Search Results (27)

Cardiovascular diseases (CVDs) continue to pose a key challenge to public health because of their high prevalence, mortality, and disability rates, together with a trend toward younger age at onset. Chronic inflammation and disordered lipid metabolism are key pathological mechanisms underlying the development and progression of CVDs. Although numerous pharmacological agents have been developed to intervene in CVDs, current therapies are still limited by adverse effects, suboptimal efficacy, and insufficient anti-inflammatory properties. Consequently, effective drug-based strategies for the prevention and treatment of certain CVDs are still insufficient. Cluster of differentiation 36 (CD36), a class B scavenger receptor, mediates the recognition and uptake of long-chain fatty acids, oxidized low-density lipoprotein, and other ligands, and is present in diverse tissues and cell types. Accumulating evidence indicates that CD36 plays a critical role in lipid metabolism and inflammatory signalling pathways implicated in CVDs, suggesting that it represents a promising focus for treatment-oriented interventions. This review synthesizes current evidence on the multifaceted roles of CD36 in lipid metabolism dysregulation and inflammation-associated pathways in CVDs and evaluates its potential as a tractable target for disease prevention and management. Full article

Neural tube defects (NTD) are congenital malformations that lead to structural abnormalities of the brain or spine. Mouse embryos deficient in Scavenger Receptor Class B Type 1 (SR-B1 KO), the main receptor for high-density lipoproteins, exhibit a high incidence of anterior NTD, which is associated with vitamin E deficiency and elevated levels of reactive oxygen species (ROS). Maternal supplementation with vitamin E, a micronutrient with antioxidant properties, completely prevents the occurrence of NTD and normalizes ROS levels in SR-B1 KO embryos, suggesting a contribution of oxidative stress to NTD in this model. In this work, we showed that SR-B1 KO embryos at gestational day E9.5 display higher levels of lipoperoxidative damage markers. Analysis of data obtained through shotgun lipidomics evidenced a selective and coordinated reorganization of fatty acid distribution, characterized by altered polyunsaturated and monounsaturated composition, together with reduced phosphatidylcholine and increased lysophosphatidylcholine levels, and diversion of fatty acids into triacylglyceride storage. Transcriptomic analysis revealed a coordinated upregulation of genes involved in phospholipid synthesis and remodeling, consistent with the altered lipid homeostasis observed in SR-B1 KO embryos. Together, these results provide novel information showing a potential link between oxidative stress and disruptions in mammalian embryonic lipid metabolism, highlighting phospholipid remodeling as a potential determinant of susceptibility to NTD. Full article

Apolipoprotein A-I (apoA-I)-coated nanoemulsion particles target scavenger receptors. Adsorbed apoA-I (from the bloodstream) mediates/facilitates this targeted molecular contact, which is followed by receptor-mediated endocytosis and subsequent transcytosis of these same nanoemulsion (nanocarrier) particles across the blood–brain barrier (BBB). When the right drugs are added in advance to these high-density lipoprotein (HDL)-like nanocarriers, multifunctional combination treatment is achieved. This medication penetrates the BBB and targets particular cell-surface scavenger receptors, mainly class B type I (SR-BI). As a result, these (drug-carrying) nanoemulsions may find application in the biomedical therapy of complex medical disorders, such as dementia, as well as some aspects of aging. According to recent research, sustained inflammatory stimulation in the gut, such as via serum amyloid A (SAA), may cause the release of proinflammatory cytokines. Thus, using this “HDL-like” nanoemulsion vehicle to target drugs early (or even proactively) toward a major SAA receptor (like SR-BI), which is implicated in SAA-mediated cell-signaling processes that lead to aging and/or cognitive decline (and eventually Alzheimer’s disease or dementia), may be a useful preventive and therapeutic strategy. Full article

Background/Objectives: Metabolic dysfunction-associated steatotic liver disease (MASLD) is a growing global health problem and the discovery of drugs is challenging. In this study, we aimed to investigate the effects of intestinal activation of the liver X receptor (LXR)α on MASH. Methods: An intestinal-specific LXRα activation model in mice was established and subjected to MASH development by combining a Western diet and carbon tetrachloride. Lipid metabolism, reverse cholesterol transport (RCT), steatosis, inflammation, and fibrosis were evaluated. In vitro models of steatosis and fibrosis were used to explore the role of scavenger receptor class B type 1 (SRB1). Results: We found that the intestinal activation of LXRα improved several MASLD features, including levels of triglycerides, RCT, steatosis, systemic and hepatic inflammatory profiles, and liver fibrosis. These effects were associated with increased high-density lipoprotein (HDL) levels and hepatic SRB1 expression. In vitro depletion of SRB1 hampered the beneficial effects of HDL on steatosis and fibrogenesis in liver cells by altering the activation of both peroxisome proliferator-activated receptors γ and small mothers against decapentaplegic homolog protein (SMAD)2/3 proteins. Conclusions: Our findings showed that the intestinal activation of LXRα and a parallel induction of hepatic SRB1 are protective against inflammation, steatosis, and advanced liver fibrosis in MASLD. Full article

