Search Results (155)

Hyperlipidemia (HLP) is a disorder of human lipid metabolism or transport, primarily characterized by abnormally elevated levels of total cholesterol (TC), triglycerides (TGs), and low-density lipoprotein cholesterol (LDL-C) in the blood. It is a key factor contributing to the development of non-alcoholic fatty liver disease, obesity, diabetes, atherosclerosis, and cardiovascular and cerebrovascular diseases. Statistics show that the prevalence of dyslipidemia among Chinese adults is as high as 35.6%, and it has shown a trend of younger onset in recent years, posing a serious threat to public health. Therefore, the prevention and treatment of dyslipidemia carry significant social significance. The pathogenesis of hyperlipidemia is complex and diverse, and currently used medications are often accompanied by side effects during treatment, making the research and development of new therapeutic approaches a current focus. Numerous studies have shown that flavonoids, which are abundant in most medicinal plants, fruits, and vegetables, exert effects on regulating lipid homeostasis and treating hyperlipidemia through a multi-target mechanism. These compounds have demonstrated significant effects in inhibiting lipid synthesis, blocking lipid absorption, promoting cholesterol uptake, enhancing reverse cholesterol transport, and suppressing oxidative stress, inflammation, and intestinal microbiota disorders. This article reviews the latest progress in the mechanisms of flavonoids in the treatment of hyperlipidemia, providing a theoretical basis for future research on drugs for hyperlipidemia. Full article

Familial hypercholesterolemia (FH) is a genetic disorder marked by significantly elevated levels of low-density lipoprotein cholesterol (LDL-C) since childhood, substantially increasing the risk of premature atherosclerosis and cardiovascular disease. While dysfunction of hepatic LDL-C receptors is the main underlying cause, the gastrointestinal tract plays a key role in cholesterol homeostasis and represents an important therapeutic target. Inhibition of intestinal cholesterol absorption has emerged as an effective strategy in the management of pediatric FH, particularly in patients for whom statins may not be the ideal first-line treatment. Ezetimibe, an inhibitor of the Niemann-Pick C1-like 1 (NPC1L1) protein, has been shown to reduce LDL-C levels in children with FH, with a greater efficacy observed when used in combination with statins. Bile acid sequestrants also enhance cholesterol excretion but are often limited by gastrointestinal side effects, while dietary interventions, such as phytosterol supplementation and fiber-enriched diets, provide additional benefits in lowering LDL-C and are generally well tolerated. Emerging therapies, including microbiota-targeted strategies and novel cholesterol absorption inhibitors, show promise for expanding future treatment options. This review explores the mechanisms of intestinal cholesterol absorption and their relevance to pediatric FH. We examine key pathways, including dietary cholesterol uptake through NPC1L1, bile acid reabsorption, and cholesterol efflux mediated by ATP-binding cassette transporters, while also discussing clinical and experimental evidence on pharmacological and dietary interventions that modulate these pathways. A deeper understanding of cholesterol metabolism, the emerging role of the gut microbiota, and innovative therapeutic agents can support the development of more effective and personalized approaches to the treatment of children with FH. Full article

High-density lipoprotein (HDL) and small dense low-density lipoprotein (sdLDL) represent two critical yet contrasting components in lipid metabolism and cardiovascular risk modulation. While HDL has traditionally been viewed as cardioprotective due to its role in reverse cholesterol transport and anti-inflammatory effects, emerging evidence emphasizes that HDL functionality—rather than concentration alone—is pivotal in atheroprotection. Conversely, sdLDL particles are increasingly recognized as highly atherogenic due to their enhanced arterial penetration, oxidative susceptibility, and prolonged plasma residence time. This review critically examined the physiological roles, pathological implications, and therapeutic interventions targeting HDL function and sdLDL burden. Lifestyle modifications, pharmacologic agents including statins, fibrates, PCSK9 inhibitors, and novel therapies such as icosapent ethyl were discussed in the context of their effects on HDL quality and sdLDL reduction. Additionally, current clinical guidelines were analyzed, highlighting a paradigm shift away from targeting HDL-C levels toward apoB-driven risk reduction. Although HDL-targeted therapies remain under investigation, the consensus supports focusing on lowering apoB-containing lipoproteins while leveraging lifestyle strategies to improve HDL functionality. In the setting of heart failure, particularly with preserved ejection fraction (HFpEF), alterations in HDL composition and elevated sdLDL levels have been linked to endothelial dysfunction and systemic inflammation, further underscoring their relevance beyond atherosclerosis. A comprehensive understanding of HDL and sdLDL dynamics is essential for optimizing cardiovascular prevention strategies. Full article

