ABSTRACT
The progression of atherosclerosis (AS), the pathological foundation of coronary artery disease (CAD), is featured by massive lipid deposition in the vessel wall. LncRNAs are implicated in lipid disorder and AS, whereas the specific role of lncRNA DANCR in atherogenesis remains unknown. Here, we demonstrated that DANCR promotes macrophage lipid accumulation by regulating the expression of membrane cholesterol transport proteins. qPCR showed that compared to control groups, CAD patients and atherosclerotic mice had higher DANCR levels. Treating human THP-1 macrophages and mouse RAW264.7 macrophages with ox-LDL significantly upregulated the expression levels of DANCR. Oil Red O staining showed that the silence of DANCR robustly reduced, while overexpression of DANCR significantly increased the numbers and size of lipid droplets in ox-LDL-treated THP-1 macrophages. In contrast, the opposite phenomena were observed in DANCR overexpressing cells. The expression of ABCA1, ABCG1, SR-BI, and NBD-cholesterol efflux was increased obviously by DANCR inhibition and decreased by DANCR overexpression, respectively. Furthermore, transfection with DANCR siRNA induced a robust decrease in the levels of CD36, SR-A, and Dil-ox-LDL uptake, while DANCR overexpression amplified the expression of CD36, SR-A and the uptake of Dil-ox-LDL in lipid-laden macrophages. Lastly, we found that the effects of DANCR on macrophage lipid accumulation and the expression of membrane cholesterol transport proteins were not likely related to miR-33a. The present study unraveled the adverse role of DANCR in foam cell formation and its relationship with cholesterol transport proteins. However, the competing endogenous RNA network underlying these phenomena warrants further exploration.
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In recent years, the role of macrophages as the primary cell type contributing to foam cell formation and atheroma plaque development has been widely acknowledged. However, it has been long recognized that diffuse intimal thickening (DIM), which precedes the formation of early fatty streaks in humans, primarily consists of lipid-loaded smooth muscle cells (SMCs) and their secreted proteoglycans. Recent studies have further supported the notion that SMCs constitute the majority of foam cells in advanced atherosclerotic plaques. Given that SMCs are a major component of the vascular wall, they serve as a significant source of microvesicles and exosomes, which have the potential to regulate the physiology of other vascular cells. Notably, more than half of the foam cells present in atherosclerotic lesions are of SMC origin. In this review, we describe several mechanisms underlying the formation of intimal foam-like cells in atherosclerotic plaques. Based on these mechanisms, we discuss novel therapeutic approaches that have been developed to regulate the generation of intimal foam-like cells. These innovative strategies hold promise for improving the management of atherosclerosis in the near future.
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BACKGROUND: Cardiovascular diseases are one of the prime causes of mortality globally. Therefore, concerted efforts are made to prevent or manage disruptions from normal functioning of the cardiovascular system. Disruption in lipid metabolism is a major contributor to cardiovascular dysfunction. This review examines how lecithin impacts lipid metabolism and cardiovascular health. It emphasizes lecithin's ability to reduce excess low-density lipoproteins (LDL) while specifically promoting the synthesis of high-density lipoprotein (HDL) particles, thus contributing to clearer understanding of its role in cardiovascular well-being. Emphasizing the importance of lecithin cholesterol acyltransferase (LCAT) in the reverse cholesterol transport (RCT) process, the article delves into its contribution in removing surplus cholesterol from cells. This review aims to clarify existing literature on lipid metabolism, providing insights for targeted strategies in the prevention and management of atherosclerotic cardiovascular disease (ASCVD). This review summarizes the potential of lecithin in cardiovascular health and the role of LCAT in cholesterol metabolism modulation, based on articles from 2000 to 2023 sourced from databases like MEDLINE, PubMed and the Scientific Electronic Library Online. MAIN BODY: While studies suggest a positive correlation between increased LCAT activities, reduced LDL particle size and elevated serum levels of triglyceride-rich lipoprotein (TRL) markers in individuals at risk of ASCVD, the review acknowledges existing controversies. The precise nature of LCAT's potential adverse effects remains uncertain, with varying reports in the literature. Notably, gastrointestinal symptoms such as diarrhea and nausea have been sporadically documented. CONCLUSIONS: The review calls for a comprehensive investigation into the complexities of LCAT's impact on cardiovascular health, recognizing the need for a nuanced understanding of its potential drawbacks. Despite indications of potential benefits, conflicting findings warrant further research to clarify LCAT's role in atherosclerosis.
