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1
Esobi, Ikechukwu, Oladosu Olanrewaju, Jing Echesabal-Chen, and Alexis Stamatikos. "Utilizing the LoxP-Stop-LoxP System to Control Transgenic ABC-Transporter Expression In Vitro." Biomolecules 12, no. 5 (May 8, 2022): 679. http://dx.doi.org/10.3390/biom12050679.
Анотація:
ABCA1 and ABCG1 are two ABC-transporters well-recognized to promote the efflux of cholesterol to apoAI and HDL, respectively. As these two ABC-transporters are critical to cholesterol metabolism, several studies have assessed the impact of ABCA1 and ABCG1 expression on cellular cholesterol homeostasis through ABC-transporter ablation or overexpressing ABCA1/ABCG1. However, for the latter, there are currently no well-established in vitro models to effectively induce long-term ABC-transporter expression in a variety of cultured cells. Therefore, we performed proof-of-principle in vitro studies to determine whether a LoxP-Stop-LoxP (LSL) system would provide Cre-inducible ABC-transporter expression. In our studies, we transfected HEK293 cells and the HEK293-derived cell line 293-Cre cells with ABCA1-LSL and ABCG1-LSL-based plasmids. Our results showed that while the ABCA1/ABCG1 protein expression was absent in the transfected HEK293 cells, the ABCA1 and ABCG1 protein expression was detected in the 293-Cre cells transfected with ABCA1-LSL and ABCG1-LSL, respectively. When we measured cholesterol efflux in transfected 293-Cre cells, we observed an enhanced apoAI-mediated cholesterol efflux in 293-Cre cells overexpressing ABCA1, and an HDL2-mediated cholesterol efflux in 293-Cre cells constitutively expressing ABCG1. We also observed an appreciable increase in HDL3-mediated cholesterol efflux in ABCA1-overexpressing 293-Cre cells, which suggests that ABCA1 is capable of effluxing cholesterol to small HDL particles. Our proof-of-concept experiments demonstrate that the LSL-system can be used to effectively regulate ABC-transporter expression in vitro, which, in turn, allows ABCA1/ABCG1-overexpression to be extensively studied at the cellular level.
2
Tavoosi, Zahra, Hemen Moradi-Sardareh, Massoud Saidijam, Reza Yadegarazari, Shiva Borzuei, Alireza Soltanian, and Mohammad Taghi Goodarzi. "Cholesterol Transporters ABCA1 and ABCG1 Gene Expression in Peripheral Blood Mononuclear Cells in Patients with Metabolic Syndrome." Cholesterol 2015 (December 15, 2015): 1–6. http://dx.doi.org/10.1155/2015/682904.
Анотація:
ABCA1 and ABCG1 genes encode the cholesterol transporter proteins that play a key role in cholesterol and phospholipids homeostasis. This study was aimed at evaluating and comparing ABCA1 and ABCG1 genes expression in metabolic syndrome patients and healthy individuals. This case-control study was performed on 36 patients with metabolic syndrome and the same number of healthy individuals in Hamadan (west of Iran) during 2013-2014. Total RNA was extracted from mononuclear cells and purified using RNeasy Mini Kit column. The expression of ABCA1 and ABCG1 genes was performed by qRT-PCR. Lipid profile and fasting blood glucose were measured using colorimetric procedures. ABCG1 expression in metabolic syndrome patients was significantly lower (about 75%) compared to that of control group, while for ABCA1 expression, there was no significant difference between the two studied groups. Comparison of other parameters such as HDL-C, FBS, BMI, waist circumference, and systolic and diastolic blood pressure between metabolic syndrome patients and healthy individuals showed significant differences (P<0.05). Decrease in ABCG1 expression in metabolic syndrome patients compared to healthy individuals suggests that hyperglycemia, related metabolites, and hyperlipidemia over the transporter capacity resulted in decreased expression of ABCG1. Absence of a significant change in ABCA1 gene expression between two groups can indicate a different regulation mechanism for ABCA1 expression.
3
Miroshnikova, V. V., A. A. Panteleeva, E. A. Bazhenova, E. P. Demina, T. S. Usenko, M. A. Nikolaev, I. A. Semenova, et al. "Regulation of ABCA1 and ABCG1 gene expression in the intraabdominal adipose tissue." Biomeditsinskaya Khimiya 62, no. 3 (2016): 283–89. http://dx.doi.org/10.18097/pbmc20166203283.
Анотація:
Tissue specific expression of genes encoding cholesterol transporters ABCA1 and ABCG1 as well as genes encoding the most important transcriptional regulators of adipogenesis – LXRa, LXRb, PPARg and RORa has been investigated in intraabdominal adipose tissue (IAT) samples.A direct correlation between the content of ABCA1 and ABCG1 proteins with RORa protein level (r=0.480, p<0.05; r=0.435, p<0.05, respectively) suggests the role of the transcription factor RORa in the regulation of IAT ABCA1 and ABCG1 protein levels. ABCA1 and ABCG1 gene expression positively correlated with obesity indicators such as body mass index (BMI) (r=0.522, p=0.004; r=0.594, p=0.001, respectively) and waist circumference (r=0.403, p=0.033; r=0.474, p=0.013, respectively). The development of obesity is associated with decreased IAT levels of RORa and LXRb mRNA (p=0.016 and p=0.002, respectively). These data suggest that the nuclear factor RORa can play a significant role in the regulation of cholesterol metabolism and control IAT expression of ABCA1 and ABCG1, while the level of IAT LXRb gene expression may be an important factor associated with the development of obesity.
4
Porsch-Özcürümez, Mustafa, Thomas Langmann, Susanne Heimerl, Hana Borsukova, Wolfgang E. Kaminski, Wolfgang Drobnik, Christian Honer, Chistoph Schumacher, and Gerd Schmitz. "The Zinc Finger Protein 202 (ZNF202) Is a Transcriptional Repressor of ATP Binding Cassette Transporter A1 (ABCA1) and ABCG1 Gene Expression and a Modulator of Cellular Lipid Efflux." Journal of Biological Chemistry 276, no. 15 (January 22, 2001): 12427–33. http://dx.doi.org/10.1074/jbc.m100218200.
Анотація:
The zinc finger gene 202 (ZNF202) located within a hypoalphalipoproteinemia susceptibility locus on chromosome 11q23 is a transcriptional repressor of various genes involved in lipid metabolism. To provide further evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia, we investigated the effect of ZNF202 expression on ATP binding cassette transporter A1 (ABCA1) and ABCG1. ABCA1 is a key regulator of the plasma high density lipoprotein pool size, whereas ABCG1 is another mediator of cellular cholesterol and phospholipid efflux in human macrophage. We demonstrate here that the full-length ZNF202m1 isoform binds to GnT repeats within the promotors of ABCA1 (−229/−210) and ABCG1 (−572/−552). ZNF202m1 expression in HepG2 cells dose-dependently repressed the promotor activities of ABCA1 and ABCG1. This transcriptional effect required the presence of the SCAN domain in ZNF202 and the functional integrity of a TATA box at position −24 of ABCA1, whereas the presence of GnT binding motifs was nonessential. The state of ZNF202 SCAN domain oligomerization affected the ability of the adjacent ZNF202 Krüppel-associated box domain to recruit the transcriptional corepressor KAP1. Overexpression of ZNF202m1 in RAW264.7 macrophages prevented the induction of ABCA1 gene expression by 20(S)OH-cholesterol and 9-cis-retinoic acid, further substantiating the interference of ZNF202 in critical elements of transcriptional activation. Finally, HDL and apoAImediated lipid efflux was significantly reduced in RAW264.7 cells stably expressing ZNF202m1. In conclusion, we have identified ABCA1 and ABCG1 as target genes for ZNF202-mediated repression and thus, provide evidence for a functional linkage between ZNF202 and hypoalphalipoproteinemia.
5
Cheng-Mao, Xie, Long Yan, Lin Li, Jin Hua, Wang Xiao-Ju, and Zhang Jie-Wen. "Placental ABCA1 Expression Is Increased in Spontaneous Preterm Deliveries Compared with Iatrogenic Preterm Deliveries and Term Deliveries." BioMed Research International 2017 (2017): 1–9. http://dx.doi.org/10.1155/2017/8248094.
Анотація:
Objective. Abnormal expression of ABCA1 and ABCG1 in the placenta can elicit lipid metabolism disorder and adverse pregnancy outcomes. However, whether it is associated with preterm delivery remains unclear. Our present study aimed to evaluate the relationship between abnormal expression of ABCA1 or ABCG1 and preterm delivery. Methods. Maternal blood and placental tissues from women with spontaneous deliveries (SPD), iatrogenic deliveries (IPD), and term deliveries (TD) were collected. The lipid content and expression of ABCA1 and ABCG1 were subsequently measured. Results. Compared with IPD and TD groups, the HDL, TD, LDL, and TC levels were lower in the maternal blood but higher (except TC) in the cord blood of the SPD group. The extracellular lipid content in the placentas of the SPD group was also notably lower relative to the IPD and TD groups. Moreover, the protein and mRNA expressions of ABCA1 in the placentas of the SPD group were significantly higher compared with the IPD and TD groups; however, there was no obvious difference among the three groups in the protein and mRNA expressions of ABCG1. Conclusions. Abnormal expression of ABCA1 may be associated with the dysregulation of placental lipid metabolism and the occurrence or development of SPD.
6
Oladosu, Olanrewaju, Ikechukwu C. Esobi, Rhonda R. Powell, Terri Bruce, and Alexis Stamatikos. "Dissecting the Impact of Vascular Smooth Muscle Cell ABCA1 versus ABCG1 Expression on Cholesterol Efflux and Macrophage-like Cell Transdifferentiation: The Role of SR-BI." Journal of Cardiovascular Development and Disease 10, no. 10 (October 2, 2023): 416. http://dx.doi.org/10.3390/jcdd10100416.
Анотація:
Cholesterol-laden macrophages are recognized as a major contributor to atherosclerosis. However, recent evidence indicates that vascular smooth muscle cells (VSMC) that accumulate cholesterol and transdifferentiate into a macrophage-like cell (MLC) phenotype also play a role in atherosclerosis. Therefore, removing cholesterol from MLC may be a potential atheroprotective strategy. The two transporters which remove cholesterol from cells are ABCA1 and ABCG1, as they efflux cholesterol to apoAI and HDL, respectively. In this study, the well-characterized immortalized VSMC line MOVAS cells were edited to generate ABCA1- and ABCG1-knockout (KO) MOVAS cell lines. We cholesterol-loaded ABCA1-KO MOVAS cells, ABCG1-KO MOVAS cells, and wild-type MOVAS cells to convert cells into a MLC phenotype. When we measured apoAI- and HDL-mediated cholesterol efflux in these cells, we observed a drastic decrease in apoAI-mediated cholesterol efflux within ABCA1-KO MOVAS MLC, but HDL-mediated cholesterol efflux was only partially reduced in ABCG1-KO MOVAS cells. Since SR-BI also participates in HDL-mediated cholesterol efflux, we assessed SR-BI protein expression in ABCG1-KO MOVAS MLC and observed SR-BI upregulation, which offered a possible mechanism explaining why HDL-mediated cholesterol efflux remains maintained in ABCG1-KO MOVAS MLC. When we used lentivirus for shRNA-mediated knockdown of SR-BI in ABCG1-KO MOVAS MLC, this decreased HDL-mediated cholesterol efflux when compared to ABCG1-KO MOVAS MLC with unmanipulated SR-BI expression. Taken together, these major findings suggest that SR-BI expression in MLC of a VSMC origin plays a compensatory role in HDL-mediated cholesterol efflux when ABCG1 expression becomes impaired and provides insight on SR-BI demonstrating anti-atherogenic properties within VSMC/MLC.
