reduced in plasma and in VLDL but increased in HDL2 and HDL3 with Ai supplementation. Rats exposed to Ai diet lowered VLDL-unesterified cholesterol (UC), LDL-HDL1-amount and LDL-HDL1-CE but increased HDL3-CE. Low levels of liver phospholipids (PL) and high CE concentrations were observed in Ai group. In aorta, TC was decreased by 37% with Ai. Feeding Ai diet decreased HDL3-PL and increased HDL2-CE and plasma LCAT activity. Moreover, Ai administration (5 g/kg for 4 weeks) improved liver and kidney function, as demonstrated by decreased plasma aspartate aminotransferase (AST) activity and creatinine, and resulted in an increase of urinary and sodium excretion. We conclude that, in addition to its Strong C and TG-lowering effect, Ai improves effectively the atherogenic lipoproteins profile by reducing the LDL-HDL1 amount and increasing the HDL-cholesterol. Furthermore, Ai increases the reverse cholesterol transport by enhancement of cholesterol: acyltransferase (LCAT) activity. These beneficial effects are considered potential mechanisms through which Ai acts as a protective agent against cholesterol-induced damage, ensuring cardiovascular safety.

Mechanistic insights into the regression of atherosclerotic plaques.

Atherosclerosis is a major contributor to cardiovascular diseases and mortality globally. The progression of atherosclerotic disease results in the expansion of plaques and the development of necrotic cores. Subsequent plaque rupture can lead to thrombosis, occluding blood vessels, and end-organ ischemia with consequential ischemic injury. Atherosclerotic plaques are formed by the accumulation of lipid particles overloaded in the subendothelial layer of blood vessels. Abnormally elevated blood lipid levels and impaired endothelial function are the initial factors leading to atherosclerosis. The atherosclerosis research has never been interrupted, and the previous view was that the pathogenesis of atherosclerosis is an irreversible and chronic process. However, recent studies have found that the progression of atherosclerosis can be halted when patients' blood lipid levels are reversed to normal or lower. A large number of studies indicates that it can inhibit the progression of atherosclerosis lesions and promote the regression of atherosclerotic plaques and necrotic cores by lowering blood lipid levels, improving the repair ability of vascular endothelial cells, promoting the reverse cholesterol transport in plaque foam cells and enhancing the ability of macrophages to phagocytize and clear the necrotic core of plaque. This article reviews the progress of research on the mechanism of atherosclerotic plaque regression. Our goal is to provide guidance for developing better therapeutic approaches to atherosclerosis by reviewing and analyzing the latest scientific findings.

MicroRNA 223 Enhances ABCA1 Protein Stability and Supports Efflux in Cholesterol-Burdened Macrophages.

Macrophages are present in all vertebrates as part of the innate immune system, which protects from pathogens and scavenges sterol rich, cellular debris and modified lipoproteins. Thus, resident macrophages are prone to excessive levels of intracellular cholesterol esters. Intramacrophage cholesterol esters can efflux via cell surface transporters, ABCA1 and ABCG1, to lipoprotein carriers such as apo-AI and HDL. Systemically, Apo-AI and HDL facilitate trafficking of cholesterol back to the liver, in a process called reverse cholesterol transport. Impaired macrophage cholesterol efflux is a primary factor in the etiology of atherosclerosis. We hypothesized that microRNA 223 (miR-223) regulated macrophage LDL metabolism, due to predicted binding to Sp1 and Sp3 mRNA, transcriptional regulators of ABCA1 expression. Primary mouse (WT, miR-223 KO) macrophages were loaded with acetylated LDL and stimulated with LPS to form an inflammatory foam cell phenotype. miR-223 KO foam cells demonstrated impaired efflux to both apo-AI and HDL. While transcriptional regulation was intact in miR-223 KO foam cells, ABCA1 protein degradation was greatly accelerated. Blockade of both proteasomal and lysosomal degradation pathways rescued miR-223 deficiency-mediated ABCA1 degradation to the WT levels. Our findings demonstrate that miR-223 expression in macrophages is required for maintenance of ABCA1 and ABCG1 proteins.