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Genetic insights help us to investigate disease pathogenesis and risk. The ABCA1 protein encoded by ABCA1 is involved in transporting cholesterol across the cell membrane. Genetic variations in the ABCA1 gene are well documented; however, their role in the development of diabetic dyslipidemia still needs to be explored. This study aimed to identify the associations of rs757194699 (K1587Q) and rs2066714 (I883M) with dyslipidemia in type 2 diabetes and performed molecular simulations. In our case-control study, 330 individuals were divided equally into a diabetic dyslipidemia cases and a healthy controls. Allele-specific polymerase chain reaction and restriction fragment length polymorphism were performed to screen selected variants of the ABCA1 gene. Sanger sequencing was also performed to find genetic mutations in exon 5 of the ABCA1 gene. The C allele of rs757194699 was observed at a high frequency in cases compared to controls and followed the overdominant genetic model (p < 0.0001, OR:3.84; CI:1.67-8.82). The frequency of G allele of rs2066714 was significantly higher in cases compared to controls and followed the genetic model of codominant (p< 0.0001, OR: 39.61; CI:9.97-157.32), dominant (p < 0.0001,OR:59.59; CI:15.19-233.81), overdominant (p< 0.0001, OR:9.75; CI:3.16-30.11), and log-additive (p< 0.0001, OR:42.15; CI:11.08-160.40). In silico modeling and docking revealed that rs2066714 and rs757194699 produced deleterious conformational changes in the ABCA1 protein, resulting in alterations in the binding of the apoA1 protein. There were no genetic variations found in exon-5 in Sanger sequencing. The G allele of rs2066714 and C allele of rs757194699 in the ABCA1 gene were found to be risk alleles in the development of dyslipidemia in type 2 diabetes. These polymorphisms could alter the binding site of ABCA1 with apoA1 thus disturbs the reverse cholesterol transport.
Subject(s)
ATP Binding Cassette Transporter 1 , Diabetes Mellitus, Type 2 , Dyslipidemias , Genetic Predisposition to Disease , Polymorphism, Single Nucleotide , Humans , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/complications , ATP Binding Cassette Transporter 1/genetics , Dyslipidemias/genetics , Male , Female , Middle Aged , Case-Control Studies , Alleles , Gene Frequency , Aged , Molecular Docking SimulationABSTRACT
Atherosclerotic plaques exhibit high cholesterol deposition and oxidative stress resulting from high reactive oxygen species (ROS). These are the major components in plaques and the main pro-inflammatory factor. Therefore, it is crucial to develop an effective therapeutic strategy that can simultaneously address the multiple pro-inflammatory factors via removing cholesterol and inhibiting the overaccumulated ROS. In this study, we constructed macrophage membrane-encapsulated biomimetic nanoparticles (MM@DA-pCD@MTX), which not only alleviate cholesterol deposition at the plaque lesion via reverse cholesterol transport but also scavenge the overaccumulated ROS. ß-Cyclodextrin (ß-CD) and the loaded methotrexate (MTX) act synergistically to induce cholesterol efflux for inhibiting the formation of foam cells. Among them, MTX up-regulated the expression of ABCA1, CYP27A1, and SR-B1. ß-CD increased the solubility of cholesterol crystals. In addition, the ROS scavenging property of dopamine (DA) was perfectly preserved in MM@DA-pCD@MTX, which could scavenge the overaccumulated ROS to alleviate the oxidative stress at the plaque lesion. Last but not least, MM-functionalized "homing" targeting of atherosclerotic plaques not only enables the targeted drug delivery but also prolongs in vivo circulation time and drug half-life. In summary, MM@DA-pCD@MTX emerges as a potent, multifunctional therapeutic platform for AS treatment, offering a high degree of biosafety and efficacy in addressing the complex pathophysiology of atherosclerosis.
Subject(s)
Atherosclerosis , Biomimetic Materials , Cholesterol , Dopamine , Macrophages , Methotrexate , Nanoparticles , Dopamine/chemistry , Dopamine/pharmacology , Nanoparticles/chemistry , Atherosclerosis/drug therapy , Atherosclerosis/metabolism , Atherosclerosis/pathology , Mice , Animals , Biomimetic Materials/chemistry , Biomimetic Materials/pharmacology , Methotrexate/chemistry , Methotrexate/pharmacology , Cholesterol/chemistry , Macrophages/drug effects , Macrophages/metabolism , Reactive Oxygen Species/metabolism , Humans , Cyclodextrins/chemistry , Cyclodextrins/pharmacology , RAW 264.7 Cells , Oxidative Stress/drug effects , Drug Carriers/chemistry , beta-CyclodextrinsABSTRACT
Obesity is a risk factor for type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). Adipose tissue (AT) extracellular vesicles (EVs) could play a role in obesity and T2DM associated CVD progression via the influence of their specific cargo on gene expression in recipient cells. The aim of this work was to evaluate the effects of AT EVs of patients with obesity with/without T2DM on reverse cholesterol transport (RCT)-related gene expression in human monocyte-derived macrophages (MDMs) from healthy donors. AT EVs were obtained after ex vivo cultivation of visceral and subcutaneous AT (VAT and SAT, respectively). ABCA1, ABCG1, PPARG, LXRß (NR1H2), and LXRα (NR1H3) mRNA levels in MDMs as well as in origine AT were determined by a real-time PCR. T2DM VAT and SAT EVs induced ABCG1 gene expression whereas LXRα and PPARG mRNA levels were simultaneously downregulated. PPARG mRNA levels also decreased in the presence of VAT EVs of obese patients without T2DM. In contrast ABCA1 and LXRß mRNA levels tended to increase with the addition of obese AT EVs. Thus, AT EVs can influence RCT gene expression in MDMs during obesity, and the effects are dependent on T2DM status.