7
Mani, Orlando, Meike Körner, Martin T. Sorensen, Kristen Sejrsen, Carlos Wotzkow, Corneille E. Ontsouka, Robert R. Friis, Rupert M. Bruckmaier, and Christiane Albrecht. "Expression, localization, and functional model of cholesterol transporters in lactating and nonlactating mammary tissues of murine, bovine, and human origin." American Journal of Physiology-Regulatory, Integrative and Comparative Physiology 299, no. 2 (August 2010): R642—R654. http://dx.doi.org/10.1152/ajpregu.00723.2009.
Анотація:
Members of the ATP-binding cassette (ABC) transporters play a pivotal role in cellular lipid efflux. To identify candidate cholesterol transporters implicated in lipid homeostasis and mammary gland (MG) physiology, we compared expression and localization of ABCA1, ABCG1, and ABCA7 and their regulatory genes in mammary tissues of different species during the pregnancy-lactation cycle. Murine and bovine mammary glands (MGs) were investigated during different functional stages. The abundance of mRNAs was determined by quantitative RT-PCR. Furthermore, transporter proteins were localized in murine, bovine, and human MGs by immunohistochemistry. In the murine MG, ABCA1 mRNA abundance was elevated during nonlactating compared with lactating stages, whereas ABCA7 and ABCA1 mRNA profiles were not altered. In the bovine MG, ABCA1, ABCG1, and ABCA7 mRNAs abundances were increased during nonlactating stages compared with lactation. Furthermore, associations between mRNA levels of transporters and their regulatory genes LXRα, PPARγ, and SREBPs were found. ABCA1, ABCG1, and ABCA7 proteins were localized in glandular MG epithelial cells (MEC) during lactation, whereas during nonlactating stages, depending on species, the proteins showed distinct localization patterns in MEC and adipocytes. Our results demonstrate that ABCA1, ABCG1, and ABCA7 are differentially expressed between lactation and nonlactating stages and in association with regulatory genes. Combined expression and localization data suggest that the selected cholesterol transporters are universal MG transporters involved in transport and storage of cholesterol and in lipid homeostasis of MEC. Because of the species-specific expression patterns of transporters in mammary tissue, mechanisms of cholesterol homeostasis seem to be differentially regulated between species.
8
Lin, Hung-Chih, Chong-Kuei Lii, Hui-Chun Chen, Ai-Hsuan Lin, Ya-Chen Yang, and Haw-Wen Chen. "Andrographolide Inhibits Oxidized LDL-Induced Cholesterol Accumulation and Foam Cell Formation in Macrophages." American Journal of Chinese Medicine 46, no. 01 (January 2018): 87–106. http://dx.doi.org/10.1142/s0192415x18500052.
Анотація:
oxLDL is involved in the pathogenesis of atherosclerotic lesions through cholesterol accumulation in macrophage foam cells. Andrographolide, the bioactive component of Andrographis paniculata, possesses several biological activities such as anti-inflammatory, anti-oxidant, and anticancer functions. Scavenger receptors (SRs), including class A SR (SR-A) and CD36, are responsible for the internalization of oxLDL. In contrast, receptors for reverse cholesterol transport, including ABCA1 and ABCG1, mediate the efflux of cholesterol from macrophage foam cells. Transcription factor liver X receptor [Formula: see text] (LXR[Formula: see text] plays a key role in lipid metabolism and inflammation as well as in the regulation of ABCA1 and ABCG1 expression. Because of the contribution of inflammation to macrophage foam cell formation and the potent anti-inflammatory activity of andrographolide, we hypothesized that andrographolide might inhibit oxLDL-induced macrophage foam cell formation. The results showed that andrographolide reduced oxLDL-induced lipid accumulation in macrophage foam cells. Andrographolide decreased the mRNA and protein expression of CD36 by inducing the degradation of CD36 mRNA; however, andrographolide had no effect on SR-A expression. In contrast, andrographolide increased the mRNA and protein expression of ABCA1 and ABCG1, which were dependent on LXR[Formula: see text]. Andrographolide enhanced LXR[Formula: see text] nuclear translocation and DNA binding activity. Treatment with the LXR[Formula: see text] antagonist GGPP and transfection with LXR[Formula: see text] siRNA reversed the ability of andrographolide to stimulate ABCA1 and ABCG1 protein expression. In conclusion, inhibition of CD36-mediated oxLDL uptake and induction of ABCA1- and ABCG1-dependent cholesterol efflux are two working mechanisms by which andrographolide inhibits macrophage foam cell formation, which suggests that andrographolide could be a potential candidate to prevent atherosclerosis.
9
Мирошникова, В. В., А. А. Пантелеева, И. А. Побожева, Н. Д. Разгильдина, К. В. Драчева, Е. А. Полякова, А. В. Марков та ін. "Аdipose tissue expression of ABCA1 and ABCG1 transporters genes in obesity, metabolic syndrome and ischemic heart disease". Nauchno-prakticheskii zhurnal «Medicinskaia genetika», № 5(214) (29 травня 2020): 56–57. http://dx.doi.org/10.25557/2073-7998.2020.05.56-57.
Анотація:
Ожирение ассоциировано с повышенным риском развития метаболических нарушений и сердечно-сосудистых заболеваний. В нашем исследовании мы показали, что экспрессия генов транспортеров холестерина ABCA1 и ABCG1 в жировой ткани может играть роль в развитии ожирения, дислипидемии, метаболического синдрома и ишемической болезни сердца (ИБС). Obesity is linked to increased cardiometabolic risk. Our study shows that cholesterol transporters ABCA1 and ABCG1 gene expression plays a role in development of obesity, dyslipidemia, metabolic syndrome and ischemic heart disease.
10
Delvecchio, Christopher J., Patricia Bilan, Parameswaran Nair, and John P. Capone. "LXR-induced reverse cholesterol transport in human airway smooth muscle is mediated exclusively by ABCA1." American Journal of Physiology-Lung Cellular and Molecular Physiology 295, no. 5 (November 2008): L949—L957. http://dx.doi.org/10.1152/ajplung.90394.2008.
Анотація:
The association of hypercholesterolemia and obesity with airway hyperresponsiveness has drawn increasing attention to the potential role of cholesterol and lipid homeostasis in lung physiology and in chronic pulmonary diseases such as asthma. We have recently shown that activation of the nuclear hormone receptor liver X receptor (LXR) stimulates cholesterol efflux in human airway smooth muscle (hASM) cells and induces expression of the ATP-binding cassette (ABC) transporters ABCA1 and ABCG1, members of a family of proteins that mediate reverse cholesterol and phospholipid transport. We show here that ABCA1 is responsible for all LXR-mediated cholesterol and phospholipid efflux to both apolipoprotein AI and high-density lipoprotein acceptors. In contrast, ABCG1 does not appear to be required for this process. Moreover, we show that hASM cells respond to increased levels of cholesterol by inducing expression of ABCA1 and ABCG1 transporters, a process that is dependent on LXR expression. These findings establish a critical role for ABCA1 in reverse cholesterol and phospholipid transport in airway smooth muscle cells and suggest that dysregulation of cholesterol homeostasis in these cells may be important in the pathogenesis of diseases such as asthma.
11
Rozhkova, Alexandra V., Veronika G. Dmitrieva, Elena V. Nosova, Alexander D. Dergunov, Svetlana A. Limborska, and Liudmila V. Dergunova. "Genomic Variants and Multilevel Regulation of ABCA1, ABCG1, and SCARB1 Expression in Atherogenesis." Journal of Cardiovascular Development and Disease 8, no. 12 (December 2, 2021): 170. http://dx.doi.org/10.3390/jcdd8120170.
Анотація:
Atheroprotective properties of human plasma high-density lipoproteins (HDLs) are determined by their involvement in reverse cholesterol transport (RCT) from the macrophage to the liver. ABCA1, ABCG1, and SR-BI cholesterol transporters are involved in cholesterol efflux from macrophages to lipid-free ApoA-I and HDL as a first RCT step. Molecular determinants of RCT efficiency that may possess diagnostic and therapeutic meaning remain largely unknown. This review summarizes the progress in studying the genomic variants of ABCA1, ABCG1, and SCARB1, and the regulation of their function at transcriptional and post-transcriptional levels in atherosclerosis. Defects in the structure and function of ABCA1, ABCG1, and SR-BI are caused by changes in the gene sequence, such as single nucleotide polymorphism or various mutations. In the transcription initiation of transporter genes, in addition to transcription factors, long noncoding RNA (lncRNA), transcription activators, and repressors are also involved. Furthermore, transcription is substantially influenced by the methylation of gene promoter regions. Post-transcriptional regulation involves microRNAs and lncRNAs, including circular RNAs. The potential biomarkers and targets for atheroprotection, based on molecular mechanisms of expression regulation for three transporter genes, are also discussed in this review.
12
Zhou, Wenjing, Jiacheng Lin, Hongen Chen, Jingjing Wang, Yan Liu, and Min Xia. "Retinoic acid induces macrophage cholesterol efflux and inhibits atherosclerotic plaque formation in apoE-deficient mice." British Journal of Nutrition 114, no. 4 (July 23, 2015): 509–18. http://dx.doi.org/10.1017/s0007114515002159.
Анотація:
It has been suggested that retinoic acid (RA) has a potential role in the prevention of atherosclerotic CVD. In the present study, we used J774A.1 cell lines and primary peritoneal macrophages to investigate the protective effects of RA on foam cell formation and atherogenesis in apoE-deficient (apoE− / −) mice. A total of twenty male apoE− / − mice (n 10 animals per group), aged 8 weeks, were fed on a high-fat diet (HFD) and treated with vehicle or 9-cis-RA for 8 weeks. The atherosclerotic plaque area in the aortic sinus of mice in the 9-cis-RA group was 40·7 % less than that of mice in the control group (P< 0·01). Mouse peritoneal macrophages from the 9-cis-RA group had higher protein expression levels of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) than those from the control group. Serum total and LDL-cholesterol concentrations were lower in the 9-cis-RA group than in the control group (P< 0·05). In vitro studies showed that incubation of cholesterol-loaded J774A.1 macrophages with 9-cis-RA (0·1, 1 and 10 μmol/l) induced cholesterol efflux in a dose-dependent manner. The 9-cis-RA treatment markedly attenuated lipid accumulation in macrophages exposed to oxidised LDL. Moreover, treatment with 9-cis-RA significantly increased the protein expression levels of ABCA1 and ABCG1 in J774A.1 macrophages in a dose-dependent manner. Furthermore, 9-cis-RA dose-dependently enhanced the protein expression level of liver X receptor-α (LXRα), the upstream regulator of ABCA1 and ABCG1. Taken together, the present results show that 9-cis-RA suppresses foam cell formation and prevents HFD-induced atherogenesis via the LXRα-dependent up-regulation of ABCA1 and ABCG1.