Abstract 4138633: Infusion of human apolipoprotein A-I (CSL112) promotes several aspects of reverse cholesterol transport

Background: High-density lipoprotein (HDL)-cholesterol is inversely correlated with cardiovascular risk, but increasing its circulating concentration is insufficient to prevent adverse cardiovascular outcomes. Instead, the emerging paradigm is on increasing the function of HDL and its major protein constituent apolipoprotein A-I (apoA-I), to increase reverse cholesterol transport. Objective: To investigate the effect of apoA-I [human] (CSL112) infusion on HDL protein composition, and provide further insights into the mechanism of action of CSL112 administered post-acute myocardial infarction (AMI). Methods: A mass spectrometry (MS)-based proteomic approach was used to evaluate changes in HDL protein composition in patients (n=50) from the AEGIS-I (ApoA-I Event Reducing in Ischemic Syndromes I) study who received either placebo or CSL112 post AMI. HDL was immuno-isolated from patient plasma using anti-apoA-I antibodies. Cholesterol esterification rate (CER) was measured to determine lecithin-cholesterol acyl transferase (LCAT) activity. Cholesterol efflux capacity (CEC) and hepatocyte uptake were assessed using patient serum in ex vivo cell-based assays. Results: CSL112 induced extensive rearrangement of HDL proteins at 4 hours post-infusion. Levels of apolipoproteins A2, B, C, and E as well as the acute phase proteins serum amyloid A1 and A4 were significantly reduced. By contrast, apoA-I, apoM, and LCAT significantly increased. Elevated apoA-I and LCAT levels on HDL were associated with an increase in CEC, plasma HDL-C levels, and CER in CSL112-treated patients. Furthermore, enhanced CEC strongly correlated with cholesterol uptake by hepatic cells (r=0.95 p<0.001). Conclusion: CSL112 altered HDL composition and increased HDL functionality by promoting multiple steps of the reverse cholesterol transport pathway.

Plasma from type 1 diabetes patients promotes pro-atherogenic cholesterol transport in human macrophages.

Hyperglycemia, one of the major risk factors for atherosclerosis, leads to the accumulation of advanced glycation end products (AGEs), contributing to cardiovascular complications. Such accumulation may accelerate the progression of vascular disease in patients with diabetes. Reverse cholesterol transport (RCT) protein, ATP-binding membrane cassette transporters A1 and G1 (ABCA1 and ABCG1) and cholesterol 27-hydroxylase facilitate cholesterol removal from macrophages. AGE inhibits RCT by reducing the expression of ABCA1 and ABCG1. This study aimed to evaluate whether plasma from poorly controlled adolescents with type 1 diabetes (T1D) disrupts cholesterol homeostasis in human monocytes/macrophages. Twenty healthy controls (HCs) and 20 patients with type 1 diabetes mellitus (T1DM), 10-19 years old, were enrolled. Naïve THP-1 macrophages were exposed to plasma from each HC and patient with T1D. Following incubation, mRNA for cholesterol efflux (ABCA1, ABCG1, and 27-hydroxylase) and cholesterol uptake (CD36, ScR-A1, lectin oxidized low-density lipoprotein (LOX)-1, and CXCL16) were isolated. Foam cell formation was quantified to confirm the pro-atherogenic effects of T1D plasma on macrophages. Results showed that T1D plasma had an elevated level of N-(carboxymethyl)-lysine-modified proteins and upregulated CXCL16 and, to a lesser degree, ScR-A1. This change in gene expression in the presence of T1D plasma is associated with increased lipid accumulation and foam cell formation by THP-1 macrophages. In our study, these cells' uptake of an AGE product occurred mainly through the SR-A1 and CXCL16 receptors, leading to increased intracellular oxidized low-density lipoprotein. We conclude that AGEs may contribute to accelerated atherosclerosis in diabetes through effects on both forward and reverse cholesterol movement.