Background: Coronary artery disease (CAD) is the leading cause of death worldwide. High-Density lipoprotein (HDL) is a well-established marker associated with CAD. The current research goes beyond the conventional HDL-C measurement in previous studies and dives into the functional intricacies of HDL. By understanding how HDL works, rather than just how much of it exists, we can better tailor diagnostic and therapeutic strategies for CAD and related conditions. Hence, the current study quantifies the serum levels of two novel HDL-associated markers, Paraoxonase-1 (PON-1) and Scavenger Receptor Class B Type 1 (SRB-1), in CAD cases vs. controls. Methods: A total of 92 subjects, including 69 CAD and 23 healthy controls, were included, based on the prevalence of the disease. Further, based on the severity of the disease, CAD cases were subcategorized as CAD-I, -II, and -III. Serum PON-1 and SRB-1 levels were measured and compared between patient and control groups. Results: The levels of PON-1 and SRB-1 (32.6 ng/mL and 12.49 ng/mL) were significantly lower in CAD patients vs. the healthy control, at 60.36 ng/mL and 15.85 ng/mL, respectively (p < 0.000). A further intergroup comparison showed a statistically significant difference between the CAT-I and -III for PON-1 (p < 0.025), the CAT-I and -III, and CAT-II and -III for SRB-1 (p < 0.000). The receiver operating characteristics (ROC) curve showed cutoff values of 48.20 ng/mL and 14.90 ng/mL for PON-1 and SRB-1. Conclusions: The current study found that serum levels of HDL-associated PON-1 and SRB-1 are significantly lower in CAD cases, and were also inversely related to the increasing severity of coronary artery disease. This inference implies that serum PON-1 and SRB-1 could be used as non-invasive tools for the identification of coronary atherosclerosis and risk assessment in CAD cases. Full article

Background: High-density lipoprotein (HDL) protects against ischemia/reperfusion (I/R) injury via signaling through scavenger-receptor class B type-I (SR-BI) and sphingosine-1-phosphate receptors (S1PRs). We recently reported that HDL protects the hearts of spontaneously hypertensive rats (SHRs) against I/R injury in an SR-BI-dependent manner. Objective: In this study, we examined the role of S1PRs in HDL-induced protection against myocardial I/R injury in hypertensive rats. Methods: Hearts from Wistar Kyoto rats (WKYs) and SHRs were subjected to I/R injury using a modified Langendorff system. The hearts were treated with or without HDL in the presence or absence of a receptor- or kinase-specific antagonist. Cardiac hemodynamics and infarct size were measured. Target proteins were analyzed by immunoblotting and ELISA, and nitrite levels were measured using Greis reagent. Results: HDL protected the hearts of WKYs and SHRs against I/R injury. HDL, however, was more protective in WKYs. HDL protection in SHRs required lipid uptake via SR-BI and S1PR1 and S1PR3 but not S1PR2. The hearts from SHRs expressed significantly lower levels of S1PR3 than the hearts from WKYs. HDL differentially activated mediators of the SAFE and RISK pathways in WKYs and SHRs and resulted in nitric oxide generation. Blockage of these pathways abrogated HDL effects. Conclusions: HDL protects against myocardial I/R injury in normotensive and hypertensive rats, albeit to varying degrees. HDL protection in hearts from hypertensive rodents involved SR-BI-mediated lipid uptake coupled with signaling through S1PR1 and S1PR3. The extent of HDL-induced cardiac protection is directly proportional to S1PR3 expression levels. Mechanistically, the safeguarding effects of HDL involved activation of the SAFE and RISK pathways and the generation of nitric oxide. Full article