13
Nyandwi, Jean-Baptiste, Young Shin Ko, Hana Jin, Seung Pil Yun, Sang Won Park, and Hye Jung Kim. "Rosmarinic Acid Increases Macrophage Cholesterol Efflux through Regulation of ABCA1 and ABCG1 in Different Mechanisms." International Journal of Molecular Sciences 22, no. 16 (August 16, 2021): 8791. http://dx.doi.org/10.3390/ijms22168791.
Анотація:
Lipid dysregulation in diabetes mellitus escalates endothelial dysfunction, the initial event in the development and progression of diabetic atherosclerosis. In addition, lipid-laden macrophage accumulation in the arterial wall plays a significant role in the pathology of diabetes-associated atherosclerosis. Therefore, inhibition of endothelial dysfunction and enhancement of macrophage cholesterol efflux is the important antiatherogenic mechanism. Rosmarinic acid (RA) possesses beneficial properties, including its anti-inflammatory, antioxidant, antidiabetic and cardioprotective effects. We previously reported that RA effectively inhibits diabetic endothelial dysfunction by inhibiting inflammasome activation in endothelial cells. However, its effect on cholesterol efflux remains unknown. Therefore, in this study, we aimed to assess the effect of RA on cholesterol efflux and its underlying mechanisms in macrophages. RA effectively reduced oxLDL-induced cholesterol contents under high glucose (HG) conditions in macrophages. RA enhanced ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) expression, promoting macrophage cholesterol efflux. Mechanistically, RA differentially regulated ABCA1 expression through JAK2/STAT3, JNK and PKC-p38 and ABCG1 expression through JAK2/STAT3, JNK and PKC-ERK1/2/p38 in macrophages. Moreover, RA primarily stabilized ABCA1 rather than ABCG1 protein levels by impairing protein degradation. These findings suggest RA as a candidate therapeutic to prevent atherosclerotic cardiovascular disease complications related to diabetes by regulating cholesterol efflux in macrophages.
14
Montaño-Samaniego, Mariela, Jorge Sánchez-Cedillo, Amellalli Lucas-González, Diana M. Bravo-Estupiñan, Ernesto Alarcón-Hernández, Sandra Rivera-Gutiérrez, José Abraham Balderas-López, and Miguel Ibáñez-Hernández. "Targeted Expression to Liver of an antimiR-33 Sponge as a Gene Therapy Strategy against Hypercholesterolemia: In Vitro Study." Current Issues in Molecular Biology 45, no. 9 (August 24, 2023): 7043–57. http://dx.doi.org/10.3390/cimb45090445.
Анотація:
Atherosclerosis is the leading cause of cardiovascular diseases in Mexico and worldwide. The membrane transporters ABCA1 and ABCG1 are involved in the reverse transport of cholesterol and stimulate the HDL synthesis in hepatocytes, therefore the deficiency of these transporters promotes the acceleration of atherosclerosis. MicroRNA-33 (miR-33) plays an important role in lipid metabolism and exerts a negative regulation on the transporters ABCA1 and ABCG1. It is known that by inhibiting the function of miR-33 with antisense RNA, HDL levels increase and atherogenic risk decreases. Therefore, in this work, a genetic construct, pPEPCK-antimiR-33-IRES2-EGFP, containing a specific antimiR-33 sponge with two binding sites for miR-33 governed under the PEPCK promoter was designed, constructed, and characterized, the identity of which was confirmed by enzymatic restriction, PCR, and sequencing. Hep G2 and Hek 293 FT cell lines, as well as a mouse hepatocyte primary cell culture were transfected with this plasmid construction showing expression specificity of the PEPCK promoter in hepatic cells. An analysis of the relative expression of miR-33 target messengers showed that the antimiR-33 sponge indirectly induces the expression of its target messengers (ABCA1 and ABCG1). This strategy could open new specific therapeutic options for hypercholesterolemia and atherosclerosis, by blocking the miR-33 specifically in hepatocytes.
15
Yuan, Ming-zhen, Ruo-an Han, Chen-xi Zhang, and You-xin Chen. "Association of Genes in the High-Density Lipoprotein Metabolic Pathway with Polypoidal Choroidal Vasculopathy in Asian Population: A Systematic Review and Meta-Analysis." Journal of Ophthalmology 2018 (June 6, 2018): 1–14. http://dx.doi.org/10.1155/2018/9538671.
Анотація:
Purpose. To assess the association of genes in the high-density lipoprotein metabolic pathway (HDLMP) with polypoidal choroidal vasculopathy (PCV) and the genetic difference in the HDLMP between PCV and age-related macular degeneration (AMD). Methods. We performed a literature search in EMBASE, PubMed, and Web of Science for genetic studies on 7 single nucleotide polymorphisms (SNPs) from 5 genes in the HDLMP including cholesteryl ester transfer protein (CETP), hepatic lipase (LIPC), lipoprotein lipase (LPL), ATP-binding cassette transporter A1 (ABCA1), and ATP-binding cassette transporter G1 (ABCG1) in PCV. All studies were published before September 30, 2017, without language restriction. Pooled odds ratios (ORs) and 95% confidence intervals (CIs) of each polymorphism were estimated. We also compared the association profiles between PCV and AMD and performed a sensitivity analysis. Results. Our result is based on 43 articles. After excluding duplicates and articles without complete information, 7 studies were applicable to meta-analysis. 7 polymorphisms were meta-analyzed: CETP rs2303790/rs3764261, LIPC rs10468017/rs493258, LPL rs12678919, ABCA1 rs1883025, and ABCG1 rs57137919. We found that in Asian population, CETP rs3764261 (T allele; OR = 1.46; 95% CI: 1.28–1.665, P<0.01), CETP rs2303790 (G allele; OR = 1.57; 95% CI: 1.258–1.96, P<0.01), and ABCG1 rs57137919 (A allele; OR = 1.168; 95% CI: 1.016–1.343, P<0.01) were significantly associated with PCV, and ABCG1 rs57137919 (A allele; OR = 1.208, 95% CI: 1.035–1.411, P<0.01) has different effects in PCV and AMD. The other 4 polymorphisms in LIPC/LPL/ABCA1 had no significant association with PCV (P>0.05). The sensitivity analysis validated the significance of our analysis. Conclusions. Our study revealed 7 polymorphisms in 5 genes. Among them, CETP (rs3764261/rs2303790) and ABCG1 (rs57137919) were the major susceptibility genes for PCV in Asian population and ABCG1 (rs57137919) showed allelic diversity between PCV and AMD. Since the size for PCV and AMD was small, we need to study these genes genotyping in larger samples.
16
He, Yi, Graziella E. Ronsein, Chongren Tang, Gail P. Jarvik, W. Sean Davidson, Vishal Kothari, Hyun D. Song, Jere P. Segrest, Karin E. Bornfeldt, and Jay W. Heinecke. "Diabetes Impairs Cellular Cholesterol Efflux From ABCA1 to Small HDL Particles." Circulation Research 127, no. 9 (October 9, 2020): 1198–210. http://dx.doi.org/10.1161/circresaha.120.317178.
Анотація:
Rationale: HDL (high-density lipoprotein) may be cardioprotective because it accepts cholesterol from macrophages via the cholesterol transport proteins ABCA1 (ATP-binding cassette transporter A1) and ABCG1 (ATP-binding cassette transporter G1). The ABCA1-specific cellular cholesterol efflux capacity (ABCA1 CEC) of HDL strongly and negatively associates with cardiovascular disease risk, but how diabetes mellitus impacts that step is unclear. Objective: To test the hypothesis that HDL’s cholesterol efflux capacity is impaired in subjects with type 2 diabetes mellitus. Methods and Results: We performed a case-control study with 19 subjects with type 2 diabetes mellitus and 20 control subjects. Three sizes of HDL particles, small HDL, medium HDL, and large HDL, were isolated by high-resolution size exclusion chromatography from study subjects. Then we assessed the ABCA1 CEC of equimolar concentrations of particles. Small HDL accounted for almost all of ABCA1 CEC activity of HDL. ABCA1 CEC―but not ABCG1 CEC―of small HDL was lower in the subjects with type 2 diabetes mellitus than the control subjects. Isotope dilution tandem mass spectrometry demonstrated that the concentration of SERPINA1 (serpin family A member 1) in small HDL was also lower in subjects with diabetes mellitus. Enriching small HDL with SERPINA1 enhanced ABCA1 CEC. Structural analysis of SERPINA1 identified 3 amphipathic α-helices clustered in the N-terminal domain of the protein; biochemical analyses demonstrated that SERPINA1 binds phospholipid vesicles. Conclusions: The ABCA1 CEC of small HDL is selectively impaired in type 2 diabetes mellitus, likely because of lower levels of SERPINA1. SERPINA1 contains a cluster of amphipathic α-helices that enable apolipoproteins to bind phospholipid and promote ABCA1 activity. Thus, impaired ABCA1 activity of small HDL particles deficient in SERPINA1 could increase cardiovascular disease risk in subjects with diabetes mellitus.
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Chen, Xuemeng, Kun Tang, Yi Peng та XiaoLe Xu. "2,3,4′,5-tetrahydroxystilbene-2-O-β-d-glycoside attenuates atherosclerosis in apolipoprotein E-deficient mice: role of reverse cholesterol transport". Canadian Journal of Physiology and Pharmacology 96, № 1 (січень 2018): 8–17. http://dx.doi.org/10.1139/cjpp-2017-0474.