Microcystin-leucine arginine (MC-LR) is a prominent water pollutant known for its potent hepatic toxicity. However, the effects of subchronic exposure to environmentally relevant concentrations of MC-LR on the fish liver remain poorly understood. This study aimed to systematically evaluate the impact of subchronic MC-LR exposure on the liver of darkbarbel catfish (Tachysurus vachelli). A total of 270 one-year-old fish were exposed to MC-LR (0, 2, and 5 μg/L) for 28 days and sampled on days 14 (D14) and 28 (D28). Histopathological analysis revealed marked hepatic inflammation in the MC-LR treatment groups, manifested as cellular degeneration, hyperemia, and inflammation. MC-LR exposure induced oxidative stress, evidenced by elevated malondialdehyde (MDA) levels and compensatory upregulation of superoxide dismutase (SOD) activity on D28. While hepatic lipid profiles were not altered by low-dose MC-LR, significant elevation of low-density lipoprotein cholesterol (LDL-C) specifically on D28 indicated incipient lipid metabolic disorder. Metabolomic analysis demonstrated a higher sensitivity, highlighting the stress response of the liver to low-dose MC-LR exposure. The results suggest MC-LR exposure disrupted hepatic phosphatidylcholine (PC) biosynthesis and inhibited lipoprotein formation, thereby impairing lipid transport and contributing to lipid metabolic disorders. In summary, subchronic exposure to environmentally relevant concentrations of MC-LR-induced hepatic tissue inflammation, oxidative stress, and lipid metabolic disorders in darkbarbel catfish. Full article

Background/Objectives: Metabolic dysfunction-associated fatty liver disease (MAFLD) is a chronic hepatic condition marked by lipid buildup, lipotoxicity, and inflammation. Prior research indicates that 3,3′-Diindolemethane (DIM), a natural indole-type phytochemical that is abundant in brassicaceae vegetables, has been reported to reduce body weight and improve lipid metabolism in mice subjected to a high-fat diet (HFD). The aryl hydrocarbon receptor (AhR), a nuclear receptor implicated in lipid metabolism and immune regulation, serves as a functional receptor for DIM. However, the underlying signaling pathways that regulate MAFLD remain elusive. Our objective is to ascertain the beneficial impact of DIM on MAFLD and the associated mechanisms. Methods: Hematoxylin and eosin staining, together with Oil Red O staining, were utilized to assess the pathological changes and lipid deposition in the liver. Biochemical analysis was employed to measure levels of triglyceride (TG), total cholesterol (TC), free fatty acid (FFA), aspartate transaminase (AST), alanine transaminase (ALT), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The cell survival rate of HepG2 cells treated with palmitic acid (PA) and DIM was assessed using the CCK-8 assay. Flow cytometry was employed to measure the fluorescence intensity emitted by lipid droplets within cells. Western blotting analysis was performed to assess AhR pathway and fatty acid transporter expression levels in hepatic tissue. Results: Our results showed that DIM significantly attenuated body weight gain and hepatic injury brought on by HFD, decreased lipid droplet accumulation in HepG2 cells, and effectively suppressed the phosphorylation of p38 MAPK and the protein expression levels of fatty acid transporters CD36 and FATP4. Conclusions: DIM reduced lipid accumulation by activating AhR and suppressing p38 MAPK phosphorylation, thereby inhibiting fatty acid transport and inflammatory responses. These findings suggest that DIM may represent a promising therapeutic candidate for MAFLD, warranting further exploration for clinical applications. Full article