Previous research has already shown that apolipoprotein (apo)A-I is adsorbed from the bloodstream onto the surface of certain colloidal lipid particles after the intravenous injection of such colloidal nanocarriers. As a result, various blood–brain barrier (BBB) scavenger receptors are targeted by these (apoA-I-coated) colloidal nanocarriers. This targeted molecular interaction is mediated/facilitated by the adsorbed apoA-I, which is then followed by receptor-mediated endocytosis and subsequent transcytosis of the nanocarrier particles across the BBB. A multifunctional combination therapy is obtained by adding the appropriate drug(s) to these biomimetic (lipid cubic phase) nanocarriers. This therapeutic targets specific cell-surface scavenger receptors, primarily class B type I (SR-BI), and crosses the blood–brain barrier. The lipid contents of artificial biomimetic (nanoemulsion) nanocarrier particles and of naturally occurring high-density lipoproteins (HDL) have been shown to be similar, which enables these nanocarrier particles to partially imitate or simulate the known heterogeneity (i.e., subpopulations or subspecies) of HDL particles. Hence, colloidal drug nanocarriers have the potential to be used in the biomedical treatment of complicated medical conditions including dementia, as well as certain elements of aging. Widespread inflammation and oxidative stress—two processes that include several pathophysiological cascades—are brought on by dementia risk factors. More recent studies suggest that proinflammatory cytokines may be released in response to a prolonged inflammatory stimulus in the gut, for example through serum amyloid A (SAA). Therefore, pharmacologically targeting a major SAA receptor implicated in the SAA-mediated cell signaling processes that cause aging and/or cognitive decline, and ultimately Alzheimer’s disease or (late-onset) dementia, could be an effective preventive and therapeutic approach. Full article

Spondyloarthropathies (SpA) are associated with increased cardiovascular risk. Among possible mechanisms is the dysfunction of serum lipoproteins in regulating cell cholesterol homeostasis. Cholesterol efflux capacity (CEC)—the atheroprotective ability of HDL (high density lipoproteins) to accept cholesterol from macrophages—might predict cardiovascular disease independently of HDL-cholesterol levels. We aimed at evaluating modifications of CEC and of the atherogenic cholesterol loading capacity (CLC) of serum lipoproteins in psoriatic arthritis (PsA) and ankylosing spondylitis (AS) following anti-rheumatic treatment. A total of 62 SpA patients (37 PsA and 25 AS) were evaluated before and after treatment with tumor necrosis factor inhibitor and/or methotrexate. CEC and CLC were measured by radioisotopic and fluorometric techniques, respectively. Endothelial function was assessed by finger plethysmography (Endopat). In the whole SpA group, total and HDL-cholesterol increased after treatment, while lipoprotein(a) decreased and CLC was unchanged. Treatment was associated with increased Scavenger Receptor class B type I (SR-BI)-mediated CEC in the AS group. SR-BI- and ABCG1-mediated CEC were negatively associated with inflammatory parameters and positively related to coffee consumption. SR-BI CEC and CLC were positively and negatively associated with endothelial function, respectively. Our pilot study suggests that anti-rheumatic treatment is associated with favorable modulation of lipoprotein quality and function in SpA, particularly in AS, in spite of the induced increase in total cholesterol levels. If confirmed in a larger population, this might represent an atheroprotective benefit beyond what is reflected by conventional serum lipid profile. Full article

Xestospongia muta is a marine sponge belonging to the family Petrosiidae. It is an important source of biologically active marine natural products, with different kinds of essential fatty acids. Scavenger receptor class B type I (SR-BI) is the main receptor for high-density lipoprotein (HDL) cholesterol, which plays a pivotal role in preventing atherosclerosis. It removes cholesterol from HDL cholesterol, returning lipid-poor lipoprotein into blood circulation. The present study investigated the effects of X. muta Fraction-7 and linoleic acid on SR-BI gene expression and HDL cholesterol uptake. In vitro studies of the activity of X. muta and linoleic acid against the therapeutic target for hypercholesterolemia were conducted using the HDL receptor SR-BI via luciferase assay and HepG2 cells. In the present study, Fraction-7 of X. muta showed the highest expression level of the SR-BI gene via luciferase assay. Profiling of Fraction-7 of X. muta by GC-MS revealed 58 compounds, comprising various fatty acids, particularly linoleic acid. The in vitro study in HepG2 cells showed that the Fraction-7 of X. muta and linoleic acid (an active compound in X. muta) increased SR-BI mRNA expression by 129% and 85%, respectively, compared to the negative control. Linoleic acid increased HDL uptake by 3.21-fold compared to the negative control. Thus, the Fraction-7 of X. muta and linoleic acid have the potential to be explored as adjuncts in the treatment of hypercholesterolemia to prevent or reduce the severity of atherosclerosis development. Full article