Анотація:
The aim of this study was to evaluate the potential effects of 2,3,4′,5-tetrahydroxystilbene-2-O-β-d-glucoside (TSG) on the development of atherosclerotic plaque in ApoE−/− mice, and explore the mechanisms involved. Our data showed that after 8 weeks of treatment, TSG ameliorated serum levels of total cholesterol, triglyceride, and low density lipoprotein cholesterol, and increased serum levels of high density lipoprotein cholesterol in ApoE−/− mice. TSG suppressed hepatic steatosis, the formation of atherosclerotic lesions, and the formation of macrophage foam cells in ApoE−/− mice. Moreover, TSG improved the expressions of hepatic SR-BI, ABCG5, and CYP7A1, and up-regulated the protein expressions of aortic ABCA1 and ABCG1. An in-vitro study showed that TSG promoted macrophage cholesterol efflux and increased the protein expressions of ABCA1 and ABCG1. Our findings provide evidence for a positive role of TSG in preventing atherosclerosis by promoting reverse cholesterol transport. These effects may be achieved by stimulating cholesterol efflux through ABCA1 and ABCG1, promoting SR-BI-mediated cholesterol uptake in the liver, increasing secretion of cholesterol into bile by ABCG5, and improving cholesterol metabolism by the CYP7A1 pathway. In addition, antioxidative and anti-inflammatory effects of TSG may also contribute to its inhibitory effects on atherosclerosis. Further study is needed to investigate whether other potential mechanisms are involved in TSG-mediated atheroprotection.
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Li, Ni, Yanni Xu, Tingting Feng, Chang Liu, Yongzhen Li, Xiao Wang та Shuyi Si. "Identification of a Selective Agonist for Liver X Receptor α (LXRα) via Screening of a Synthetic Compound Library". Journal of Biomolecular Screening 19, № 4 (13 грудня 2013): 566–74. http://dx.doi.org/10.1177/1087057113516004.
Анотація:
Liver X receptor α (LXRα) plays an important role in reverse cholesterol transport (RCT), and activation of LXRα could reduce atherosclerosis. In the present study, we developed a screening method to identify new potential LXRα agonists using an LXRα-GAL4 chimera reporter assay. A novel analogue of N,N-disubstituted 2,8-diazaspiro[4.5]decane, IMB-151, was identified as an LXRα agonist by using this method. IMB-151 showed a significant activation effect on LXRα, with an EC50 value of 1.47 µM. IMB-151 also increased the expression of ATP-binding cassette transporter A1 (ABCA1) and G1 (ABCG1) in RAW264.7 macrophages. The upregulating effects of IMB-151 on ABCA1 and ABCG1 markedly decreased when coincubated with geranylgeranyl pyrophosphate (GGPP) ammonium salt or LXRα small interfering RNA (siRNA). Our data indicated that the upregulation of ABCA1 and ABCG1 by IMB-151 depended on activation of LXRα. Moreover, IMB-151 significantly reduced cellular lipid accumulation and increased cholesterol efflux in RAW264.7 macrophages. Interestingly, IMB-151 slightly increased sterol response element binding protein 1c (SREBP-1c) protein expression levels in HepG2 cells compared with TO901317, and this indicated that IMB-151 might have less lipogenesis side effect in vivo. These results suggested that IMB-151 was identified as a selective agonist for LXRα by using a screening method and could be used as a potential antiatherosclerotic lead compound in the future.
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Li, Heng, Zhenchi Huang та Fuhua Zeng. "Opuntia dillenii Haw. Polysaccharide Promotes Cholesterol Efflux in THP-1-Derived Foam Cells via the PPARγ-LXRα Signaling Pathway". Molecules 27, № 24 (7 грудня 2022): 8639. http://dx.doi.org/10.3390/molecules27248639.
Анотація:
There is increasing evidence supporting a role for enhanced macrophage cholesterol efflux in ameliorating atherosclerosis. Opuntia dillenii Haw. polysaccharide (ODP-Ia), the most important functional component obtained from Opuntia dillenii Haw. stem, has anti-atherosclerosis effects. Therefore, we propose that ODP-Ia could promote cholesterol efflux via the PPARγ-LXRα signaling pathway. In this study, THP-1 foam cells derived from macrophages were treated with different concentrations of ODP-Ia, GGPP (antagonist of LXRα) and GW9662 (antagonist of PPARγ), with or without 15 nmol ODP-Ia. The total cholesterol content in the cells was measured. The mRNA of ABCA1, ABCG1, PPARγ, LXRα and their protein levels in the foam cells were detected by RT–PCR and Western blot, respectively. The results showed that ODP-Ia plays a role in significantly promoting cholesterol efflux (p < 0.05) by upregulating the expression of ABCA1, ABCG1, SR-BI, PPARγ, PPARα and LXRα. Meanwhile, PPARγ and LXRα antagonists dramatically interfered the cholesterol efflux mediated by ODP-Ia (p < 0.05) and dramatically inhibited the upregulating effect of ODP-Ia on the expression of PPARγ, LXRα, ABCA1 and ABCG1 at both protein and mRNA levels (p < 0.05). In conclusion, ODP-Ia promotes cholesterol efflux in the foam cells through activating the PPARγ-LXRα signaling pathway. This bioactivity suggested that ODP-Ia may be of benefit in treating atherosclerosis.
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Karpouzas, G., B. Papotti, S. Ormseth, M. Palumbo, E. Hernandez, M. P. Adorni, F. Zimetti, M. Budoff, and N. Ronda. "POS0343 STATINS INFLUENCE THE RELATIONSHIP BETWEEN ATP-BINDING CASSETTE TRANSPORTER A1 (ABCA1)-MEDIATED CHOLESTEROL EFFLUX AND CORONARY ATHEROSCLEROSIS IN RHEUMATOID ARTHRITIS." Annals of the Rheumatic Diseases 82, Suppl 1 (May 30, 2023): 419–20. http://dx.doi.org/10.1136/annrheumdis-2023-eular.1708.
Анотація:
BackgroundHigh-density lipoprotein (HDL) mediated cholesterol efflux capacity (CEC) is facilitated by various membrane transporters based on the maturity of the acceptor HDL particles. ATP-binding-cassette membrane transporter A1 (ABCA1) exports cholesterol to immature discoidal HDL particles triggering their maturation to spherical HDL, which in turn serve as cholesterol acceptors for antiatherogenic ABCG1 mediated export. In the context of active RA, increasing ABCA1 CEC may result from reduced HDL particle maturation due to impairment of lecithin-cholesterol acyltransferase, leading to decreased ABCG1 CEC, cholesterol transfer from discoidal HDL to low-density lipoprotein (LDL) and its reloading on macrophages, as well as increased triglycerides favoring a proatherogenic phenotype. Beyond lowering LDL levels, statins have various pleiotropic effects including anti-inflammatory activities, but it is unknown whether they modulate the impact of HDL CEC on atherosclerosis in RA.ObjectivesWe here explored associations between ABCA1 CEC, coronary atherosclerosis and cardiovascular risk in RA and the influence of statins on those relationships.MethodsCoronary atherosclerosis (noncalcified, partially or fully calcified, low attenuation plaques and coronary artery calcium [CAC] score) was evaluated with computed tomography angiography in 140 patients without cardiovascular disease and reassessed in 99 after 6.9±0.4 years. ABCA1 CEC and ABCG1 CEC were measured in J774 macrophages and Chinese hamster ovary cells as previously described. Cox regression evaluated the association between ABCA1 and cardiovascular risk. Multivariable negative binomial and robust logistic regression tested associations of ABCA1 CEC and its interactions with statin therapy on various plaque numbers at baseline, follow-up and CAC progression.ResultsABCA1 CEC inversely correlated with ABCG1 CEC (Pearson r = -0.167, p=0.049) and directly correlated with triglyceride levels (Pearson r = 0.239, p=0.004), reflecting its association with a proatherogenic phenotype. ABCA1 CEC (per 1 SD increment) associated with long-term cardiovascular risk after adjustments for cardiovascular risk score and baseline plaque burden [HR 2.05 (95% CI 1.20-3.48), Figure 1A]. ABCA1 CEC had no main effect on baseline plaque burden or progression. Instead, its impact on the respective outcomes was influenced by baseline statin use and daily average dose of statin correspondingly. ABCA1 CEC inversely associated with stenotic plaque severity in statin users but not in nonusers (p for interaction = 0.011, Figure 1B). Higher ABCA1 CEC further associated with fewer noncalcified plaques (Figure 1C) and lower noncalcified plaque stenotic severity (Figure 1D) in statin users but not nonusers (p for interaction = 0.024 and 0.023 respectively). Higher ABCA1 CEC associated with fewer low attenuation plaques in statin users but more in nonusers (p for interaction ≤0.001, Figure 1E) and statin users displayed fewer low attenuation plaques compared to nonusers at high (≥+1 SD) but not low (≤-1 SD) ABCA1 CEC. Moreover, ABCA1 CEC inversely associated with CAC progression in patients using high daily atorvastatin equivalent dose (+1 SD) but not nonusers (p for interaction = 0.008, Figure 1F).ConclusionIn a proatherogenic milieu typical of active RA, including a block in HDL maturation, increased triglycerides and LDL oxidation, increasing ABCA1 activity as the predominant CEC pathway is insufficient to counterbalance and may in fact associate with vascular damage and plaque vulnerability. Statin use, by decreasing triglycerides, LDL levels and oxidation, may reduce cell cholesterol overload, thus unmasking the atheroprotective effects of ABCA1 CEC.Figure 1.Associations of ABCA1 with cardiovascular risk (A) and influence of statins on the relationships between ABCA1, baseline plaque burden (B-E) and CAC progression (F)REFERENCES:NIL.Acknowledgements:NIL.Disclosure of InterestsGeorge Karpouzas Speakers bureau: Sanofi/Genzyme/Regeneron, BMS, Consultant of: Sanofi/Genzyme/Regeneron, Janssen, Scipher, Grant/research support from: Pfizer, Bianca Papotti: None declared, Sarah Ormseth: None declared, Marcella Palumbo: None declared, Elizabeth Hernandez: None declared, Maria Pia Adorni: None declared, Francesca Zimetti: None declared, Matthew Budoff: None declared, Nicoletta Ronda: None declared.
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Vuilleumier, Nicolas, Sabrina Pagano, Fabrizio Montecucco, Alessandra Quercioli, Thomas H. Schindler, François Mach, Eleonora Cipollari, Nicoletta Ronda, and Elda Favari. "Relationship between HDL Cholesterol Efflux Capacity, Calcium Coronary Artery Content, and Antibodies against ApolipoproteinA-1 in Obese and Healthy Subjects." Journal of Clinical Medicine 8, no. 8 (August 15, 2019): 1225. http://dx.doi.org/10.3390/jcm8081225.