Subject(s)
ATP Binding Cassette Transporter 1 , ATP Binding Cassette Transporter, Subfamily G, Member 1 , Adipose Tissue , Cholesterol , Diabetes Mellitus, Type 2 , Extracellular Vesicles , Liver X Receptors , Macrophages , Obesity , PPAR gamma , Humans , Diabetes Mellitus, Type 2/metabolism , Diabetes Mellitus, Type 2/genetics , Diabetes Mellitus, Type 2/pathology , Extracellular Vesicles/metabolism , Extracellular Vesicles/genetics , Obesity/metabolism , Obesity/genetics , Liver X Receptors/metabolism , Liver X Receptors/genetics , Macrophages/metabolism , Cholesterol/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 1/metabolism , ATP Binding Cassette Transporter, Subfamily G, Member 1/genetics , Adipose Tissue/metabolism , PPAR gamma/metabolism , PPAR gamma/genetics , Female , ATP Binding Cassette Transporter 1/metabolism , ATP Binding Cassette Transporter 1/genetics , Male , Middle Aged , Biological Transport , Gene Expression Regulation , Adult , RNA, Messenger/metabolism , RNA, Messenger/geneticsABSTRACT
BACKGROUND: Gualou is derived from the fruit of Trichosanthes kirilowii Maxim, while Xiebai from the bulbs of Allium macrostemon Bunge. Gualou and Xiebai herb pair (2:1) is widely used in clinical practice to treat atherosclerotic cardiovascular diseases. However, the mechanism underlying its potential activity on atherosclerosis (AS) has not been fully elucidated. METHODS: The extract of Gualou-Xiebai herb pair (GXE) was prepared from Gualou (80 g) and Xiebai (40 g) by continuous refluxing with 50% ethanol for 2 h at 80°C. In vivo, ApoE-/- mice were fed a high-fat diet (HFD) for 10 weeks to induce an AS model, and then the mice were treated with GXE (3, 6, 12 g/kg) or atorvastatin (10 mg/kg) via oral gavage. Besides, RAW264.7 macrophages were stimulated by ox-LDL to establish a foam cell model in vitro. RESULTS: GXE suppressed plaque formation, regulated plasma lipids, and promoted liver lipid clearance in AS mice. In addition, 0.5, 1, and 2 mg/mL GXE significantly reduced the TC and FC levels in ox-LDL (50 µg/mL)-stimulated foam cells. GXE increased cholesterol efflux from the foam cells to ApoA-1 and HDL, and enhanced the protein expressions of ABCA1, ABCG1, and SR-BI, which were reversed by the PPARγ inhibitor. Meanwhile, GXE increased the LCAT levels, decreased the lipid levels and increased the TBA levels in the liver of AS mice. Molecular docking indicated that some compounds in GXE showed favorable binding energy with PPARγ, LCAT and CYP7A1 proteins, especially apigenin-7-O-ß-D-glucoside and quercetin. CONCLUSION: In summary, our results suggested that GXE improved lipid metabolism disorders by enhancing RCT, providing a scientific basis for the clinical use of GXE in AS treatment.
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Aim: Atractylodes macrocephala Rhizome (AM) has been used to treat hyperlipidemia for centuries, but its functional components and mechanisms are not clear. This research aimed to investigate the active components in AM and the mechanisms that underlie its anti-hyperlipidemia effect. Methods: SD rats were fed a high-sucrose high-fat diet in conjunction with alcohol (HSHFDAC) along with different AM extracts (AMW, AMO, AME, and AMP) for 4 weeks. AM's active components were analyzed using multiple databases, and their mechanisms were explored through network pharmacology. The relationship between AM's effect of enhancing serum HDL-c and regulating the expression of reverse cholesterol transport (RCT)-related proteins (Apo-A1, LCAT, and SR-BI) was further validated in the HSHFDAC-induced hyperlipidemic rats. The kidney and liver functions of the rats were measured to evaluate the safety of AM. Results: AMO, mainly comprised of volatile and liposoluble components, contributed the most significant anti-hyperlipidemia effect among the four extracts obtained from AM, significantly improving the blood lipid profile. Network pharmacology analysis also suggested that volatile and liposoluble components, comprise AM's main active components and they might act on signaling pathways associated with elevated HDL-c. Validation experiments found that AMO substantially and dose-dependently increased HDL-c levels, upregulated the expression of Apo-A1, SR-BI, and LCAT, improved the pathological changes in the kidney and liver, and significantly reduced the serum creatinine levels in rats with hyperlipidemia. Conclusion: The main anti-hyperlipidemia active components of AM are its volatile and liposoluble components, which may enhance serum HDL-c by increasing the expression of the RCT-related proteins Apo-A1, LCAT, and SR-BI.
