Figure 5 - uploaded by Blake J Cochran
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Filamentous ABCG1 co-localizes with Lck10. ABCG1 (green) and Lck10 (red) localization in control (a,b) and cholesterol treated (c,d) CHO-K1 cell membrane sheets.
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The ATP-binding cassette sub-family G member 1 (ABCG1) exports cellular cholesterol to high-density lipoproteins (HDL). However, a number of recent studies have suggested ABCG1 is predominantly localised to intracellular membranes. In this study, we found that ABCG1 was organized into two distinct cellular pools: one at the plasma membrane and the...
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... filamen- tous ABCG1, an inner membrane leaflet peptide, Lck10-mCherry, was expressed in CHO-K1 cells. Lck10 was previously shown to organize along actin filaments in cholesterol rich plasma membrane domains 21 . Filamentous organization of both Lck10 and ABCG1 was observed in cell membrane sheets under control and cholesterol treated conditions (Fig. 5). Lck10 formed continuous filaments similar to that previously observed for actin, with ABCG1 aligned with Lck10 and localized to punctuated clusters. Cholesterol increases ABCG1 diffusion. In order to explore further the association of ABCG1 and actin filaments, we evaluated the mobility of ABCG1 by time series imaging of membrane ...
Citations
... In mice and humans, it is expressed in a variety of cell types including adrenocortical cells (14)(15)(16)(17)(18)(19)(20)(21)(22). Its subcellular localization is still a matter of debate: Abcg1 has been found in both endosomes and in the plasma membrane, and in association with actin filaments (23)(24)(25)(26)(27). It is thought to mobilize cholesterol from the endoplasmic reticulum and to redistribute it to the plasma membrane, favoring cholesterol efflux to a variety of extracellular acceptors (15,(28)(29)(30). ...
Cholesterol is the precursor of all steroids, but how cholesterol flux is controlled in steroidogenic tissues is poorly understood. The cholesterol exporter ABCG1 is an essential component of the reverse cholesterol pathway and its global inactivation results in neutral lipid redistribution to tissue macrophages. The function of ABCG1 in steroidogenic tissues, however, has not been explored. To model this, we inactivated Abcg1 in the mouse adrenal cortex, which led to an adrenal-specific increase in transcripts involved in cholesterol uptake and de novo synthesis. Abcg1 inactivation did not affect adrenal cholesterol content, zonation, or serum lipid profile. Instead, we observed a moderate increase in corticosterone production that was not recapitulated by the inactivation of the functionally similar cholesterol exporter Abca1. Altogether, our data imply that Abcg1 controls cholesterol uptake and biosynthesis and regulates glucocorticoid production in the adrenal cortex, introducing the possibility that ABCG1 variants may account for physiological or subclinical variation in stress response.
... Interestingly, incubation of hMϕ with PCSK9 failed to induce its expression in these cells. Furthermore, PCSK9 treatment of hMϕ downregulated the levels of genes involved in lipid metabolism, particularly those that modulate cholesterol synthesis (SREBP1, FASN, and HMGCR) and efflux (ABCA1), but not ABCG1, which is more abundant in the membranes of the endoplasmic reticulum, contributing to phospholipid mobilization [50]. This downregulation of ABCA1 mRNA levels impairs the cholesterol efflux favoring lipid aggregation [51]. ...
Atherosclerosis is a cardiovascular disease caused mainly by dyslipidemia and is characterized by the formation of an atheroma plaque and chronic inflammation. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a protease that induces the degradation of the LDL receptor (LDLR), which contributes to increased levels of LDL cholesterol and the progress of atherosclerosis. Given that macrophages are relevant components of the lipidic and inflammatory environment of atherosclerosis, we studied the effects of PCSK9 treatment on human macrophages. Our data show that human macrophages do not express PCSK9 but rapidly incorporate the circulating protein through the LDLR and also activate the pro-inflammatory TLR4 pathway. Both LDLR and TLR4 are internalized after incubation of macrophages with exogenous PCSK9. PCSK9 uptake increases the production of reactive oxygen species and reduces the expression of genes involved in lipid metabolism and cholesterol efflux, while enhancing the production of pro-inflammatory cytokines through a TLR4-dependent mechanism. Under these conditions, the viability of macrophages is compromised, leading to increased cell death. These results provide novel insights into the role of PCSK9 in the crosstalk of lipids and cholesterol metabolism through the LDLR and on the pro-inflammatory activation of macrophages through TLR4 signaling. These pathways are relevant in the outcome of atherosclerosis and highlight the relevance of PCSK9 as a therapeutic target for the treatment of cardiovascular diseases.
... ABCG5/G8 is localized on the canalicular membranes of the bile ducts in the liver and the brush border of enterocytes in the small intestines, where it mediates the final step of the RCT. 9,12-14 ABCG1 and ABCG4 translocate cholesterol within the plasma membrane and in endosomes [15][16] and play a key role in the regulating cholesterol balance in the lung, the brain and in macrophage-rich tissues. [17][18][19][20] ABCG5/G8 undergoes obligatory heterodimerization and is unique in its capability of preferential efflux for dietary plant sterols over cholesterol. ...