Анотація:
Aims: To explore the associations between cholesterol efflux capacity (CEC), coronary artery calcium (CAC) score, Framingham risk score (FRS), and antibodies against apolipoproteinA-1 (anti-apoA-1 IgG) in healthy and obese subjects (OS). Methods and Results: ABCA1-, ABCG1-, passive diffusion (PD)-CEC and anti-apoA-1 IgG were measured in sera from 34 controls and 35 OS who underwent CAC score determination by chest computed tomography. Anti-apoA-1 IgG ability to modulate CEC and macrophage cholesterol content (MCC) was tested in vitro. Controls and OS displayed similar ABCG1-, ABCA1-, PD-CEC, CAC and FRS scores. Logistic regression analyses indicated that FRS was the only significant predictor of CAC lesion. Overall, anti-apoA-1 IgG were significantly correlated with ABCA1-CEC (r = 0.48, p < 0.0001), PD-CEC (r = −0.33, p = 0.004), and the CAC score (r = 0.37, p = 0.03). ABCA1-CEC was correlated with CAC score (r = 0.47, p = 0.004) and FRS (r = 0.18, p = 0.29), while PD-CEC was inversely associated with the same parameters (CAC: r = −0.46, p = 0.006; FRS: score r = −0.40, p = 0.01). None of these associations was replicated in healthy controls or after excluding anti-apoA-1 IgG seropositive subjects. In vitro, anti-apoA-1 IgG inhibited PD-CEC (p < 0.0001), increased ABCA1-CEC (p < 0.0001), and increased MCC (p < 0.0001). Conclusions: We report a paradoxical positive association between ABCA1-CEC and the CAC score, with the latter being inversely associated with PD in OS. Corroborating our clinical observations, anti-apoA-1 IgG enhanced ABCA1 while repressing PD-CEC, leading to MCC increase in vitro. These results indicate that anti-apoA-1 IgG have the potential to interfere with CEC and macrophage lipid metabolism, and may underpin paradoxical associations between ABCA1-CEC and cardiovascular risk.
22
Litvinov, Dmitry Y., Eugeny V. Savushkin, and Alexander D. Dergunov. "Intracellular and Plasma Membrane Events in Cholesterol Transport and Homeostasis." Journal of Lipids 2018 (August 6, 2018): 1–22. http://dx.doi.org/10.1155/2018/3965054.
Анотація:
Cholesterol transport between intracellular compartments proceeds by both energy- and non-energy-dependent processes. Energy-dependent vesicular traffic partly contributes to cholesterol flux between endoplasmic reticulum, plasma membrane, and endocytic vesicles. Membrane contact sites and lipid transfer proteins are involved in nonvesicular lipid traffic. Only “active" cholesterol molecules outside of cholesterol-rich regions and partially exposed in water phase are able to fast transfer. The dissociation of partially exposed cholesterol molecules in water determines the rate of passive aqueous diffusion of cholesterol out of plasma membrane. ATP hydrolysis with concomitant conformational transition is required to cholesterol efflux by ABCA1 and ABCG1 transporters. Besides, scavenger receptor SR-B1 is involved also in cholesterol efflux by facilitated diffusion via hydrophobic tunnel within the molecule. Direct interaction of ABCA1 with apolipoprotein A-I (apoA-I) or apoA-I binding to high capacity binding sites in plasma membrane is important in cholesterol escape to free apoA-I. ABCG1-mediated efflux to fully lipidated apoA-I within high density lipoprotein particle proceeds more likely through the increase of “active” cholesterol level. Putative cholesterol-binding linear motifs within the structure of all three proteins ABCA1, ABCG1, and SR-B1 are suggested to contribute to the binding and transfer of cholesterol molecules from cytoplasmic to outer leaflets of lipid bilayer. Together, plasma membrane events and intracellular cholesterol metabolism and traffic determine the capacity of the cell for cholesterol efflux.
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Helal, Olfa, Hicham Berrougui, Soumaya Loued, and Abdelouahed Khalil. "Extra-virgin olive oil consumption improves the capacity of HDL to mediate cholesterol efflux and increases ABCA1 and ABCG1 expression in human macrophages." British Journal of Nutrition 109, no. 10 (October 10, 2012): 1844–55. http://dx.doi.org/10.1017/s0007114512003856.
Анотація:
The present study was aimed to investigate the effect of 12 weeks of extra-virgin olive oil (EVOO) consumption on the capacity of HDL to promote cholesterol efflux (CE) and to determine which CE pathways are modulated by EVOO consumption. Whole HDL and HDL2/HDL3 subclasses were isolated from the plasma of twenty-six healthy volunteers before and after 12 weeks of EVOO consumption (25 ml/d). EVOO consumption increased the capacity of serum and HDL to mediate CE from THP-1, J774 macrophages and Fu5AH cells by 9·8–24·57 %, depending on the cell type. The increase in CE was independent of both HDL concentration and subclass distribution. The three HDL-mediated CE pathways (ATP-binding cassette (ABC) A1, ABCG1 and scavenger receptor class B type I (SR-BI)) were modulated by EVOO consumption. The fluidity of the phospholipidic layer of HDL increased by 13 % (P< 0·001) following EVOO consumption compared with baseline. EVOO consumption also increased the release of excess cholesterol from human monocyte-derived macrophages (HMDM) by 44 % (P< 0·001), and ABCA1 and ABCG1 mRNA transcription by 16·08 % (P< 0·001) and 35·79 % (P< 0·01), respectively. The protein expression of these two cholesterol transporters also increased after EVOO consumption. In contrast, SR-BI mRNA and protein expression in HMDM were significantly lower after 12 weeks of EVOO consumption. Incubating J774 macrophages with EVOO polyphenol extracts induced a concentration-dependent up-regulation of ABCA1 and ABCG1 expression in macrophages. After 12 weeks of EVOO consumption, the capacity of HDL to mediate CE was improved and the ability of HMDM to release excess cholesterol was enhanced by increasing the expression of ABCA1 and ABCG1 transporters.
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Matsuo, Michinori, and Kazumitsu Ueda. "Function of ABCA1 and ABCG1 in Cholesterol Homeostasis." MEMBRANE 32, no. 5 (2007): 240–46. http://dx.doi.org/10.5360/membrane.32.240.
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Cassim Bawa, Fathima N., Raja Gopoju, Yanyong Xu, Shuwei Hu, Yingdong Zhu, Shaoru Chen, Kavita Jadhav та Yanqiao Zhang. "Retinoic Acid Receptor Alpha (RARα) in Macrophages Protects from Diet-Induced Atherosclerosis in Mice". Cells 11, № 20 (11 жовтня 2022): 3186. http://dx.doi.org/10.3390/cells11203186.
Анотація:
Retinoic acid signaling plays an important role in regulating lipid metabolism and inflammation. However, the role of retinoic acid receptor alpha (RARα) in atherosclerosis remains to be determined. In the current study, we investigated the role of macrophage RARα in the development of atherosclerosis. Macrophages isolated from myeloid-specific Rarα-/- (RarαMac-/-) mice showed increased lipid accumulation and inflammation and reduced cholesterol efflux compared to Rarαfl/fl (control) mice. All-trans retinoic acid (AtRA) induced ATP-binding cassette subfamily A member 1 (Abca1) and Abcg1 expression and cholesterol efflux in both RarαMac-/- mice and Rarαfl/fl mice. In Ldlr-/- mice, myeloid ablation of RARα significantly reduced macrophage Abca1 and Abcg1 expression and cholesterol efflux, induced inflammatory genes, and aggravated Western diet-induced atherosclerosis. Our data demonstrate that macrophage RARα protects against atherosclerosis, likely via inducing cholesterol efflux and inhibiting inflammation.
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Adorni, Maria Pia, Marta Biolo, Francesca Zimetti, Marcella Palumbo, Nicoletta Ronda, Paolo Scarinzi, Paolo Simioni, et al. "HDL Cholesterol Efflux and Serum Cholesterol Loading Capacity Alterations Associate to Macrophage Cholesterol Accumulation in FH Patients with Achilles Tendon Xanthoma." International Journal of Molecular Sciences 23, no. 15 (July 26, 2022): 8255. http://dx.doi.org/10.3390/ijms23158255.
Анотація:
Achilles tendon xanthoma (ATX) formation involves macrophage cholesterol accumulation within the tendon, similar to that occurring in atheroma. Macrophage cholesterol homeostasis depends on serum lipoprotein functions, namely the high-density lipoprotein (HDL) capacity to promote cell cholesterol efflux (cholesterol efflux capacity, CEC) and the serum cholesterol loading capacity (CLC). We explored the HDL-CEC and serum CLC, comparing 16 FH patients with ATX to 29 FH patients without ATX. HDL-CEC through the main efflux mechanisms mediated by the transporters ATP binding cassette G1 (ABCG1) and A1 (ABCA1) and the aqueous diffusion (AD) process was determined by a cell-based radioisotopic technique and serum CLC fluorimetrically. Between the two groups, no significant differences were found in terms of plasma lipid profile. A trend toward reduction of cholesterol efflux via AD and a significant increase in ABCA1-mediated HDL-CEC (+18.6%) was observed in ATX compared to no ATX patients. In ATX-presenting patients, ABCG1-mediated HDL-CEC was lower (−11%) and serum CLC was higher (+14%) compared to patients without ATX. Considering all the patients together, ABCG1 HDL-CEC and serum CLC correlated with ATX thickness inversely (p = 0.013) and directly (p < 0.0001), respectively. In conclusion, lipoprotein dysfunctions seem to be involved in ATX physiopathology and progression in FH patients.
27
Hussain, Syed Saad, Megan T. Harris, Alex J. B. Kreutzberger, Candice M. Inouye, Catherine A. Doyle, Anna M. Castle, Peter Arvan, and J. David Castle. "Control of insulin granule formation and function by the ABC transporters ABCG1 and ABCA1 and by oxysterol binding protein OSBP." Molecular Biology of the Cell 29, no. 10 (May 15, 2018): 1238–57. http://dx.doi.org/10.1091/mbc.e17-08-0519.
Анотація:
In pancreatic β-cells, insulin granule membranes are enriched in cholesterol and are both recycled and newly generated. Cholesterol’s role in supporting granule membrane formation and function is poorly understood. ATP binding cassette transporters ABCG1 and ABCA1 regulate intracellular cholesterol and are important for insulin secretion. RNAi interference–induced depletion in cultured pancreatic β-cells shows that ABCG1 is needed to stabilize newly made insulin granules against lysosomal degradation; ABCA1 is also involved but to a lesser extent. Both transporters are also required for optimum glucose-stimulated insulin secretion, likely via complementary roles. Exogenous cholesterol addition rescues knockdown-induced granule loss (ABCG1) and reduced secretion (both transporters). Another cholesterol transport protein, oxysterol binding protein (OSBP), appears to act proximally as a source of endogenous cholesterol for granule formation. Its knockdown caused similar defective stability of young granules and glucose-stimulated insulin secretion, neither of which were rescued with exogenous cholesterol. Dual knockdowns of OSBP and ABC transporters support their serial function in supplying and concentrating cholesterol for granule formation. OSBP knockdown also decreased proinsulin synthesis consistent with a proximal endoplasmic reticulum defect. Thus, membrane cholesterol distribution contributes to insulin homeostasis at production, packaging, and export levels through the actions of OSBP and ABCs G1 and A1.
28
Zhang, Xinyuan, Kaiyue Wang, Ling Zhu, and Qiyun Wang. "Reverse Cholesterol Transport Pathway and Cholesterol Efflux in Diabetic Retinopathy." Journal of Diabetes Research 2021 (October 26, 2021): 1–11. http://dx.doi.org/10.1155/2021/8746114.