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BACKGROUND/OBJECTIVES: High levels of plasma low-density lipoprotein (LDL) cholesterol are an important determinant of atherosclerotic lesion formation. The disruption of cholesterol efflux or reverse cholesterol transport (RCT) in peripheral tissues and macrophages may promote atherogenesis. The aim of the current study was to examine whether bioactive ellagic acid, a functional food component, improved RCT functionality and high-density lipoprotein (HDL) function in diet-induced atherogenesis of apolipoproteins E (apoE) knockout (KO) mice. MATERIALS/METHODS: Wild type mice and apoE KO mice were fed a high-cholesterol Paigen diet for 10 weeks to induce hypercholesterolemia and atherosclerosis, and concomitantly received 10 mg/kg ellagic acid via gavage. RESULTS: Supplying ellagic acid enhanced induction of apoE and ATP-binding cassette (ABC) transporter G1 in oxidized LDL-exposed macrophages, facilitating cholesterol efflux associated with RCT. Oral administration of ellagic acid to apoE KO mice fed on Paigen diet improved hypercholesterolemia with reduced atherogenic index. This compound enhanced the expression of ABC transporters in peritoneal macrophages isolated from apoE KO mice fed on Paigen diet, indicating increased cholesterol efflux. Plasma levels of cholesterol ester transport protein and phospholipid transport protein involved in RCT were elevated in mice lack of apoE gene, which was substantially reduced by supplementing ellagic acid to Paigen diet-fed mice. In addition, ellagic acid attenuated hepatic lipid accumulation in apoE KO mice, evidenced by staining of hematoxylin and eosin and oil red O. Furthermore, the supplementation of 10 mg/kg ellagic acid favorably influenced the transcriptional levels of hepatic LDL receptor and scavenger receptor-B1 in Paigen diet-fed apoE KO mice. CONCLUSION: Ellagic acid may be an athero-protective dietary compound encumbering diet-induced atherogenesis though improving the RCT functionality.
ABSTRACT
Cholesterol efflux from foam cells in atherosclerotic plaques is crucial for reverse cholesterol transport (RCT), an important antiatherogenic event. ATP-binding cassette (ABC) transporters, ABCA1 and ABCG1, are key receptors in the cholesterol efflux pathway. C1q/tumor necrosis factor-related protein-9 (CTRP9) is a newly discovered adipokine and exhibits an atheroprotective activity. However, the role of CTRP9 in RCT still remains unknown. In this work, we investigated the effect of subcutaneous administration of CTRP9 protein on RCT and atherosclerotic lesion formation in ApoE-/- mice fed with a high-fat diet. CTRP9-dependent regulation of cholesterol efflux and ABC transporters in RAW 264.7 foam cells was determined. Our results showed that CTRP9 protein decreased atherosclerotic lesions, increased cholesterol efflux, and upregulated liver ABCA1 and ABCG1 expression in ApoE-/- mice. CTRP9 treatment dose-dependently increased mRNA and protein expression of ABCA1, ABCG1, and LXR-α in RAW 264.7 foam cells. Moreover, the expression and phosphorylation of AMPK was potentiated upon CTRP9 treatment. Notably, CTRP9-induced cholesterol efflux and upregulation of ABCA, ABCG1, and LXR-α were impaired when AMPK was knocked down. AMPK depletion restored cholesterol accumulation in CTRP9-treated RAW 264.7 cells. Taken together, subcutaneous injection is an effective novel delivery route for CTRP9 protein, and exogenous CTRP9 can facilitate cholesterol efflux and promote RCT in an animal model of atherosclerosis. The atheroprotective activity of CTRP9 is mediated through the activation of AMPK signaling.