Sodium-glucose co-transporter 2 inhibitors (SGLT2i) preserve cardiac and renal function by mechanisms that are not completely elucidated. Among other things, SGLT2i promote nutrient-deprivation signalling, which might affect the immune function. As the fate of immune cells is controlled by their metabolism, we aimed to study the mitochondrial integrity of lymphocytes isolated from renal transplant recipients with type 2 diabetes (T2D) upon SGLT2i therapy instauration and six-month follow up. In this real-world pilot study, the mitochondrial respiration of isolated peripheral blood mononuclear cells was monitored in a Seahorse XFp extracellular-flux analyzer and cells were photographed with a confocal microscope. Mitochondrial mass, membrane potential, and superoxide content of lymphocyte subpopulations were measured by flow cytometry (MitoTracker^TM Green, TMRM, and MitoSOX^TM Red probes). Leveraging in vivo conditions of immune cells, we evaluated their metabolic profiles associated with immune activation. Herein, we identified changes in redox homeostasis with sustained membrane polarization, and an increased mitochondrial biogenesis upon PHA stimulation that significantly correlated with changes in body weight and LDL-cholesterol levels, and a resultant compensatory mitochondrial function of lymphocytes. Our data suggest novel mechanisms induced by SGLT2i to modulate immune cells, which probably underlie the observed beneficial effects in kidney transplant recipients. Nonetheless, further mechanistic studies are required to extend these exploratory findings and encourage the use of this therapeutic strategy. Full article

Atherosclerotic cardiovascular disease is a major complication of diabetes, whose progression is significantly accelerated by hyperglycemia. Imeglimin, a novel oral antidiabetic agent, has demonstrated efficacy in glucose control; however, its role in diabetes-related cardiovascular complications has not yet been fully explored. This study aimed to investigate the effects of imeglimin on foam cell formation and atherosclerosis in the context of diabetes. THP-1 macrophages were treated with oxidized low-density lipoprotein (LDL) and high glucose to induce foam cell formation in vitro. Additionally, ApoE^−/− mice with streptozotocin-induced diabetes were used to determine the effects of imeglimin in vivo by analyzing metabolic parameters and atherosclerotic plaque formation. Imeglimin inhibited macrophage-derived foam cell formation by promoting the expression of ATP-binding cassette transporters (ABC) A1 and ABCG1 and downregulating the expression of CD36. The effects of imeglimin on ABCG1 and CD36 expression regulation was mediated by AMPK. In diabetic ApoE^−/− mice, imeglimin reduced the atherosclerotic plaque area, decreased fasting glucose and LDL cholesterol levels, and upregulated ABCG1 expression in the liver and aorta. These findings suggest that imeglimin may have a preventive effect on foam cell formation and a therapeutic role in atherosclerosis progression in diabetic conditions. Full article

Elevated plasma low-density lipoprotein cholesterol (LDL-C) is associated with an increased risk for atherosclerosis and development of cardiovascular disease. An elevated plasma LDL-C concentration is the result of enhanced C synthesis, C absorption, and/or altered C homeostasis. Plasma LDL-C lowering can be achieved using pharmaceutical means. Statin therapy inhibits endogenous C synthesis and leads to a mean 40% LDL-C reduction. Ezetimibe inhibits C absorption and achieves an average 20% LDL-C reduction with a 10 mg daily intake. Phytosterol therapy is established by dietary supplements enriched in phytosterols and/or phytostanols. A dosage of 2 to 3 g a day reduces C absorption and leads to an average 10% LDL-C reduction. This dosage expresses a 10-fold increased daily intake for phytosterols or a 100-fold increased intake of phytostanols. Phytosterol- and -stanol-enriched dietary supplements are freely available in the supermarket. The majority of consumers may be healthy subjects with a plasma LDL-C in the normal range. Scientific evidence reveals that increased phytosterol intake may be associated with the development of atherosclerosis. The degree of increased risk is dependent on the patient’s genetic polymorphisms in NPC1L1 and ABCG5/G8 transport proteins as well as on the established risk reduction due to LDL-C lowering. Subjects with a normal or only slightly elevated LDL-C have only minimal LDL-C lowering and lack the compensation for the potential increased risk for atherosclerosis by phytosterols. Full article

