scholarly journals Reverse Cholesterol Transport Pathway and Cholesterol Efflux in Diabetic Retinopathy

2021 ◽  
Vol 2021 ◽  
pp. 1-11
Author(s):  
Xinyuan Zhang ◽  
Kaiyue Wang ◽  
Ling Zhu ◽  
Qiyun Wang
Keyword(s):  
Diabetic Retinopathy ◽  
Cholesterol Metabolism ◽  
Underlying Mechanism ◽  
The Body ◽  
Plasma Lipoproteins ◽  
Atp Binding ◽  
Transport Pathway ◽  
Reverse Transport ◽  
Essential Components ◽  
Atp Binding Cassette

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.

scholarly journals Human Lupus Plasma Pro-Atherogenic Effects on Cultured Macrophages Are Not Mitigated by Statin Therapy: A Mechanistic LAPS Substudy

Medicina ◽  
2019 ◽  
Vol 55 (9) ◽  
pp. 514 ◽  
Author(s):  
Reiss ◽  
Arain ◽  
Kasselman ◽  
Renna ◽  
Zhen ◽  
...  
Keyword(s):  
Gene Expression ◽  
Lupus Erythematosus ◽  
Cholesterol Metabolism ◽  
Lipid Lowering ◽  
Cholesterol Transport ◽  
Atp Binding ◽  
Peroxisome Proliferator ◽  
Atherosclerotic Cardiovascular Disease ◽  
Peroxisome Proliferator Activated Receptor ◽  
Atp Binding Cassette

Background and Objectives: Atherosclerotic cardiovascular disease (CVD) remains a major cause of morbidity and mortality in persons with systemic lupus erythematosus (SLE, lupus). Atherosclerosis, which involves interplay between cholesterol metabolism and cellular inflammatory pathways, is primarily treated with statins since statins have lipid-lowering and anti-inflammatory properties. The Lupus Atherosclerosis Prevention Study (LAPS) was designed to investigate the efficacy of statins against CVD in SLE patients. LAPS demonstrated that 2 years of atorvastatin administration did not reduce atherosclerosis progression in lupus patients. In this LAPs substudy, we use cultured macrophages to explore the atherogenic properties of plasma from LAPS subjects to explain the mechanistic rationale for the inability of statins to reduce CVD in lupus. Materials and Methods: THP-1 differentiated macrophages were treated for 18 h with 10% SLE patient plasma obtained pre- and post-atorvastatin therapy or placebo. Gene expression of the following cholesterol transport genes was measured by qRT-PCR. For efflux—ATP binding cassette transporter (ABC)A1 and ABCG1, 27-hydroxylase, peroxisome proliferator-activated receptor (PPAR)γ, and liver X receptor (LXR)α; and for influx—cluster of differentiation 36 (CD36) and scavenger receptor (ScR)A1. Results: Macrophages exposed to plasma from both statin-treated and placebo-treated groups showed a significant decrease in cholesterol efflux proteins ATP binding cassette (ABC) transporters A1 and ABCG1, an increase in 27-hydroxylase, an increase in the LDL receptor and a decrease in intracellular free cholesterol. No change in influx receptors ScRA1 and CD36, nor nuclear proteins LXRα and PPARγ was observed. Conclusions: Statins do not normalize pro-atherogenic changes induced by lupus and these changes continue to worsen over time. This study provides mechanistic insight into LAPS findings by demonstrating that statins are overall ineffective in altering the balance of cholesterol transport gene expression in human macrophages. Furthermore, our study suggests that statins as a CVD treatment may not be useful in attenuating lipid overload in the SLE environment.

scholarly journals The Effects of High Hydrostatic Pressure Extract of Mulberry Fruit on Hepatic Cholesterol Metabolism in Rats (P06-013-19)

2019 ◽  
Vol 3 (Supplement_1) ◽  
Author(s):  
Jaerin Lee ◽  
Soojin Lee ◽  
Mak-Soon Lee ◽  
Yoonjin Lee ◽  
Jiyeon Kim ◽  
...  
Keyword(s):  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
High Cholesterol Diet ◽  
Atp Binding ◽  
Mrna Levels ◽  
Cholesterol Diet ◽  
Hepatic Cholesterol ◽  
High Cholesterol ◽  
Mulberry Fruit ◽  
Atp Binding Cassette