Анотація:
Cholesterol esters, synthesized from cholesterol with long-chain fatty acids, are essential components of plasma lipoproteins and cell membranes that participate in various metabolic processes in the body. Cholesterol can be excreted through the cholesterol reverse transport (RCT) pathway when excessive cholesterol is produced in the extrahepatic cells, which is regulated by the liver X receptor (LXR) and its downstream regulators ATP-binding cassette subfamily A member 1 (ABCA1) and ATP-binding cassette subfamily G member 1 (ABCG1) genes. Abnormal cholesterol metabolism is closely associated with the development of diabetic retinopathy (DR). However, the precise underlying mechanism of the RCT pathway in the pathogenesis of DR is still not fully understood. This review focused on cholesterol metabolism, with a particular emphasis on the RCT pathway and its correlation with the development of DR. Particular attention has been paid to the key regulators of the RCT pathway: LXR, ABCA1, and ABCG1 genes and their potential therapeutic targets in the management of DR.
29
Nyul, Thomas E., Keely Beyries, Taylor Hojnacki, Rebecca Glynn, Kayla E. Paulosky, Anitej Gedela, Ariana Majer, et al. "Menin Maintains Cholesterol Content in Colorectal Cancer via Repression of LXR-Mediated Transcription." Cancers 15, no. 16 (August 16, 2023): 4126. http://dx.doi.org/10.3390/cancers15164126.
Анотація:
Background and Aims: Menin is a nuclear scaffold protein that regulates gene transcription in an oftentimes tissue-specific manner. Our previous work showed that menin is over-expressed in colorectal cancer (CRC); however, the full spectrum of menin function in colonic neoplasia remains unclear. Herein, we aimed to uncover novel menin-regulated pathways important for colorectal carcinogenesis. Methods: RNA-Seq analysis identified that menin regulates LXR-target gene expressions in CRC cell lines. Isolated colonic epithelium from Men1f/f;Vil1-Cre and Men1f/f mice was used to validate the results in vivo. Cholesterol content was quantified via an enzymatic assay. Results: RNA-Seq analysis in the HT-29 CRC cell line identified that menin inhibition upregulated LXR-target genes, specifically ABCG1 and ABCA1, with protein products that promote cellular cholesterol efflux. Similar results were noted across other CRC cell lines and with different methods of menin inhibition. Consistent with ABCG1 and ABCA1 upregulation, and similarly to LXR agonists, menin inhibition reduced the total cellular cholesterol in both HT-29 and HCT-15 cells. To confirm the effects of menin inhibition in vivo, we assessed Men1f/f;Vil1-Cre mice lacking menin expression in the colonic epithelium. Men1f/f;Vil1-Cre mice were found to have no distinct baseline phenotype compared to control Men1f/f mice. However, similarly to CRC cell lines, Men1f/f;Vil1-Cre mice showed an upregulation of Abcg1 and a reduction in total cellular cholesterol. Promoting cholesterol efflux, either via menin inhibition or LXR activation, was found to synergistically suppress CRC cell growth under cholesterol-depleted conditions and when administered concomitantly with small molecule EGFR inhibitors. Conclusions: Menin represses the transcription of LXR-target genes, including ABCA1 and ABCG1 in the colonic epithelium and CRC. Menin inhibition conversely upregulates LXR-target genes and reduces total cellular cholesterol, demonstrating that menin inhibition may be an important mechanism for targeting cholesterol-dependent pathways in colorectal carcinogenesis.
30
Kim, Geun Hyang, Keunhee Park, Seon-Yong Yeom, Kyung Jin Lee, Gukhan Kim, Jesang Ko, Dong-Kwon Rhee, et al. "Characterization of ASC-2 as an Anti-Atherogenic Transcriptional Coactivator of Liver X Receptors in Macrophages." Endocrine Reviews 30, no. 4 (June 1, 2009): 415. http://dx.doi.org/10.1210/edrv.30.4.9986.
Анотація:
ABSTRACT Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic (Tg) macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apoE transcripts, as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-Tg mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an anti-atherogenic coactivator of LXRs in macrophages.
31
Kim, Geun Hyang, Keunhee Park, Seon-Yong Yeom, Kyung Jin Lee, Gukhan Kim, Jesang Ko, Dong-Kwon Rhee, et al. "Characterization of ASC-2 as an Antiatherogenic Transcriptional Coactivator of Liver X Receptors in Macrophages." Molecular Endocrinology 23, no. 7 (July 1, 2009): 966–74. http://dx.doi.org/10.1210/me.2008-0308.
Анотація:
Abstract Activating signal cointegrator-2 (ASC-2) functions as a transcriptional coactivator of many nuclear receptors and also plays important roles in the physiology of the liver and pancreas by interacting with liver X receptors (LXRs), which antagonize the development of atherosclerosis. This study was undertaken to establish the specific function of ASC-2 in macrophages and atherogenesis. Intriguingly, ASC-2 was more highly expressed in macrophages than in the liver and pancreas. To inhibit LXR-specific activity of ASC-2, we used DN2, which contains the C-terminal LXXLL motif of ASC-2 and thereby acts as an LXR-specific, dominant-negative mutant of ASC-2. In DN2-overexpressing transgenic macrophages, cellular cholesterol content was higher and cholesterol efflux lower than in control macrophages. DN2 reduced LXR ligand-dependent increases in the levels of ABCA1, ABCG1, and apolipoprotein E (apoE) transcripts as well as the activity of luciferase reporters driven by the LXR response elements (LXREs) of ABCA1, ABCG1, and apoE genes. These inhibitory effects of DN2 were reversed by overexpression of ASC-2. Chromatin immunoprecipitation analysis demonstrated that ASC-2 was recruited to the LXREs of the ABCA1, ABCG1, and apoE genes in a ligand-dependent manner and that DN2 interfered with the recruitment of ASC-2 to these LXREs. Furthermore, low-density lipoprotein receptor (LDLR)-null mice receiving bone marrow transplantation from DN2-transgenic mice showed accelerated atherogenesis when administered a high-fat diet. Taken together, these results indicate that suppression of the LXR-specific activity of ASC-2 results in both defective cholesterol metabolism in macrophages and accelerated atherogenesis, suggesting that ASC-2 is an antiatherogenic coactivator of LXRs in macrophages.
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Mei, Jun, Fengqin Xu, Qingbing Zhou, Ying Zhang, Jie Ji, and Meng Li. "Tetramethylpyrazine and Paeoniflorin Synergistically Attenuate Cholesterol Efflux in Macrophage Cells via Enhancing ABCA1 and ABCG1 Expression." Evidence-Based Complementary and Alternative Medicine 2022 (November 5, 2022): 1–8. http://dx.doi.org/10.1155/2022/4304790.
Анотація:
The formation of foam cells is a characteristic of the occurrence and development of atherosclerosis. ATP-binding cassette subfamily A1 and G1 (ABCA1 and ABCG1) and scavenger receptor B1 (SR-B1) play critical roles in promoting intracellular cholesterol efflux to high-density lipoprotein (HDL) or apolipoprotein A1 (apoA1). We attempted to test the effect of the tetramethylpyrazine-paeoniflorin pair (TP) on cholesterol outflow in foam cells derived from macrophages. In this study, RAW264.7 macrophages were treated with 80 mg/L oxidized low-density lipoprotein (ox-LDL) for 24 h to obtain foam cells. Then they were intervened with TP (tetramethylpyrazine 40 ug/ml plus paeoniflorin 80 ug/ml) for additional 24 h. The distribution of cholesterol in foam cells was evaluated by oil red O staining. The contents of total cholesterol (TC) and free cholesterol (FC) were assessed with commercial kits. Fluorescent imaging was observed with a fluorescent inverted microscope. The capacity of cholesterol efflux was measured with a fluorescent plate reader, and the transcript and protein levels of ABCA1, ABCG1, and SR-B1 were detected by Western blot and quantitative polymerase chain reactions (Q-PCRs). Cytokines in the medium were detected by ELISA and adjusted by total cellular proteins. The results showed that TP decreased ox-LDL-induced cholesterol deposition and foam cell formation by promoting cholesterol efflux to apoA1, which was related to the upregulation of ABCA1 and ABCG1. Moreover, TP decreased the secretion of ox-LDL-induced tumor necrosis factor alpha (TNF-α), interleukin 1 beta (IL-1β), and monocyte chemotactic protein-1 (MCP-1), an important profoam cell cytokine in atherosclerosis.
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Palmer, Megan A., Eleanor Smart, and Iain S. Haslam. "Localisation and regulation of cholesterol transporters in the human hair follicle: mapping changes across the hair cycle." Histochemistry and Cell Biology 155, no. 5 (January 6, 2021): 529–45. http://dx.doi.org/10.1007/s00418-020-01957-8.
Анотація:
AbstractCholesterol has long been suspected of influencing hair biology, with dysregulated homeostasis implicated in several disorders of hair growth and cycling. Cholesterol transport proteins play a vital role in the control of cellular cholesterol levels and compartmentalisation. This research aimed to determine the cellular localisation, transport capability and regulatory control of cholesterol transport proteins across the hair cycle. Immunofluorescence microscopy in human hair follicle sections revealed differential expression of ATP-binding cassette (ABC) transporters across the hair cycle. Cholesterol transporter expression (ABCA1, ABCG1, ABCA5 and SCARB1) reduced as hair follicles transitioned from growth to regression. Staining for free cholesterol (filipin) revealed prominent cholesterol striations within the basement membrane of the hair bulb. Liver X receptor agonism demonstrated active regulation of ABCA1 and ABCG1, but not ABCA5 or SCARB1 in human hair follicles and primary keratinocytes. These results demonstrate the capacity of human hair follicles for cholesterol transport and trafficking. Future studies examining the role of cholesterol transport across the hair cycle may shed light on the role of lipid homeostasis in human hair disorders.
34
Luquain-Costaz, Céline, Maaike Kockx, Malcolm Anastasius, Vincent Chow, Anatol Kontush, Wendy Jessup, and Leonard Kritharides. "Increased ABCA1 (ATP-Binding Cassette Transporter A1)-Specific Cholesterol Efflux Capacity in Schizophrenia." Arteriosclerosis, Thrombosis, and Vascular Biology 40, no. 11 (November 2020): 2728–37. http://dx.doi.org/10.1161/atvbaha.120.314847.