Elevated free cholesterol levels due to impaired reverse cholesterol transport are a risk factor for polymicrobial sepsis in mice

Dysregulated lipid metabolism is commonly observed in septic patients, but how it contributes to sepsis remains largely unknown. Reverse cholesterol transport (RCT) is crucial for regulating cholesterol metabolism in circulation. During RCT, high-density lipoprotein (HDL) collects cholesterol from peripheral tissues and transports it to the liver’s scavenger receptor BI (SR-BI), where SR-BI mediates the uptake of cholesteryl esters from HDL for excretion via bile. In this study, we utilized AlbCreSR-BIfl/fl mice, a model with impaired RCT, to investigate the impact of RCT on sepsis. We found that AlbCreSR-BIfl/fl mice were significantly more susceptible to cecal ligation and puncture (CLP)-induced polymicrobial sepsis, with a survival rate of 14.3% compared to 80% in SR-BIfl/fl littermates. Mechanistically, sepsis disrupted cholesterol metabolism, causing a 4.8-fold increase in free cholesterol (FC) levels and a 4-fold increase in the FC/cholesteryl ester (CE) ratio in AlbCreSR-BIfl/fl mice compared to SR-BIfl/fl littermates. This disruption led to hemolysis and death. Notably, administering the cholesterol-lowering drug probucol normalized FC levels and the FC/CE ratio, and significantly improved survival in CLP-AlbCreSR-BIfl/fl mice. However, probucol treatment reduced survival in CLP-LDLR-/- mice, which had elevated CE levels with a low FC/CE ratio. These results highlight that elevated FC levels with high FC/CE ratio are a risk factor for sepsis. Therefore, selectively targeting elevated FC levels and FC/CE ratio could be a promising therapeutic strategy for managing sepsis.

Metabolic Effects of Loquat Juice (Eriobotrya japonica Lindl Mkarkeb Variety) on Lipid Homeostasis, Liver Steatosis, and Oxidative Stress in Hyperlipidemic Mice Fed a High-Fat-High-Fructose Diet.

Loquat fruit is consumed for its flavorful taste and a rich array of health-promoting compounds like phenolics, flavonoids, and carotenoids. This study aimed at the biochemical characterization of fresh juice from the Moroccan Mkarkeb variety of loquat and evaluating its effects on lipid homeostasis and liver steatosis in hyperlipidemic mice. The biochemical characterization followed AOAC methods. In vivo study involved hyperlipidemic mice fed a high-fat, high-fructose diet for 6 weeks and treated with loquat juice at 3.5 and 7 mL kg-1 or fenofibrate at 4 mg·kg-1. The concentrations of lipids in plasma, liver, adipose tissue, feces, and bile and blood glucose levels were quantified. Liver steatosis was visually examined and confirmed histologically, and liver injury markers (AST, ALT, ALP, LDH, and TB) were measured. Liver oxidative stress was assessed by measuring MDA content and antioxidative enzyme activities. Our findings indicate that fresh loquat juice is poor in fat and protein and contains moderate sugars with a low energy value (40.82 ± 0.25 kcal/100 g). It is also rich in minerals, vitamin C, phenolic acids, flavonoids, and carotenoids. The juice effectively restored lipid metabolism by enhancing reverse cholesterol transport and lowering LDL-cholesterol, triglycerides, and the atherogenic index. The studied juice decreases blood glucose and prevents weight gain and lipid accumulation in the liver and adipose tissue. The juice prevents lipotoxicity-induced liver injury, corrects toxicity markers, and improves the liver's morphological and histological structures. It also reduces oxidative stress by lowering MDA and activating SOD and catalase. The juice holds high nutritional and medicinal value, potentially preventing lipid disorders and cardiovascular issues.