Abstract Objectives The objective of this study is to investigate the effects of high hydrostatic pressure (HHP) extract of mulberry fruit on the regulation of hepatic cholesterol metabolism in high-cholesterol diet fed rats. Methods Male Sprague-Dawley rats(6-week-old) were randomly divided into 5 groups, and fed with a normal diet (NOR), High cholesterol diet (HC), HC supplemented with 0.4% mulberry (ML) or 0.8% mulberry (MH) and HC treated with statin (ST) for 4 weeks. Results The HHP extract of mulberry fruit did not affect body weight gain and food intake and reduced the serum and liver lipids in the mulberry supplemented groups (ML, MH). In this study, we found that the HHP extract of mulberry fruit changed the level of genes involved in hepatic cholesterol metabolism. In the MH group, the mRNA levels of apolipoprotein A-1 (apoA-1), ATP-binding cassette transporter A1 (ABCA1) and lecithin-cholesterol acyltransferase (LCAT), which are involved in hepatic HDL biogenesis, were significantly increased by 1.80-, 1.77- and 2.65-fold, respectively, compared with the HC group. The MH group also significantly upregulated mRNA levels of cholesterol efflux related gene such as the liver X receptor α (LXRα), ATP-binding cassette protein G5 (ABCG5) and ATP-binding cassette protein G8 (ABCG8) compared to the HC group in the liver tissue. ABCG5 and ABCG8 expression levels of the MH group were also higher than those of the ST group. The mRNA level of cholesterol 7a-hydroxylase (CYP7A1), which is bile acid synthetic rate-limiting enzyme was higher in the MH group than that of the HC group. Furthermore, the immunohistochemical staining intensity became evident for CYP7A1 in liver of the MH group. Conclusions These results suggest at least partial involvement of HDL cholesterol synthesis, cholesterol efflux and bile acid synthesis in HHP extract of mulberry fruit mediated beneficial effects on hepatic cholesterol metabolism. Funding Sources None.

ATP-binding cassette transporter A1: regulation of cholesterol efflux

2004 ◽  
Vol 32 (1) ◽  
pp. 124-127 ◽  
Author(s):  
B.L. Knight
Keyword(s):  
Cholesterol Efflux ◽  
Cholesterol Metabolism ◽  
Dietary Cholesterol ◽  
Density Lipoprotein ◽  
Cholesterol Absorption ◽  
Apolipoprotein A1 ◽  
Whole Body ◽  
Atp Binding ◽  
Atp Binding Cassette Transporter ◽  
Atp Binding Cassette

The ATP-binding cassette transporter A1 (ABCA1) is involved in the regulation of cholesterol efflux from cells. Mutations in ABCA1 give rise to familial high-density lipoprotein (HDL) deficiency and Tangier disease, which is characterized by very low levels of HDL in plasma and cholesteryl ester accumulation in tonsils and other reticuloendothelial cells. The mechanism of action of ABCA1 is still unclear, but requires the transfer of phospholipid and cholesterol to apolipoprotein A1 bound by or close to the transporter. An important factor in the regulation of ABCA1 is cholesterol itself, which provides oxysterol ligands for liver X receptors that stimulate ABCA1 transcription. ABCA1-deficient mice show increased cholesterol absorption, suggesting that ABCA1 could also help to transport dietary cholesterol back out of intestinal absorptive cells into the lumen. Thus ABCA1 is intimately connected to various aspects of the regulation of whole-body cholesterol metabolism and probably plays an important role in protecting against the development of cardiovascular disease.

scholarly journals Lactobacillus plantarum CUL66 can impact cholesterol homeostasis in Caco-2 enterocytes

2016 ◽  
Vol 7 (3) ◽  
pp. 443-451 ◽  
Author(s):  
D.R. Michael ◽  
J.W.E. Moss ◽  
D. Lama Calvente ◽  
I. Garaiova ◽  
S.F. Plummer ◽  
...  
Keyword(s):  
Lactobacillus Plantarum ◽  
Cholesterol Metabolism ◽  
Culture Media ◽  
Cholesterol Homeostasis ◽  
In Vivo Studies ◽  
Western Society ◽  
Bile Salt Hydrolase ◽  
Atp Binding ◽  
Atp Binding Cassette

Hypercholesterolemia drives the development of cardiovascular disease, the leading cause of mortality in western society. Supplementation with probiotics that interfere with cholesterol metabolism may provide a contribution to disease prevention. Lactobacillus plantarum CUL66 (NCIMB 30280) has been assessed in vitro for its ability to impact cholesterol absorption. L. plantarum CUL66 tested positive for bile salt hydrolase activity and the ability to assimilate cholesterol from culture media. RT-qPCR analysis showed that the bacterium significantly decreased the expression of Niemann-Pick C1-like 1 and ATP-binding cassette transporter-1 in polarised Caco-2 cells after 6 h exposure. Conversely, the expression of ATP-binding cassette sub-family G member (ABCG)-5 and ABCG-8, and 3-hydroxy-3-methylglutaryl-CoA reductase were significantly increased. Using a radiolabelled assay, we also observed significant reductions in the uptake and basolateral efflux of cholesterol by Caco-2 cells exposed to L. plantarum CUL66. This in vitro study identified L. plantarum CUL66 as a cholesterol lowering bacteria by highlighting its ability to beneficially regulate multiple in vitro events associated with intestinal cholesterol metabolism and provides evidence of efficacy for its inclusion in future in vivo studies.

scholarly journals Lipopolysaccharide Down Regulates Both Scavenger Receptor B1 and ATP Binding Cassette Transporter A1 in RAW Cells

2002 ◽  
Vol 70 (6) ◽  
pp. 2995-3003 ◽  
Author(s):  
Irina Baranova ◽  
Tatyana Vishnyakova ◽  
Alexander Bocharov ◽  
Zhigang Chen ◽  
Alan T. Remaley ◽  
...  
Keyword(s):  
Cholesterol Metabolism ◽  
Foam Cell ◽  
Scavenger Receptor ◽  
Control Level ◽  
Density Lipoprotein ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Dependent Manner ◽  
Macrophage Foam Cell ◽  
Atp Binding Cassette