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High-density lipoproteins (HDLs) play a vital role in lipid metabolism and cardiovascular health, as they are intricately involved in cholesterol transport and inflammation modulation. The proteome of HDL particles is indeed complex and distinct from other components in the bloodstream. Proteomics studies have identified nearly 285 different proteins associated with HDL; however, this review focuses more on the 15 or so traditionally named "apo" lipoproteins. Important lipid metabolizing enzymes closely working with the apolipoproteins are also discussed. Apolipoproteins stand out for their integral role in HDL stability, structure, function, and metabolism. The unique structure and functions of each apolipoprotein influence important processes such as inflammation regulation and lipid metabolism. These interactions also shape the stability and performance of HDL particles. HDLs apolipoproteins have multifaceted roles beyond cardiovascular diseases (CVDs) and are involved in various physiological processes and disease states. Therefore, a detailed exploration of these apolipoproteins can offer valuable insights into potential diagnostic markers and therapeutic targets. This comprehensive review article aims to provide an in-depth understanding of HDL apolipoproteins, highlighting their distinct structures, functions, and contributions to various physiological processes. Exploiting this knowledge holds great potential for improving HDL function, enhancing cholesterol efflux, and modulating inflammatory processes, ultimately benefiting individuals by limiting the risks associated with CVDs and other inflammation-based pathologies. Understanding the nature of all 15 apolipoproteins expands our knowledge of HDL metabolism, sheds light on their pathological implications, and paves the way for advancements in the diagnosis, prevention, and treatment of lipid and inflammatory-related disorders.
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Our understanding of sterol transport proteins (STPs) has increased exponentially in the last decades with advances in the cellular and structural biology of these important proteins. However, small molecule probes have only recently been developed for a few selected STPs. Here we describe the synthesis and evaluation of potential proteolysis-targeting chimeras (PROTACs) based on inhibitors of the STP Aster-A. Based on the reported Aster-A inhibitor autogramin-2, ten PROTACs were synthesized. Pomalidomide-based PROTACs functioned as fluorescent probes due to the intrinsic fluorescent properties of the aminophthalimide core, which in some cases was significantly enhanced upon Aster-A binding. Most PROTACs maintained excellent binary affinity to Aster-A, and one compound, NGF3, showed promising Aster-A degradation in cells. The tools developed here lay the foundation for optimizing Aster-A fluorescent probes and degraders and studying its activity and function in vitro and in cells.
Subject(s)
Carrier Proteins , Fluorescent Dyes , Fluorescent Dyes/pharmacology , Sterols , ProteolysisABSTRACT
Atherosclerosis is caused by cholesterol accumulation within arteries. The intima is where atherosclerotic plaque accumulates and where lipid-laden foam cells reside. Intimal foam cells comprise of both monocyte-derived macrophages and macrophage-like cells (MLC) of vascular smooth muscle cell (VSMC) origin. Foam cells can remove cholesterol via apoAI-mediated cholesterol efflux and this process is regulated by the transporter ABCA1. The microRNA miR-33a-5p is thought to be atherogenic via silencing ABCA1 which promotes cholesterol retention and data has shown inhibiting miR-33a-5p in macrophages may be atheroprotective via enhancing apoAI-mediated cholesterol efflux. However, it is not entirely elucidated whether precisely inhibiting miR-33a-5p in MLC also increases ABCA1-dependent cholesterol efflux. Therefore, the purpose of this work is to test the hypothesis that inhibition of miR-33a-5p in cultured MLC enhances apoAI-mediated cholesterol efflux. In our study, we utilized the VSMC line MOVAS cells in our experiments, and cholesterol-loaded MOVAS cells to convert this cell line into MLC. Inhibition of miR-33a-5p was accomplished by transducing cells with a lentivirus that expresses an antagomiR directed at miR-33a-5p. Expression of miR-33a-5p was analyzed by qRT-PCR, ABCA1 protein expression was assessed via immunoblotting, and apoAI-mediated cholesterol efflux was measured using cholesterol efflux assays. In our results, we demonstrated that lentiviral vector-mediated knockdown of miR-33a-5p resulted in decreasing expression of this microRNA in cultured MLC. Moreover, reduction of miR-33a-5p in cultured MLC resulted in de-repression of ABCA1 expression, which caused ABCA1 protein upregulation in cultured MLC. Additionally, this increase in ABCA1 protein expression resulted in enhancing ABCA1-dependent cholesterol efflux through increasing apoAI-mediated cholesterol efflux in cultured MLC. From these findings, we conclude that inhibiting miR-33a-5p in MLC may protect against atherosclerosis by promoting ABCA1-dependent cholesterol efflux.
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Cholesterol homeostasis is crucial for cellular and systemic function. The disorder of cholesterol metabolism not only accelerates the onset of cardiovascular disease (CVD) but is also the fundamental cause of other ailments. The regulation of cholesterol metabolism in the human is an extremely complex process. Due to the dynamic balance between cholesterol synthesis, intake, efflux and storage, cholesterol metabolism generally remains secure. Disruption of any of these links is likely to have adverse effects on the body. At present, increasing evidence suggests that abnormal cholesterol metabolism is closely related to various systemic diseases. However, the exact mechanism by which cholesterol metabolism contributes to disease pathogenesis remains unclear, and there are still unknown factors. In this review, we outline the metabolic process of cholesterol in the human body, especially reverse cholesterol transport (RCT). Then, we discuss separately the impact of abnormal cholesterol metabolism on common diseases and potential therapeutic targets for each disease, including CVD, tumors, neurological diseases, and immune system diseases. At the end of this review, we focus on the effect of cholesterol metabolism on eye diseases. In short, we hope to provide more new ideas for the pathogenesis and treatment of diseases from the perspective of cholesterol.