Statins are the primary drugs used to prevent cardiovascular disease by inhibiting the HMG-CoA reductase, an enzyme crucial for the synthesis of LDL cholesterol in the liver. A significant number of patients experience adverse drug reactions (ADRs), particularly musculoskeletal problems, which can affect adherence to treatment. Recent clinical guidelines, such as those from the Clinical Pharmacogenetics Implementation Consortium (CPIC) in 2022, recommend adjusting rosuvastatin doses based on genetic variations in the ABCG2 and SLCO1B1 genes to minimize ADRs and improve treatment efficacy. Despite these adjustments, some patients still experience ADRs. So, we performed a candidate gene study to better understand the pharmacogenetics of rosuvastatin. This study included 119 healthy volunteers who participated in three bioequivalence trials of rosuvastatin alone or in combination with ezetimibe at the Clinical Trials Unit of the Hospital Universitario de La Princesa (UECHUP). Participants were genotyped using a custom OpenArray from ThermoFisher that assessed 124 variants in 38 genes associated with drug metabolism and transport. No significant differences were observed according to sex or biogeographic origin. A significant increase in t_1/2 (p_multivariate(p_mv) = 0.013) was observed in the rosuvastatin plus ezetimibe trial compared with the rosuvastatin alone trials. Genetic analysis showed that decreased (DF) and poor function (PF) volunteers for the ABCG2 transporter had higher AUC_∞/DW (adjusted dose/weight), AUC_72h/DW and C_max/DW compared to normal function (NF) volunteers (p_mv< 0.001). DF and PF volunteers for SLCO1B1 showed an increase in AUC_72h/DW (p_mv = 0.020) compared to increased (IF) and NF individuals. Results for ABCG2 and SLCO1B1 were consistent with the existing literature. In addition, AUC_∞/DW, AUC_72h/DW and C_max/DW were increased in intermediate (IA) and poor (PA) NAT2 acetylators (p_mv = 0.001, p_mv< 0.001, p_mv< 0.001, respectively) compared to rapid acetylators (RA), which could be associated through a secondary pathway that was previously unknown. Full article

Coenzyme Q10 (CoQ10) plays a crucial role in facilitating electron transport during oxidative phosphorylation, thus contributing to cellular energy production. Statin treatment causes a decrease in CoQ10 levels in muscle tissue as well as in serum, which may contribute to the musculoskeletal side effects. Therefore, we aimed to assess the effect of newly initiated statin treatment on serum CoQ10 levels after acute ST-elevation myocardial infarction (STEMI) and the correlation of CoQ10 levels with key biomarkers of subclinical or clinically overt myopathy. In this study, we enrolled 67 non-diabetic, statin-naïve early-onset STEMI patients with preserved renal function. Plasma CoQ10 level was determined by ultra-high-performance liquid chromatography–tandem mass spectrometry (UPLC/MS-MS), while the myopathy marker serum fatty acid-binding protein 3 (FABP3) level was measured with enzyme-linked immunosorbent assay (ELISA) at hospital admission and after 3 months of statin treatment. The treatment significantly decreased the plasma CoQ10 (by 43%) and FABP3 levels (by 79%) as well as total cholesterol, low-density lipoprotein cholesterol (LDL-C), apolipoprotein B100 (ApoB100), and oxidized LDL (oxLDL) levels. The change in CoQ10 level showed significant positive correlations with the changes in total cholesterol, LDL-C, ApoB100, and oxLDL levels, while it did not correlate with the change in FABP3 level. Our results prove the CoQ10-reducing effect of statin treatment and demonstrate its lipid-lowering efficacy but contradict the role of CoQ10 reduction in statin-induced myopathy. Full article

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. Full article

Hyperlipidemia and consequent endothelial inflammation, along with foam cell generation, promote the progression of atherosclerosis (AS). Here, we aimed to investigate the effects of 2-acetamidophenol (2-AAP), which was selected by zebrafish phenotypic screening, in alleviating AS by relieving hyperlipidemia and inhibiting foam cell formation, as well as the underlying mechanisms. In a zebrafish hyperlipidemia model, 2-AAP increased lipid-lowering efficacy; alleviated TC, TG, LDL-C, and MDA levels; elevated HDL-C and T-SOD levels; significantly improved intravascular macrophage aggregation; and improved blood flow. In an ox-LDL-induced RAW264.7 model, 2-AAP inhibited lipid phagocytosis in RAW264.7 cells; reduced the intracellular TC, TG, FC, and CE contents; and decreased the CE/TC ratio, thus slowing foam cell generation. In addition, 2-AAP alleviated intracellular ROS and ferrous ion accumulation in RAW264.7 cells, reduced the MDA content, and increased GPX4 viability. Furthermore, transcriptome analyses and gene expression validation showed 2-AAP treatment upregulates genes related to GSH synthesis and transport, such as gclc, gclm, gss, and gpx4a, and enhanced the expression levels of genes involved in the storage and transportation of iron ions, such as fpn1, fth, and g6pd, indicating that 2-AAP dramatically regulated the ferroptosis and glutathione metabolic pathways. Overall, our study demonstrated that 2-AAP demonstrated potential in AS by alleviating hyperlipidemia and attenuating the ferroptosis pathway and provided evidence supporting the future application of 2-AAP in AS treatment. Full article