The ATP-binding cassette (ABC) sterol transporters are responsible for maintaining cholesterol homeostasis in mammals by participating in reverse cholesterol transport (RCT) or transintestinal cholesterol efflux (TICE). The heterodimeric ABCG5/G8 carries out selective sterol excretion, preventing the abnormal accumulation of plant sterols in human bodies, while homodimeric ABCG1 contributes to the biogenesis and metabolism of high-density lipoproteins. A sterol-binding site on ABCG5/G8 was proposed at the interface of the transmembrane domain and the core of lipid bilayers. In this study, we have determined the crystal structure of ABCG5/G8 in a cholesterol-bound state. The structure combined with amino acid sequence analysis shows that in the proximity of the sterol-binding site, a highly conserved phenylalanine array supports functional implications for ABCG cholesterol/sterol transporters. Lastly, in silico docking analysis of cholesterol and stigmasterol (a plant sterol) suggests sterol-binding selectivity on ABCG5/G8, but not ABCG1. Together, our results provide a structural basis for cholesterol binding on ABCG5/G8 and the sterol selectivity by ABCG transporters.
... The exact mechanism of ABCA1's ability to move cholesterol out of the cell remains under investigation, but it is generally thought that ABCA1 flips phospholipids and cholesterol through the membrane, which then allows apolipoproteins (e.g., Apo-AI) to accept the newly accumulated cholesterol that now sits on the outer leaflet [31]. In contrast, ABCG1 is expressed intracellularly in endosomes, where it facilitates the movement of cholesterol from the ER to the inner leaflet via endosomal vesicles [32]. LXR activity, and correspondingly, ABCA1 and ABCG1 expression, can be altered by a wide array of inflammatory signals in macrophages. ...
Cholesterol is a critical lipid for all mammalian cells, ensuring proper membrane integrity, fluidity, and biochemical function. Accumulating evidence indicates that macrophages rapidly and profoundly reprogram their cholesterol metabolism in response to activation signals to support host defense processes. However, our understanding of the molecular details underlying how and why cholesterol homeostasis is specifically reshaped during immune responses remains less well understood. This review discusses our current knowledge of cellular cholesterol homeostatic machinery and introduces emerging concepts regarding how plasma membrane cholesterol is partitioned into distinct pools. We then discuss how proinflammatory signals can markedly reshape the cholesterol metabolism of macrophages, with a focus on the differences between MyD88-dependent pattern recognition receptors and the interferon signaling pathway. We also discuss recent work investigating the capacity of these proinflammatory signals to selectively reshape plasma membrane cholesterol homeostasis. We examine how these changes in plasma membrane cholesterol metabolism influence sensitivity to a set of microbial pore-forming toxins known as cholesterol-dependent cytolysins that specifically target cholesterol for their effector functions. We also discuss whether lipid metabolic reprogramming can be leveraged for therapy to mitigate tissue damage mediated by cholesterol-dependent cytolysins in necrotizing fasciitis and other related infections. We expect that advancing our understanding of the crosstalk between metabolism and innate immunity will help explain how inflammation underlies metabolic diseases and highlight pathways that could be targeted to normalize metabolic homeostasis in disease states.
... It is known that ABCG1 is distributed in lipid rafts of plasma membrane and in endosomes. Conversely, some studies reported that ABCG1 is restricted to endosomes and secretory granules in pancreatic betacells 170 . ...
The ATP‐binding cassette (ABC) transporter superfamily is one of the largest membrane protein families existing in wide spectrum of organisms from prokaryotes to human. ABC transporters are also known as efflux pumps because they mediate the cross‐membrane transportation of various endo‐ and xenobiotic molecules energized by ATP hydrolysis. Therefore, ABC transporters have been considered closely to multidrug resistance (MDR) in cancer, where the efflux of structurally distinct chemotherapeutic drugs causes reduced itherapeutic efficacy. Besides, ABC transporters also play other critical biological roles in cancer such as signal transduction. During the past decades, extensive efforts have been made in understanding the structure‐function relationship, transportation profile of ABC transporters, as well as the possibility to overcome MDR via targeting these transporters. In this review, we discuss the most recent knowledge regarding ABC transporters and cancer drug resistance in order to provide insights for the development of more effective therapies.
... These analyses were done using a custom-built MATLAB code, which first converted the images into binary images. The binary mask was cleaned by morphological operations using the MATLAB built-in operation of structuring element, dilation, and erosion [24]. ...