ABSTRACT Lipopolysaccharide (LPS) has recently been shown to facilitate macrophage foam cell formation and has been suggested to be a proatherogenic factor. The mechanism of LPS induced cholesterol accumulation, however, is unclear. In this report, using the macrophage-like RAW 264.7 cell line, we provide experimental evidence that LPS's proatherogenic effects may at least in part reflect altered cholesterol metabolism. Data presented demonstrate that in a dose-dependent manner, LPS is able to down regulate the mRNA expression of the two primary high-density lipoprotein (HDL) receptors, scavenger receptor B1 (SR-B1) and ATP binding cassette A1 (ABCA1), with a 50% inhibitory concentration of less than 0.2 ng/ml, as well as to decrease SR-B1 protein expression by 80%. We also found that LPS treatment resulted in a significant decrease (to 20% of the control level) of the specific 125I-HDL binding as well as in 50% inhibition of the HDL-mediated cholesterol efflux compared to untreated cells. In addition, we compared the potencies of various modified LPS preparations and demonstrated that the phosphorylated lipid A portion of LPS, which is highly conserved among gram-negative microorganisms, including Chlamydia, is primarily responsible for the effects of LPS on SR-B1 and ABCA1 expression. Inhibitors of NF-κB activation were observed to efficiently block the suppressive effect of LPS on SR-B1 and ABCA1, suggesting a mechanism involving NF-κB. These data indicate that the LPS effects on cholesterol metabolism may contribute to the proatherogenic properties of LPS.

scholarly journals Structure of ABCB1/P-Glycoprotein in the Presence of the CFTR Potentiator Ivacaftor

Membranes ◽  
2021 ◽  
Vol 11 (12) ◽  
pp. 923
Author(s):  
Alessandro Barbieri ◽  
Nopnithi Thonghin ◽  
Talha Shafi ◽  
Stephen M. Prince ◽  
Richard F. Collins ◽  
...  
Keyword(s):  
Conformational Changes ◽  
Competitive Inhibitor ◽  
The Body ◽  
Atp Binding ◽  
Phase Plate ◽  
Microscopy Imaging ◽  
Binding Domains ◽  
Atp Binding Cassette Transporter ◽  
P Glycoprotein ◽  
Atp Binding Cassette

ABCB1/P-glycoprotein is an ATP binding cassette transporter that is involved in the clearance of xenobiotics, and it affects the disposition of many drugs in the body. Conformational flexibility of the protein within the membrane is an intrinsic part of its mechanism of action, but this has made structural studies challenging. Here, we have studied different conformations of P-glycoprotein simultaneously in the presence of ivacaftor, a known competitive inhibitor. In order to conduct this, we used high contrast cryo-electron microscopy imaging with a Volta phase plate. We associate the presence of ivacaftor with the appearance of an additional density in one of the conformational states detected. The additional density is in the central aqueous cavity and is associated with a wider separation of the two halves of the transporter in the inward-facing state. Conformational changes to the nucleotide-binding domains are also observed and may help to explain the stimulation of ATPase activity that occurs when transported substrate is bound in many ATP binding cassette transporters.

ABCG subfamily of human ATP-binding cassette proteins

2002 ◽  
Vol 74 (11) ◽  
pp. 2057-2081 ◽  
Author(s):  
Stefan Lorkowski ◽  
Paul Cullen
Keyword(s):  
Abc Transporters ◽  
Foam Cell ◽  
Current Knowledge ◽  
Cell Formation ◽  
Evolutionary Relationship ◽  
The Body ◽  
High Density Lipoproteins ◽  
Foam Cell Formation ◽  
Atp Binding ◽  
Atp Binding Cassette

ATP-binding cassette (ABC) proteins form one of the largest known protein families and have been found in all known organisms. Most members of the human ABC protein family are membrane-spanning transporters that use energy derived from the hydrolysis of ATP to transport specific substrates across cell membranes. Mutations in certain human ABC transporters of the subfamilies A, B, C, and D have been shown to cause a wide variety of inherited diseases such as the lung condition cystic fibrosis, the nervous degenerative condition adrenoleukodystrophy (of Lorenzo’s Oil fame), hereditary macular degeneration of the eye (Stargardt’s disease), and inherited deficiency of circulating high-density lipoproteins (Tangier disease or familial hypoalphalipoproteinemia). Very recent studies showed that mutations in two members of the subfamily G of human ABC transporters (ABCG5 and ABCG8) cause a condition called sitosterolemia in which plant sterols accumulate in the body and may be responsible for influencing total body sterol homeostasis. In addition, other members of the subfamily G, namely ABCG1 and ABCG4, have also been shown to be involved in cellular lipid trafficking and are thought to play important roles during foam cell formation of human macrophages. By contrast, ABCG2 is a multidrug resistance transporter.In this review, we focus on the current knowledge and physiological background of the members of the subfamily G. We also present new insights on the evolutionary relationship of human and nonhuman ABCG proteins.

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