ANGPTL3 as a target for treating lipid disorders in type 2 diabetes patients

Type 2 diabetes mellitus (T2DM) is a globally prevalent metabolic disorder, and cardiovascular disease (CVD) is a significant cause of mortality and morbidity in diabetic individuals. In addition to hyperglycemia, lipid abnormalities associated with T2DM play a crucial role in the development of CVD complications. Diabetic dyslipidemia is characterized by elevated levels of triglyceride (TG)-rich lipoproteins and small dense low-density lipoprotein (LDL) particles, reduced high-density lipoprotein (HDL) cholesterol, and impaired HDL function. Angiopoietin protein-like 3 (ANGPTL3) is a liver-derived protein that plays a crucial role in regulating plasma lipoprotein metabolism by inhibiting lipoprotein lipase and influencing lipid levels. Inhibiting ANGPTL3 has shown promising effects in promoting HDL-mediated cholesterol reverse transport and reducing the levels of TG-rich lipoproteins and LDL cholesterol. Here, we explore the potential of ANGPTL3 as a therapeutic target for lipid management in T2DM patients.

Gliflozins, sucrose and flavonoids are allosteric activators of lecithin-cholesterol acyltransferase

Lecithin-cholesterol acyltransferase (LCAT) serves as a pivotal enzyme in preserving cholesterol homeostasis via reverse cholesterol transport, a process closely associated with the onset of atherosclerosis. Impaired LCAT function can lead to severe LCAT deficiency disorders for which no pharmacological treatment exists. LCAT-based therapies, such as small molecule positive allosteric modulators (PAMs), against LCAT deficiencies and atherosclerosis hold promise, although their efficacy against atherosclerosis remains challenging. Herein we utilized a quantitative in silico metric to predict the activity of novel PAMs and tested their potencies with in vitro enzymatic assays. As predicted, sodium-glucose cotransporter 2 (SGLT2) inhibitors (gliflozins), sucrose and flavonoids activate LCAT. This has intriguing implications for the mechanism of action of gliflozins, which are commonly used in the treatment of type 2 diabetes, and for the endogenous activation of LCAT. Our results underscore the potential of molecular dynamics simulations in rational drug design.

Exploration of anti-atherosclerotic activity of 1,8-cineole through network pharmacology, molecular docking, and in vivo efficacy studies in high-fat-diet-induced atherosclerosis in hamsters.

The anti-atherogenic potential of liver X receptors (LXRs) has been attributed to their inhibitory role in macrophage-mediated inflammation and promotion of reverse cholesterol transport. This study aimed to evaluate the efficacy of an LXR agonist, 1,8-cineole (Eucalyptol), in atherosclerosis through network pharmacology, molecular docking, and in vivo efficacy studies in high-fat-diet-induced atherosclerosis in hamsters. Network pharmacology analysis was performed by identifying potential targets of 1,8-Cineole and atherosclerosis, followed by the construction of component-target-disease and protein-protein interaction networks. Gene Ontology and KEGG pathway enrichment analysis of targets were performed. The top 5 targets were selected for molecular docking studies. Atherosclerosis was induced in male Golden Syrian hamsters, and the results of network pharmacology were verified. Fifty-one overlapped targets were identified for 1,8-cineole and atherosclerosis. In the protein-protein interaction studies, the top 5 ranked proteins were PPARG, FXR, ABCA-1, ABCG1, and LXRΑ. KEGG pathway analysis and molecular docking showed that ABCA-1 and LXRΑ were correlated in atherosclerosis. Animal studies showed amelioration of atherosclerotic lesions in the aorta of animals treated with 1,8-cineole compared to disease control aortas. A dose-dependent attenuation in ABCA-1 levels and inflammatory markers was observed in animals treated with 1,8-cineole, comparable to its levels in normal animals. In conclusion, 1,8-cineole showed anti-atherosclerotic effects in Golden Syrian hamsters via LXRΑ-induced ABCA-1 overexpression.