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The human system's secret organ, the gut microbiome, has received considerable attention. Emerging research has yielded substantial scientific evidence indicating that changes in gut microbial composition and microbial metabolites may contribute to the development of atherosclerotic cardiovascular disease. The burden of cardiovascular disease on healthcare systems is exacerbated by atherosclerotic cardiovascular disease, which continues to be the leading cause of mortality globally. Reverse cholesterol transport is a powerful protective mechanism that effectively prevents excessive accumulation of cholesterol for atherosclerotic cardiovascular disease. It has been revealed how the gut microbiota modulates reverse cholesterol transport in patients with atherosclerotic risk. In this review, we highlight the complex interactions between microbes, their metabolites, and their potential impacts in reverse cholesterol transport. We also explore the feasibility of modulating gut microbes and metabolites to facilitate reverse cholesterol transport as a novel therapy for atherosclerosis.
Subject(s)
Atherosclerosis , Cholesterol , Gastrointestinal Microbiome , Humans , Atherosclerosis/microbiology , Atherosclerosis/metabolism , Atherosclerosis/prevention & control , Cholesterol/metabolism , Cholesterol/blood , Animals , Biological Transport , Dysbiosis , Bacteria/metabolismABSTRACT
Numerous studies have shown that a low level of high-density lipoprotein cholesterol (HDL-C) is an independent biomarker of cardiovascular disease. High-density lipoprotein (HDL) is considered to be a protective factor for atherosclerosis (AS). Therefore, raising HDL-C has been widely recognized as a promising strategy to treat atherosclerotic cardiovascular diseases (ASCVD). However, several studies have found that increasing HDL-C levels does not necessarily reduce the risk of ASCVD. HDL particles are highly heterogeneous in structure, composition, and biological function. Moreover, HDL particles from atherosclerotic patients exhibit impaired anti-atherogenic functions and these dysfunctional HDL particles might even promote ASCVD. This makes it uncertain that HDL-raising therapy will prevent and treat ASCVD. It is necessary to comprehensively analyze the structure and function of HDL subfractions. We review current advances related to HDL subfractions remodeling and highlight how current lipid-modifying drugs such as niacin, statins, fibrates, and cholesteryl ester transfer protein inhibitors regulate cholesterol concentration of HDL and specific HDL subfractions.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Cardiovascular Diseases/prevention & control , Lipoproteins, HDL , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Cholesterol , Cholesterol, HDL , Atherosclerosis/drug therapy , Atherosclerosis/prevention & controlABSTRACT
As a main cause of serious cardiovascular diseases, atherosclerosis is characterized by deposited lipid and cholesterol crystals (CCs), which is considered as a great challenge to the current treatments. In this study, a dual-track reverse cholesterol transport strategy is used to overcome the cumulative CCs in the atherosclerotic lesions via a targeting nanoplatform named as LPLCH. Endowed with the active targeting ability to the plaques, the nanoparticles can be efficiently internalized and achieve a pH-triggered charge conversion for the escape from lysosomes. During this procedure, the liver X receptor (LXR) agonists loaded in nanoparticles are replaced by the deposited lysosomal CCs, leading to a LXR mediated up-regulation of ATP-binding cassette transporte ABCA1/G1 with the local CCs carrying at the same time. Thus, the cumulative CCs are removed in a dual-track way of ABCA1/G1 mediated efflux and nanoparticle-based carrying. The in vivo investigations indicate that LPLCH exhibits a favorable inhibition on the plaque progression and a further reversal of formed lesions when under a healthy diet. And the RNA-sequencing suggests that the cholesterol transport also synergistically activates the anti-inflammation effect. The dual-track reverse cholesterol transport strategy performed by LPLCH delivers an exciting candidate for the effective inhibition and degradation of atherosclerosis.