Approximately 25% of human neuroblastoma is caused by amplification of the MYCN oncogene, which leads to over‐expression of N‐Myc oncoprotein. The survival rate for this patient subtype is less than 50%. Here we show that N‐Myc protein bound to the DEAD‐box RNA helicase DDX21 gene promoter and upregulated DDX21 mRNA and protein expression. Genome‐wide differential gene expression studies identified centrosomal protein CEP55 as one of the genes most dramatically down‐regulated after DDX21 knockdown in MYCN‐amplified neuroblastoma cells. Knocking down DDX21 or CEP55 reduced neuroblastoma cell cytoskeleton stability and cell proliferation and all but abolished clonogenic capacity. Importantly, DDX21 knockdown initially induced tumor regression in neuroblastoma‐bearing mice and suppressed tumor progression. In human neuroblastoma tissues, a high level of DDX21 expression correlated with a high level of N‐Myc expression and with CEP55 expression, and independently predicted poor patient prognosis. Taken together, our data show that DDX21 induces CEP55 expression, MYCN‐amplified neuroblastoma cell proliferation and tumorigenesis, and that DDX21 and CEP55 are valid therapeutic targets for the treatment of MYCN‐amplified neuroblastoma.
... The advantage of this level of regulation is that local levels of the transporter can be regulated in a quicker fashion compared to transcriptional regulation via LXR ligands. Cellular cholesterol status was furthermore shown to affect ABCG1 cycling between intracellular and plasma membrane pools, and loading cells with cholesterol significantly enhanced the recruitment of ABCG1 to the plasma membrane [43]. ...
... In contrast to ABCA1, ABCG1 promotes sterol efflux to various relatively nonspecific acceptors such as HDL, low-density lipoprotein (LDL), and cyclodextrin, but not to ApoA-I [69]. Although several authors have argued that ABCG1 is mainly localized in endosomes, it is now clear that ABCG1 traffics to the plasma membrane, where it increases the cholesterol cell removal [70,71], apparently tightly in contact with actin cytoskeleton [72]. ...
The plasma membrane (PM) spatiotemporal organization is one of the major factors controlling cell signaling and whole-cell homeostasis. The PM lipids, including cholesterol, determine the physicochemical properties of the membrane bilayer and thus play a crucial role in all membrane-dependent cellular processes. It is known that lipid content and distribution in the PM are not random, and their transversal and lateral organization is highly controlled. Mainly sphingolipid- and cholesterol-rich lipid nanodomains, historically referred to as rafts, are extremely dynamic “hot spots” of the PM controlling the function of many cell surface proteins and receptors. In the first part of this review, we will focus on the recent advances of PM investigation and the current PM concept. In the second part, we will discuss the importance of several classes of ABC transporters whose substrates are lipids for the PM organization and dynamics. Finally, we will briefly present the significance of lipid ABC transporters for immune responses.
... 242,389 The human ABC transporter subfamily G is mostly responsible for sterol (especially cholesterol) transport. ABCG1 and ABCG4 mediate cholesterol trafficking in the plasma membrane and endosomes 390,391 and are believed to regulate cholesterol homeostasis in the brain and the macrophage-rich tissues. ABCG5 and ABCG8 function as a heterodimer and are mainly responsible for cholesterol transport across the canalicular membrane of hepatocytes. ...
The liver is beyond any doubt the most important metabolic organ of the human body. This function requires an intensive crosstalk within liver cellular structures, but also with other organs. Membrane transport proteins are therefore of upmost importance as they represent the sensors and mediators that shuttle signals from outside to the inside of liver cells and/or vice versa. In this review, we summarize the known literature of liver transport proteins with a clear emphasis on functional and structural information on ATP binding cassette (ABC) transporters, which are expressed in the human liver. These primary active membrane transporters form one of the largest families of membrane proteins. In the liver, they play an essential role in for example bile formation or xenobiotic export. Our review provides a state of the art and comprehensive summary of the current knowledge of hepatobiliary ABC transporters. Clearly, our knowledge has improved with a breath-taking speed over the last few years and will expand further. Thus, this review will provide the status quo and will lay the foundation for new and exciting avenues in liver membrane transporter research. CONTENTS
... ABCG1 mainly accumulates in cells [56]. ABCG1 is expressed in the ER, trans-Golgi network (TGN) and endosomal recycling compartment (ERC) [5]. ...
Abstract Currently, many people worldwide suffer from metabolic diseases caused by heredity and external factors, such as diet. One of the symptoms of metabolic diseases is abnormal lipid metabolism. ATP binding cassette (ABC) transporters are one of the largest transport protein superfamilies that exist in nearly all living organisms and are mainly located on lipid-processing cells. ABC transporters have been confirmed to be closely related to the pathogenesis of diseases such as metabolic diseases, cancer and Alzheimer’s disease based on their transport abilities. Notably, the capability to transport lipids makes ABC transporters critical in metabolic diseases. In addition, gene polymorphism in ABC transporters has been reported to be a risk factor for metabolic diseases, and it has been reported that relevant miRNAs have significant roles in regulating ABC transporters. In this review, we integrate recent studies to examine the roles of ABC transporters in metabolic diseases and aim to build a network with ABC transporters as the core, linking their transport abilities with metabolic and other diseases.