Hyperlipidemia-associated lipid disorders are considered the cause of atherosclerotic cardiovascular disease. Reverse cholesterol transport (RCT) is a mechanism by which excess peripheral cholesterol is transported to the liver and further converted into bile acid for excretion from the body in feces, which contributes to reducing hyperlipidemia as well as cardiovascular disease. We previously found that the recombinant humanized IgG1 antibody promotes macrophages to engulf lipids and increases cholesterol efflux to high-density lipoprotein (HDL) through ATP-binding cassette sub-family A1 (ABCA1), one of the key proteins related to RCT. In the present study, we explored other RCT related proteins expression on hepatocytes, including scavenger receptor class B type I (SR-BI), apolipoprotein A-I (ApoA-I), and apolipoprotein A-II (ApoA-II), and its modulation mechanism involved. We confirmed that the recombinant humanized IgG1 antibody selectively activated ERK1/2 to upregulate SR-BI, ApoA-I, and ApoA-II expression in mice liver and human hepatocellular carcinoma cell lines HepG2 cells. The rate-limiting enzymes of bile acid synthesis, including cholesterol 7α-hydroxylase (CYP7A1) and sterol 27-hydroxylase (CYP27A1), exhibited a significant increase when treated with the recombinant humanized IgG1 antibody, as well as increased excretion of bile acids in feces. Besides, abolishment or mutation of peroxisome proliferator-activated receptor α (PPARα)/RXR binding site on SR-BI promoter eliminated SR-BI reporter gene luciferase activity even in the presence of the recombinant humanized IgG1 antibody. Knock down the neonatal Fc receptor (FcRn) on hepatocytes impaired the effect of recombinant humanized IgG1 antibody on activation of ERK1/2, as well as upregulation of SR-BI, ApoA-I, and ApoA-II expression. In conclusion, one of the mechanisms on the recombinant humanized IgG1 antibody attenuates hyperlipidemia in ApoE^−/− mice model fed with high-fat-diet might be through reinforcement of liver RCT function in an FcRn-ERK1/2-PPARα dependent manner. Full article

This study examined the effect of extruded Portulaca oleracea L. extract (PE) in rats fed a high-cholesterol diet through the AMP-activated protein kinase (AMPK) and microRNA (miR)-33/34a pathway. Sprague–Dawley rats were randomized into three groups and fed either a standard diet (SD), a high-cholesterol diet containing 1% cholesterol and 0.5% cholic acid (HC), or an HC diet containing 0.8% PE for 4 weeks. PE supplementation improved serum, liver, and fecal lipid profiles. PE upregulated the expression of genes involved in cholesterol efflux and bile acids’ synthesis such as liver X receptor alpha (LXRα), ATP-binding cassette subfamily G5/G8 (ABCG5/8), and cholesterol 7 alpha-hydroxylase (CYP7A1), and downregulated farnesoid X receptor (FXR) in the liver. In addition, hepatic gene expression levels of apolipoprotein A-l (apoA-1), paraoxonase 1 (PON1), ATP-binding cassette subfamily A1/G1 (ABCA1/G1), lecithin-cholesterol acyltransferase (LCAT), and scavenger receptor class B type 1 (SR-B1), which are related to serum high-density lipoprotein cholesterol metabolism, were upregulated by PE. Furthermore, hepatic AMPK activity in the PE group was higher than in the HC group, and miR-33/34a expression levels were suppressed. These results suggest that PE improves the cholesterol metabolism by modulating AMPK activation and miR-33/34a expression in the liver. Full article

As opposed to adults, high-density lipoprotein (HDL) is the main cholesterol carrying lipoprotein in fetal circulation. The major HDL receptor, scavenger receptor class B type I (SR-BI), contributes to local cholesterol homeostasis. Arterial endothelial cells (ECA) from human placenta are enriched with cholesterol compared to venous endothelial cells (ECV). Moreover, umbilical venous and arterial plasma cholesterol levels differ markedly. We tested the hypothesis that the uptake of HDL-cholesteryl esters differs between ECA and ECV because of the differential expression of SR-BI. We aimed to identify the key regulators underlying these differences and the functional consequences. Immunohistochemistry was used for visualization of SR-BI in situ. ECA and ECV were isolated from the chorionic plate of human placenta and used for RT-qPCR, Western Blot, and HDL uptake assays with ³H- and ¹²⁵I-labeled HDL. DNA was extracted for the methylation profiling of the SR-BI promoter. SR-BI regulation was studied by exposing ECA and ECV to differential oxygen concentrations or shear stress. Our results show elevated SR-BI expression and protein abundance in ECA compared to ECV in situ and in vitro. Immunohistochemistry demonstrated that SR-BI is mainly expressed on the apical side of placental endothelial cells in situ, allowing interaction with mature HDL circulating in the fetal blood. This was functionally linked to a higher increase of selective cholesterol ester uptake from fetal HDL in ECA than in ECV, and resulted in increased cholesterol availability in ECA. SR-BI expression on ECV tended to decrease with shear stress, which, together with heterogeneous immunostaining, suggests that SR-BI expression is locally regulated in the placental vasculature. In addition, hypomethylation of several CpG sites within the SR-BI promoter region might contribute to differential expression of SR-BI between chorionic arteries and veins. Therefore, SR-BI contributes to a local cholesterol homeostasis in ECA and ECV of the human feto-placental vasculature. Full article