Background: 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. Methods: 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. Results: 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. Conclusions: The juice holds high nutritional and medicinal value, potentially preventing lipid disorders and cardiovascular issues. Full article

Background/Objectives: Atherosclerosis is a chronic inflammatory disease of the arterial wall, which involves multiple cell types. Peptide OG-5 is identified from collagen hydrolysates derived from Salmo salar and exhibits an inhibitory effect on early atherosclerosis. The primary objective of this study was to investigate the impact of OG-5 on advanced atherosclerotic lesions as well as its stability during absorption. Methods: In this study, the ApoE-/- mice were employed to establish advanced atherosclerosis model to investigate the treatment effect of peptide OG-5. Results: The results showed that oral administration of OG-5 at a dosage of 150 mg/kg bw resulted in a 30% reduction in the aortic plaque formation area in ApoE^−/− mice with few bleeding risks. Specifically, intervention with a low dose of OG-5 (50 mg/kg bw), initiated in the early stage of atherosclerosis, continues to provide benefits into the middle and late stages without bleeding risks. Furthermore, treatment of OG-5 increased expression levels of contractile phenotype markers and reduced the accumulation of lipoprotein in VSMCs induced by ox-LDL. Peptide OG-5 could ensure transport across Caco-2 cell monolayers, exhibiting a P_app value of 1.80 × 10⁻⁵ cm/s, and exhibited a robust stability in plasma with remaining content >70% after 8 h incubation. In vivo studies revealed that OG-5 reached maximum concentration in blood after 120 min. Conclusion: The present results demonstrate the potential efficacy of peptide OG-5 as a promising agent for intervention in anti-atherogenesis strategies. Full article

Bempedoic acid is a new drug that improves the control of cholesterol levels, either as monotherapy or in combination with existing lipid-lowering therapies, and shows clinical efficacy in cardiovascular disease patients. Thus, patients with comorbidities and under multiple therapies may be eligible for bempedoic acid, thus facing the potential problem of drug–drug interactions (DDIs). Bempedoic acid is a prodrug administered orally at a fixed daily dose of 180 mg. The dicarboxylic acid is enzymatically activated by conjugation with coenzyme A (CoA) to form the pharmacologically active thioester (bempedoic acid–CoA). This process is catalyzed by very-long-chain acyl-CoA synthetase 1 (ACSVL1), expressed almost exclusively at the hepatic level. Bempedoic acid–CoA is a potent and selective inhibitor of ATP citrate lyase (ACL), a key enzyme in the biosynthetic pathway of cholesterol and fatty acids. The drug reduces low-density lipoprotein–cholesterol (LDL-C) (20–25%), non-high-density lipoprotein–cholesterol (HDL-C) (19%), apolipoprotein B (apoB) (15%), and total cholesterol (16%) in patients with hypercholesterolemia or mixed dyslipidemia. The drug has a favorable pharmacokinetics profile. Bempedoic acid and its metabolites are not substrates or inhibitors/inducers of cytochrome P450 (CYP450) involved in drug metabolism. On the other hand, bempedoic acid–glucuronide is a substrate for organic anion transporter 3 (OAT3). Bempedoic acid and its glucuronide are weak inhibitors of the OAT2, OAT3, and organic anion-transporting polypeptide 1B1 (OATP1B1) and 1B3 (OATP1B3). Thus, bempedoic acid could inhibit (perpetrator) the hepatic uptake of OATP1B1/3 substrate drugs and the renal elimination of OAT2 and OAT3 substrates and could suffer (victim) the effect of OAT3 transporter inhibitors, reducing its renal elimination. Based on these pharmacological characteristics, here, we describe the potential DDIs of bempedoic acid with concomitant medications and the possible clinical implications. Full article