Subject(s)
Atherosclerosis , Plaque, Atherosclerotic , Humans , Atherosclerosis/drug therapy , Plaque, Atherosclerotic/drug therapy , Plaque, Atherosclerotic/pathology , Cholesterol/metabolism , Biological TransportABSTRACT
BACKGROUND: Tetranucleotide repeat domain protein 39B (TTC39B) was found to combine with ubiquitin ligase E3, and promote the ubiquitination modification of liver X receptor (LXR), which led to the inhibition of reverse cholesterol transport and development of atherosclerosis. QiShenYiQi pill (QSYQ) is a modern Chinese patent drug for treating ischemic cardiovascular diseases, the underlying mechanism is found to promote the expression of LXR-α/ ATP-binding cassette transporter G5 (ABCG5) in the liver of atherosclerotic mice. PURPOSE: The aim of this study is to investigate the effect of QSYQ on TTC39B-LXR mediated reverse cholesterol transport in atherosclerotic mice. STUDY DESIGN AND METHODS: Male apolipoprotein E gene knockout mice (7 weeks old) were fed with high-fat diet and treated with low dose of QSYQ (QSYQ-l, 0.3 g/kg·d), high dose of QSYQ (QSYQ-H, 1.2 g/kg·d) and LXR-α agonist (LXR-A, GW3965 10 mg/kg·d) for 8 weeks. C57BL/6 J mice were fed with normal diet and used as negative control. Oil red O staining, HE staining, ELISA, RNA sequencing, western blot, immunohistochemistry, RT-PCR, cell culture and RNA interference were performed to analyze the effect of QSYQ on atherosclerosis. RESULTS: HE staining showed that QSYQ reduced the atherosclerotic lesion significantly when compared to the control group. ELISA measurement showed that QSYQ decreased serum VLDL and increased serum ApoA1. Oil Red O staining showed that QSYQ reduced the lipid content of liver and protect liver function. Comparative transcriptome RNA-sequence of liver showed that DEGs after QSYQ treatment enriched in high-density lipoprotein particle, ubiquitin ligase complex, bile secretion, etc. Immunohistochemical staining and western blot proved that QSYQ increased the protein expression of hepatic SR-B1, LXR-α, LXR-ß, CYP7A1 and ABCG5. Targeted inhibiting Ttc39b gene in vitro further established that QSYQ inhibited the gene expression of Ttc39b, increased the protein expression of SR-B1, LXR-α/ß, CYP7A1 and ABCG5 in rat hepatocyte. CONCLUSION: Our results demonstrated the new anti-atherosclerotic mechanism of QSYQ by targeting TTC39B-LXR mediated reverse cholesterol transport in liver. QSYQ not only promoted reverse cholesterol transport, but also improved fatty liver and protected liver function.
Subject(s)
Atherosclerosis , Azo Compounds , Drugs, Chinese Herbal , Lipoproteins , Male , Mice , Rats , Animals , Liver X Receptors/metabolism , Cholesterol/metabolism , Orphan Nuclear Receptors/genetics , Orphan Nuclear Receptors/metabolism , Orphan Nuclear Receptors/therapeutic use , ATP Binding Cassette Transporter, Subfamily G, Member 5/metabolism , Mice, Inbred C57BL , Liver , Mice, Knockout , Atherosclerosis/drug therapy , Atherosclerosis/metabolismABSTRACT
ETHNOPHARMACOLOGICAL RELEVANCE: Hyperlipidemia is characterized by the disorder of lipid metabolism accompanied by oxidative stress damage, and low-grade inflammation, with the pathway of cholesterol and bile acid metabolic are an important triggering mechanism. Polymethoxyflavones (PMFs) are the active constituents of Aurantii Fructus Immaturus, which have many biological effects, including anti-inflammatory, antioxidant activities, anti-obesity, suppressing adipogenesis in adipocytes, and ameliorate type 2 diabetes, with potential roles for regulation of lipid metabolism. However, its associated mechanisms on hyperlipidemia remain unclear. AIM OF THE STUDY: This study aims to identify the anti-hypercholesterolemia effects and mechanisms of PMFs in a hypercholesterolemia model triggered by high-fat compounds in an excessive alcohol diet (HFD). MATERIALS AND METHODS: A hypercholesterolemia rat model was induced by HFD, and PMFs was intragastric administered at 125 and 250 mg/kg daily for 16 weeks. The effects of PMFs on hypercholesterolemia were assessed using serum lipids, inflammatory cytokines, and oxidative stress levels. Hematoxylin & eosin (H&E) and Oil Red O staining were performed to evaluate histopathological changes in the rat liver. The levels of total cholesterol (TC) and total bile acid (TBA) in the liver and feces were determined to evaluate lipid metabolism. RAW264.7 and BRL cells loaded with NBD-cholesterol were used to simulate the reverse cholesterol transport (RCT) process in vitro. The signaling pathway of cholesterol and bile acid metabolic was evaluated by Western Blotting (WB) and qRT-PCR. RESULTS: Lipid metabolism disorders, oxidative stress injury, and low-grade inflammation in model rats were ameliorated by PMFs administration. Numerous vacuoles and lipid droplets in hepatocytes were markedly reduced. In vitro experiments results revealed decreased NBD-cholesterol levels in RAW264.7 cells and increased NBD-cholesterol levels in BRL cells following PMFs intervention. PMFs upregulated the expression of proteins associated with the RCT pathway, such as LXRα, ABCA1, LDLR, and SR-BI, thereby promoting TC entry into the liver. Meanwhile, the expression of proteins associated with cholesterol metabolism and efflux pathways such as CYP7A1, CYP27A1, CYP7B1, ABCG5/8, ABCB1, and BSEP were regulated, thereby promoting cholesterol metabolism. Moreover, PMFs treatment regulated the expression of proteins related to the pathway of enterohepatic circulation of bile acids, such as ASBT, OSTα, NTCP, FXR, FGF15, and FGFR4, thereby maintaining lipid metabolism. CONCLUSIONS: PMFs might ameliorate hypercholesterolemia by promoting the entry of cholesterol into the liver through the RCT pathway, followed by excretion via metabolism pathways of cholesterol and bile acid. These findings provide a promising therapeutic potential for PMFs to treat hypercholesterolemia.