Анотація:
Objective: Patients with schizophrenia have increased long-term mortality attributable to cardiovascular disease and commonly demonstrate features of mixed dyslipidemia with low HDL-C (high-density lipoprotein cholesterol). The removal of cholesterol from cells by HDL via specific ATP-binding cholesterol transporters is a major functional property of HDL, and its measurement as cholesterol efflux capacity (CEC) can predict cardiovascular risk. Whether HDL function is impaired in patients with schizophrenia is unknown. Approach and Results: We measured basal and ABCA1 (ATP-binding cassette transporter A1)- and ABCG1 (ATP-binding cassette transporter G1)-dependent CEC, comparing patients with schizophrenia with age- and sex-matched healthy controls, and related our findings to nuclear magnetic resonance analysis of lipoprotein subclasses. Total plasma cholesterol and LDL-C (low-density lipoprotein cholesterol) were comparable between healthy controls (n=51) and patients (n=120), but patients with schizophrenia had increased total plasma triglyceride, low HDL-C and apo (apolipoprotein) A-I concentrations. Nuclear magnetic resonance analysis indicated a marked (15-fold) increase in large triglyceride-rich lipoprotein particle concentration, increased small dense LDL particles, and fewer large HDL particles. Despite lower HDL-C concentration, basal CEC was 13.7±1.6% higher, ABCA1-specific efflux was 35.9±1.6% higher, and ABCG1 efflux not different, in patients versus controls. In patients with schizophrenia, ABCA1-specific efflux correlated with the abundance of small 7.8 nm HDL particles but not with serum plasminogen or triglyceride levels. Conclusions: Patients with schizophrenia have increased concentrations of atherogenic apoB-containing lipoproteins, decreased concentrations of large HDL particles, but enhanced ABCA1-mediated CEC. In this population, preventative strategies should focus on reducing atherogenic lipoproteins rather than increasing CEC.
35
Baumann, M., M. Körner, X. Huang, F. Wenger, D. Surbek, and C. Albrecht. "Placental ABCA1 and ABCG1 expression in gestational disease: Pre-eclampsia affects ABCA1 levels in syncytiotrophoblasts." Placenta 34, no. 11 (November 2013): 1079–86. http://dx.doi.org/10.1016/j.placenta.2013.06.309.
36
Puttabyatappa, Muraly, Catharine A. VandeVoort та Charles L. Chaffin. "hCG-Induced Down-Regulation of PPARγ and Liver X Receptors Promotes Periovulatory Progesterone Synthesis by Macaque Granulosa Cells". Endocrinology 151, № 12 (6 жовтня 2010): 5865–72. http://dx.doi.org/10.1210/en.2010-0698.
Анотація:
An ovulatory stimulus induces the rapid and dramatic increase in progesterone synthesis by the primate ovarian follicle. However, little is known about the early events leading to the shift from estrogen to progesterone production. Because steroidogenesis represents an aspect of cholesterol metabolism, it was hypothesized that transcription factors regulating cholesterol balance would be among the earliest to change in response to an ovulatory stimulus. Granulosa cells were isolated from rhesus monkey follicles following controlled ovarian stimulation protocols before or up to 24 hr after an ovulatory human chorionic gonadotropin (hCG) bolus. The peroxisome proliferator-activated receptor-γ (PPARG) and the liver X receptors [nuclear receptor (NR)1H2, NR1H3] decreased within 3 hr of hCG, as did the reverse cholesterol transporters ATP-binding cassette (ABC)A1 and ABCG1. Treatment of granulosa cells isolated before an ovulatory stimulus with hCG and rosiglitizone resulted in an increase in NR1H3 and ABCG1, and decreased steroidogenic acute regulatory (STAR) protein and scavenger receptor-BI (SCARB1). A liver X receptor agonist attenuated hCG-induced progesterone synthesis in vitro and increased the expression of ABCA1 and ABCG1, and suppressed STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B, and SCARB1. These data suggest that an initial action of LH/CG on the primate preovulatory follicle is to rapidly reduce the expression of PPARG, resulting in reduced NR1H3 with the consequence shifting the balance from cholesterol efflux via ABCA1 and ABCG1 to cholesterol uptake (SCARB1) and metabolism (STAR, P450 side-chain cleavage A1, hydroxysteroid dehydrogenase 3B). That the regulation of PPARG and the liver X receptors occurs within 3 hr strongly indicates that early events in the primate luteinizing follicle are critical to successful ovulation and luteal formation.
37
Horihata, Kei, Shin Yoshioka, Masahiro Sano, Yuki Yamamoto, Koji Kimura, Dariusz J. Skarzynski, and Kiyoshi Okuda. "Expressions of lipoprotein receptors and cholesterol efflux regulatory proteins during luteolysis in bovine corpus luteum." Reproduction, Fertility and Development 29, no. 7 (2017): 1280. http://dx.doi.org/10.1071/rd15538.
Анотація:
The corpus luteum (CL) synthesises and secretes progesterone (P4), which is essential for the establishment and maintenance of pregnancy in mammals. P4 is synthesised from cholesterol. Cholesterol is internalised by low-density lipoprotein receptor (LDLR) and/or scavenger receptor B1 (SR-BI), and is effluxed by ATP-binding cassette (ABC) transporter A1 (ABCA1) and G1 (ABCG1). To test the hypothesis that lipoprotein receptors and ABC transporters are involved in functional luteolysis, we examined the expression of LDLR, SR-BI, ABCA1 and ABCG1 in bovine CL during the luteal stages and after injection of prostaglandin (PG) F2α on Day 10 after ovulation. Expression of LDLR and SR-BI mRNA and protein was lower in the regressed luteal than late luteal stage. Injection of cows with a PGF2α did not affect LDLR mRNA and protein levels in the CL. Although expression of SR-BI mRNA did not change, SR-BI protein expression decreased 12 and 24 h after PGF2α injection. The overall findings of the present study suggest that the decreased expression of SR-BI induced by PGF2α is one of the factors responsible for the continuous decrease in P4 production during functional luteolysis.
38
Dracheva, Kseniia V., Irina A. Pobozheva, Kristina A. Anisimova, Aleksandra A. Panteleeva, Luiza A. Garaeva, Stanislav G. Balandov, Zarina M. Hamid, Dmitriy I. Vasilevsky, Sofya N. Pchelina, and Valentina V. Miroshnikova. "Extracellular Vesicles Secreted by Adipose Tissue during Obesity and Type 2 Diabetes Mellitus Influence Reverse Cholesterol Transport-Related Gene Expression in Human Macrophages." International Journal of Molecular Sciences 25, no. 12 (June 12, 2024): 6457. http://dx.doi.org/10.3390/ijms25126457.
Анотація:
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, LXRβ (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 LXRβ 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.
39
Tall, A. "Abstract: S3-34 ROLE OF ABCA1 AND ABCG1 IN ATHEROGENESIS." Atherosclerosis Supplements 10, no. 2 (June 2009): e1704. http://dx.doi.org/10.1016/s1567-5688(09)71651-4.
40
Gelissen, Ingrid, Kerry-Anne Rye, Carmel Quinn, Andrew Brown, Maaike Kockx, Sian Cartland, Leonard Kritharides, and Wendy Jessup. "Concerted action of ABCA1 and ABCG1 in cell cholesterol export." Vascular Pharmacology 45, no. 3 (September 2006): e23. http://dx.doi.org/10.1016/j.vph.2006.08.107.
41
Wang, Mengxi, Qian Xiang, Weixin Sun, Haowen Zhang, Ruijie Shi, Jun Guo, Huaqin Tong та ін. "Qihuang Zhuyu Formula Attenuates Atherosclerosis via Targeting PPARγ to Regulate Cholesterol Efflux and Endothelial Cell Inflammation". Oxidative Medicine and Cellular Longevity 2022 (5 грудня 2022): 1–30. http://dx.doi.org/10.1155/2022/2226168.
Анотація:
At present, due to the limitations of drug therapy targets for atherosclerosis, some patients fail to achieve satisfactory efficacy. Cholesterol efflux dysfunction and endothelial cell inflammation are considered to be important factors in the development of atherosclerosis. Peroxisome proliferator-activated receptor gamma (PPARγ), a promising therapeutic target for atherosclerosis, plays a dual role in regulating cholesterol efflux and endothelial cell inflammation. However, the use of PPARγ agonist in clinical practice is greatly limited as it could lead to water and sodium retention and hence result in congestive heart failure. Qihuang Zhuyu Formula (QHZYF) is a hospital preparation of Jiangsu Province Hospital of Chinese Medicine which has definite effect in the treatment of atherosclerosis, but its pharmacological mechanism has not been clear. In this study, we successfully predicted that QHZYF might regulate cholesterol efflux and endothelial inflammation via targeting PPARγ-mediated PPARγ/LXRα/ABCA1-ABCG1 and PPARγ/NF-κB p65 pathways by using UPLC-Q-TOF/MS, network pharmacology, bioinformatics analysis, and molecular docking technology. Subsequently, we confirmed in vivo that QHZYF could attenuate atherosclerosis in ApoE−/− mice and regulate the expression levels of related molecules in PPARγ/LXRα/ABCA1-ABCG1 and PPARγ/NF-κB p65 pathways of ApoE−/− mice and C57BL/6 wild-type mice. Finally, in in vitro experiments, we found that QHZYF could reduce lipid content and increase cholesterol efflux rate of RAW 264.7 cells, inhibit the inflammatory response of HUVECs, and regulate the expression levels of related molecules in the two pathways. In addition, the above effects of QHZYF were significantly weakened after PPARγ knockdown in the two kinds of cells. In conclusion, our study revealed that QHZYF attenuates atherosclerosis via targeting PPARγ-mediated PPARγ/LXRα/ABCA1-ABCG1 and PPARγ/NF-κB p65 pathways to regulate cholesterol efflux and endothelial cell inflammation. More importantly, our study offers a promising complementary and alternative therapy which is expected to make up for the limitation of current drug treatment methods and provide a valuable reference for new drugs development in the future.
42
Costet, Philippe, Florent Lalanne, Marie C. Gerbod-Giannone, Jennifer R. Molina, Xuan Fu, Erik G. Lund, Lorraine J. Gudas, and Alan R. Tall. "Retinoic Acid Receptor-Mediated Induction of ABCA1 in Macrophages." Molecular and Cellular Biology 23, no. 21 (November 1, 2003): 7756–66. http://dx.doi.org/10.1128/mcb.23.21.7756-7766.2003.
Анотація:
ABSTRACT ABCA1, the mutant molecule in Tangier Disease, mediates efflux of cellular cholesterol to apoA-I and is induced by liver X receptor (LXR)/retinoid X receptor (RXR) transcription factors. Retinoic acid receptor (RAR) activators (all-trans-retinoic acid [ATRA] and TTNPB) were found to increase ATP-binding cassette transporter 1 (ABCA1) mRNA and protein in macrophages. In cellular cotransfection assays, RARγ/RXR activated the human ABCA1 promoter, via the same direct repeat 4 (DR4) promoter element as LXR/RXR. Chromatin immunoprecipitation analysis in macrophages confirmed the binding of RARγ/RXR to the ABCA1 promoter DR4 element in the presence of ATRA, with weaker binding of RARα/RXR, and no binding of RARβ/RXR. However, in macrophages from RARγ−/− mice, TTNPB still induced ABCA1, in association with marked upregulation of RARα, suggesting that high levels of RARα can compensate for the absence of RARγ. Dose-response experiments with ATRA in mouse primary macrophages showed that other LXR target genes were weakly induced (ABCG1 and SREBP-1c) or not induced (apoE and LXRα). The more specific RAR activator TTNPB did not induce SREBP-1c in mouse primary macrophages or liver. These studies indicate a direct role of RARγ/RXR in induction of macrophage ABCA1.