The placenta participates in cholesterol biosynthesis and metabolism and regulates exchange between the maternal and fetal compartments. The fetus has high cholesterol requirements, and it is taken up and synthesized at elevated rates during pregnancy. In placental cells, the major source of cholesterol is the internalization of lipoprotein particles from maternal circulation by mechanisms that are not fully understood. As in hepatocytes, syncytiotrophoblast uptake of lipoprotein cholesterol involves lipoprotein receptors such as low-density lipoprotein receptor (LDLR) and scavenger receptor class B type I (SR-BI). Efflux outside the cells requires proteins such as the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1. However, mechanisms associated with intracellular traffic of cholesterol in syncytiotrophoblasts are mostly unknown. In hepatocytes, uptaken cholesterol is transported to acidic late endosomes (LE) and lysosomes (LY). Proteins such as Niemann–Pick type C 1 (NPC1), NPC2, and StAR related lipid transfer domain containing 3 (STARD3) are required for cholesterol exit from the LE/LY. These proteins transfer cholesterol from the lumen of the LE/LY into the LE/LY-limiting membrane and then export it to the endoplasmic reticulum, mitochondria, or plasma membrane. Although the production, metabolism, and transport of cholesterol in placental cells are well explored, there is little information on the role of proteins related to intracellular cholesterol traffic in placental cells during physiological or pathological pregnancies. Such studies would be relevant for understanding fetal and placental cholesterol management. Oxidative stress, induced by generating excess reactive oxygen species (ROS), plays a critical role in regulating various cellular and biological functions and has emerged as a critical common mechanism after lysosomal and mitochondrial dysfunction. This review discusses the role of cholesterol, lysosomal and mitochondrial dysfunction, and ROS in the development and progression of hypercholesterolemic pregnancies. Full article

Black elderberry (Sambucus Nigar) with high polyphenol content has been reported to have a hypolipidemic effect, but its underlying mechanisms have not been well characterized. In the present study, we investigated the effects of polyphenol-rich black elderberry (BEE) on oxidative stress and hepatic lipid metabolism. The total antioxidant activity of BEE was evaluated. The expression of genes for lipid metabolism was measured in 50 or 100 μg/mL of BEE-treated HepG2 cells. The mRNA and protein levels of genes for cholesterol metabolisms, i.e., sterol regulatory element-binding protein 2, 3-hydroxy-3-methylglutaryl coenzyme A reductase, and low-density lipoprotein receptor, were decreased by BEE. There was marked induction of genes for high-density lipoprotein metabolism, i.e., scavenger receptor class B type 1and ATP-binding cassette (ABC) transporter A1 in BEE-treated cells. The expression of canalicular efflux transporter for hepatic cholesterol and bile acids, such as ABCG5/G8 and ABCB11, was significantly increased by BEE treatment. There was no alteration of the lipogenic genes, whereas BEE significantly decreased the expression of genes for fatty acid oxidation. BEE significantly altered the expression of histone deacetylase and sirtuins. These data suggest that the hypocholesterolemic effects of BEE may be attributed to the alteration of genes for hepatic cholesterol synthesis and flux. Full article

The transmissible respiratory disease COVID-19, caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has affected millions of people worldwide since its first reported outbreak in December of 2019 in Wuhan, China. Since then, multiple studies have shown an inverse correlation between the levels of high-density lipoprotein (HDL) particles and the severity of COVID-19, with low HDL levels being associated with an increased risk of severe outcomes. Some studies revealed that HDL binds to SARS-CoV-2 particles via the virus’s spike protein and, under certain conditions, such as low HDL particle concentrations, it facilitates SARS-CoV-2 binding to angiotensin-converting enzyme 2 (ACE2) and infection of host cells. Other studies, however, reported that HDL suppressed SARS-CoV-2 infection. In both cases, the ability of HDL to enhance or suppress virus infection appears to be dependent on the expression of the HDL receptor, namely, the Scavenger Receptor Class B type 1 (SR-B1), in the target cells. SR-B1 and HDL represent crucial mediators of cholesterol metabolism. Herein, we review the complex role of HDL and SR-B1 in SARS-CoV-2-induced disease. We also review recent advances in our understanding of HDL structure, properties, and function during SARS-CoV-2 infection and the resulting COVID-19 disease. Full article