Subject(s)
Hypercholesterolemia , Hyperlipidemias , Rats , Animals , Hypercholesterolemia/drug therapy , Hypercholesterolemia/metabolism , Hypercholesterolemia/pathology , Cholesterol , Liver , Hyperlipidemias/metabolism , Lipid Metabolism , Cholesterol 7-alpha-Hydroxylase/metabolism , Inflammation/pathology , Bile Acids and Salts/metabolism , Diet, High-FatABSTRACT
ObjectiveTo observe the effect of the combination of total saponin of Astragali Radix-total alkaloids of Nelumbinis Folium on reversal cholesterol transport (RCT) in hyperlipidemia rats, and to discuss its mechanism. MethodSixty SD rats were randomly divided into control group, high-fat diet group, total saponin of Astragali Radix-total alkaloids of Nelumbinis Folium low (17 mg·kg-1+40 mg·kg-1), middle (34 mg·kg-1+80 mg·kg-1), high dose (68 mg·kg-1+160 mg·kg-1) groups and simvastatin (2.1 mg·kg-1) group, with 10 mice in each group. The Hyperlipidemia model was duplicated by feeding rats with a high-fat diet for 6 weeks. From the 3rd week, except for the control group and the high-fat diet group given distilled water, other groups were given corresponding drugs intragastric treatment for 4 weeks. The changes in blood lipid and liver function of rats were detected by an automatic biochemical analyzer. Hematoxylin-eosin (HE) and oil red O staining were used to observe the pathological morphological changes and steatosis of rat liver tissue. The contents of total cholesterol (TC) and total bile acid (TBA) in rat liver tissue and feces were determined by a semi-automatic biochemical analyzer. The mRNA and protein expression levels of peroxisome proliferators-activated receptors γ (PPARγ), liver X receptors α (LXRα), ATP-binding cassette transporter G1 (ABCG1) and cholesterol 7α-hydroxylase (CYP7A1) in rat liver tissue were detected by Real-time fluorescence quantitative polymerase chain reaction (Real-time PCR) and Western blot. ResultCompared with the control group, the contents or activities of TC, triglyceride (TG), low-density lipoprotein cholesterol (LDL-C), TBA, aspartate aminotransferase (AST), alanine aminotransferase (ALT) in serum were significantly increased (P<0.01), and the contents of high-density lipoprotein cholesterol (HDL-C) in the high-fat diet group were significantly decreased (P<0.01). The hepatocyte was clearly swollen like ballooning degeneration, with a lot of fat vacuoles and red fat droplets. The contents of TC and TBA in liver tissue and feces were significantly increased (P<0.01), and the mRNA and protein expression levels of PPARγ, LXRα, ABCG1, and CYP7A1 in liver tissue were significantly decreased (P<0.01). Compared with the high-fat diet group, the contents or activities of TC, TG, LDL-C, TBA, AST, and ALT in the serum of rats in administered groups were significantly decreased (P<0.01), while the content of HDL-C was significantly increased (P<0.01). Hepatocyte swelling was significantly reduced, and the ballooning degeneration, fat vacuoles, and red lipid droplets in liver tissue were significantly decreased. The contents of TC and TBA in liver tissue were significantly decreased (P<0.05, P<0.01), and the contents of TC and TBA in feces were significantly increased (P<0.05, P<0.01). The mRNA and protein expression levels of PPARγ, LXRα, ABCG1, and CYP7A1 in liver tissue were significantly increased (P<0.05, P<0.01). ConclusionTotal saponin of Astragali Radix-total alkaloids of Nelumbinis Folium has a positive effect on the prevention and treatment of hyperlipidemia rats, and its mechanism may be related to the activation of PPARγ/LXRα/ABCG1 signaling pathway and regulation of RCT.