43
Chen, Min, Wenjing Li, Nanping Wang, Yi Zhu та Xian Wang. "ROS and NF-κB but not LXR mediate IL-1β signaling for the downregulation of ATP-binding cassette transporter A1". American Journal of Physiology-Cell Physiology 292, № 4 (квітень 2007): C1493—C1501. http://dx.doi.org/10.1152/ajpcell.00016.2006.
Анотація:
ATP-binding cassette transporter A1 (ABCA1), a pivotal regulator of cholesterol efflux from cells to apolipoproteins, plays an important role in cholesterol homeostasis. As an inflammatory factor, IL-1β has been shown to downregulate ABCA1 in macrophages and facilitates foam cell formation. However, the molecular mechanism underlining the downregulated ABCA1 by IL-1β is still elusive. In the present study, we demonstrated that IL-1β downregulated ABCA1 but not ABCG1 at mRNA and protein levels in a time- and dose-dependent manner in THP-1 and A549 cells. IL-1β attenuated ABCA1 promoter activity through an LXR (liver X receptor)-independent pathway, since IL-1β did not alter the expression and activities of LXRα/β, and deletion of the LXR responsive element from the ABCA1 promoter failed to reverse the IL-1β effect. In contrast, NF-κB inhibition by pyrrolidine dithiocarbamate and MG132 prevented the suppression of ABCA1 by IL-1β. Cotransfection with ABCA1 luciferase reporter and the expression plasmids of Rel A decreased ABCA1 promoter activities. An adenovirus expressing NF-κB inhibitor subunit-α inhibited NF-κB activities and also reversed the IL-1β effect at the promoter activity and protein levels of ABCA1. In addition, IL-1β could induce the production of reactive oxygen species (ROS), and N-acetyl-l-cysteine, a scavenger of ROS, reversed the decreased level of ABCA1 induced by IL-1β. H2O2decreased ABCA1 at the mRNA and protein levels and the promoter activity. Thus our data provide strong evidence that ROS and NF-κB, but not LXR, mediate the IL-1β-induced downregulation of ABCA1 via a novel transcriptional mechanism, which might play an important role of proinflammation in the alteration of lipid metabolism.
44
Marasinghe, Chathuri Kaushalya, Won-Kyo Jung, and Jae-Young Je. "OxLDL-Induced Foam Cell Formation Inhibitory Activity of Pepsin Hydrolysate of Ark Shell (Scapharca subcrenata (Lischke, 1869)) in RAW264.7 Macrophages." Journal of Food Biochemistry 2023 (February 3, 2023): 1–9. http://dx.doi.org/10.1155/2023/6905673.
Анотація:
Inhibitory effect of ark shell (Scapharca subcrenata (Lischke, 1869)) proteolytic hydrolysates (ASHs) on oxidized low-density lipoprotein (oxLDL)-induced macrophage foam cell formation was investigated. Two types of ASHs were prepared by Alcalase® and pepsin, ASAH (ark shell-Alcalase® hydrolysates), and ASPH (ark shell-pepsin hydrolysate). Oil Red O staining results showed that ASPH suppressed foam cell formation and lipid accumulation more than ASAH in oxLDL-induced foam cell formation of RAW264.7 macrophages. ASPH reduced the levels of total cholesterol, cholesterol ester, and free cholesterol in oxLDL-treated RAW264.7 macrophages. It was found that ASPH increased cholesterol efflux and decreased cholesterol influx rate. In this regard, protein expressions of CD36 and scavenger receptor class A1 (SR-A1) for cholesterol influx and ATP-binding cassette transporter A1 and G1 (ABCA1 and ABCG1) for cholesterol efflux were investigated. ASPH treatment resulted in an increase of ABCA1 and ABCG1 expression but downregulated CD36 and SR-A1 expression. Furthermore, ASPH suppressed production of proinflammatory cytokines, including tumor necrosis factor-α and interleukin-6 and -1β, through regulating nuclear factor-kappa B (NF-κB) in oxLDL-induced foam cell formation of RAW264.7 macrophages. Taken together, our data indicate that ASPH might be a useful ingredient in functional foods for ameliorating atherosclerosis by preventing foam cell formation.
45
Wang, Yafang, Yang Liu, Yan Wang, Yidong Wu, Zhixuan Chen, Feng Wang, Xiaoling Wan, Fenghua Wang, and Xiaodong Sun. "MacrophageSult2b1promotes pathological neovascularization in age-related macular degeneration." Life Science Alliance 6, no. 11 (August 7, 2023): e202302020. http://dx.doi.org/10.26508/lsa.202302020.
Анотація:
Disordered immune responses and cholesterol metabolism have been implicated in age-related macular degeneration (AMD), the leading cause of blindness in elderly individuals. SULT2B1, the key enzyme of sterol sulfonation, plays important roles in inflammation and cholesterol metabolism. However, the role and underlying mechanism of SULT2B1 in AMD have not been investigated thus far. Here, we report that SULT2B1 is specifically expressed in macrophages in choroidal neovascularization lesions.Sutl2b1deficiency significantly reduced leakage areas and inhibited pathological angiogenesis by inhibiting M2 macrophage activation in vivo and in vitro. Mechanistically, loss ofSult2b1activated LXRs and subsequently increased ABCA1 and ABCG1 (ABCA1/G1)-mediated cholesterol efflux from M2 macrophages. LXR inhibition (GSK2033 treatment) inSult2b1−/−macrophages reversed M2 polarization and decreased intracellular cholesterol capacity to promote pathological angiogenesis. In contrast to SULT2B1, STS, an enzyme of sterol desulfonation, protected against choroidal neovascularization development by activating LXR–ABCA1/G1 signalling to block M2 polarization. Collectively, these data reveal a cholesterol metabolism axis related to macrophage polarization in neovascular AMD.
46
Zhao, Jin-Feng, Shr-Jeng Jim Leu, Song-Kun Shyue, Kuo-Hui Su, Jeng Wei та Tzong-Shyuan Lee. "Novel Effect of Paeonol on the Formation of Foam Cells: Promotion of LXRα-ABCA1–Dependent Cholesterol Efflux in Macrophages". American Journal of Chinese Medicine 41, № 05 (січень 2013): 1079–96. http://dx.doi.org/10.1142/s0192415x13500730.
Анотація:
Paeonol, a phenolic component purified from Paeonia suffruticosa (Cortex Moutan), is used in traditional Chinese medicine to treat inflammatory diseases. However, little is known about the effect of paeonol on cholesterol metabolism. We investigated the efficacy of paeonol on cholesterol metabolism and the underlying mechanism in macrophages and apolipoprotein E deficient (apoE-/-) mice. Treatment with paeonol markedly attenuated cholesterol accumulation induced by oxidized LDL in macrophages, which was due to increased cholesterol efflux. Additionally, paeonol enhanced the mRNA and protein expression of ATP-binding membrane cassette transport protein A1 (ABCA1) but did not alter the protein level of ABCG1 or other scavenger receptors. Inhibition of ABCA1 activity with a pharmacological inhibitor, neutralizing antibody or small interfering RNA (siRNA), negated the effects of paeonol on cholesterol efflux and cholesterol accumulation. Furthermore, paeonol induced the nuclear translocation of liver X receptor α (LXRα) by increasing its activity. siRNA knockdown of LXRα abolished the paeonol-induced upregulation of ABCA1, promotion of cholesterol efflux and suppression of cholesterol accumulation. Moreover, atherosclerotic lesions, hyperlipidemia and systemic inflammation were reduced and the protein expression of ABCA1 was increased in aortas of paeonol-treated apoE-/- mice. Paeonol may alleviate the formation of foam cells by enhancing LXRα-ABCA1–dependent cholesterol efflux.
47
Dib, Shiraz, Rodrigo Azevedo Loiola, Emmanuel Sevin, Julien Saint-Pol, Fumitaka Shimizu, Takashi Kanda, Jens Pahnke та Fabien Gosselet. "TNFα Activates the Liver X Receptor Signaling Pathway and Promotes Cholesterol Efflux from Human Brain Pericytes Independently of ABCA1". International Journal of Molecular Sciences 24, № 6 (22 березня 2023): 5992. http://dx.doi.org/10.3390/ijms24065992.
Анотація:
Neuroinflammation and brain lipid imbalances are observed in Alzheimer’s disease (AD). Tumor necrosis factor-α (TNFα) and the liver X receptor (LXR) signaling pathways are involved in both processes. However, limited information is currently available regarding their relationships in human brain pericytes (HBP) of the neurovascular unit. In cultivated HBP, TNFα activates the LXR pathway and increases the expression of one of its target genes, the transporter ATP-binding cassette family A member 1 (ABCA1), while ABCG1 is not expressed. Apolipoprotein E (APOE) synthesis and release are diminished. The cholesterol efflux is promoted, but is not inhibited, when ABCA1 or LXR are blocked. Moreover, as for TNFα, direct LXR activation by the agonist (T0901317) increases ABCA1 expression and the associated cholesterol efflux. However, this process is abolished when LXR/ABCA1 are both inhibited. Neither the other ABC transporters nor the SR-BI are involved in this TNFα-mediated lipid efflux regulation. We also report that inflammation increases ABCB1 expression and function. In conclusion, our data suggest that inflammation increases HBP protection against xenobiotics and triggers an LXR/ABCA1 independent cholesterol release. Understanding the molecular mechanisms regulating this efflux at the level of the neurovascular unit remains fundamental to the characterization of links between neuroinflammation, cholesterol and HBP function in neurodegenerative disorders.
48
Zhang, Shun, Lu Li, Jie Wang, Tingting Zhang, Ting Ye, Shuai Wang, Dongming Xing, and Wujun Chen. "Recent advances in the regulation of ABCA1 and ABCG1 by lncRNAs." Clinica Chimica Acta 516 (May 2021): 100–110. http://dx.doi.org/10.1016/j.cca.2021.01.019.
49
Morales, Carlos R., Andrea L. Marat, Xiaoyan Ni, Yang Yu, Richard Oko, Brian T. Smith, and W. Scott Argraves. "ATP-binding cassette transporters ABCA1, ABCA7, and ABCG1 in mouse spermatozoa." Biochemical and Biophysical Research Communications 376, no. 3 (November 2008): 472–77. http://dx.doi.org/10.1016/j.bbrc.2008.09.009.
50
Cavelier, Clara, Iris Lorenzi, Lucia Rohrer, and Arnold von Eckardstein. "Lipid efflux by the ATP-binding cassette transporters ABCA1 and ABCG1." Biochimica et Biophysica Acta (BBA) - Molecular and Cell Biology of Lipids 1761, no. 7 (July 2006): 655–66. http://dx.doi.org/10.1016/j.bbalip.2006.04.012.