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Biology
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ABCG1 and HDL in Health and Disease
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ABCG1 and HDL in Health and Disease

A special issue of Biology (ISSN 2079-7737).

Deadline for manuscript submissions: 2 July 2025 | Viewed by 1615

Special Issue Editors

Dr. Alexis Stamatikos

E-Mail Website
Guest Editor
Department of Food, Nutrition, and Packaging Sciences, College of Agriculture, Forestry & Life Sciences, Clemson University, Clemson, SC 29634, USA
Interests: ABCA1; ABCG1; atherosclerosis; cholesterol efflux; miR-33; reverse cholesterol transport
Dr. Terri F. Bruce

E-Mail Website
Guest Editor
Clemson Light Imaging Facility, Clemson University, Clemson, SC 29634, USA
Interests: biomarker; cell biology; exosome; extracellular vesicle; nanoparticle

Special Issue Information

Dear Colleagues,

Intracellular cholesterol content is crucial to influencing several conditions and disease states, as altering intracellular cholesterol levels impacts membrane fluidity, lipid raft formation/disruption, and signaling pathways. Cellular cholesterol metabolism is regulated by numerous factors and the removal of cellular cholesterol is considered to be primarily controlled by cholesterol efflux. Two major proteins which regulate cholesterol efflux are the transporter ABCG1 and the lipoprotein HDL. However, both of these proteins appear to modulate other biological effects besides the removal of cholesterol. For instance, ABCG1 expression has been shown to be anti-inflammatory, and HDL is considered to have both antioxidant and anti-inflammatory properties. Interestingly, while HDL is largely thought to be atheroprotective, some data suggest certain HDL particles may be harmful to health. Moreover, it is not entirely elucidated whether the biological effects that ABCG1 and HDL exhibit rely entirely on ABCG1/HDL-mediated cholesterol efflux. It is also poorly understood whether ABCG1 expression in certain cells and tissues may either promote health or be a factor in the development of certain diseases.

This Special Issue of Biology welcomes any novel and innovative research articles as well as comprehensive reviews which focus on the impact of ABCG1 and/or HDL in the context of health and disease.

Dr. Alexis Stamatikos
Dr. Terri F. Bruce
Guest Editors

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Submitted manuscripts should not have been published previously, nor be under consideration for publication elsewhere (except conference proceedings papers). All manuscripts are thoroughly refereed through a single-blind peer-review process. A guide for authors and other relevant information for submission of manuscripts is available on the Instructions for Authors page. Biology is an international peer-reviewed open access monthly journal published by MDPI.

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Keywords

  • atherosclerosis
  • cancer
  • cardiovascular disease
  • cholesterol efflux
  • diet-related disease
  • inflammation
  • lipid raft
  • reverse cholesterol transport

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Published Papers (2 papers)

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Research

Jump to: Review

20 pages, 3024 KiB  
Article
Exosome-Mediated Transfer of X-Motif-Tagged Anti-MiR-33a-5p Antagomirs to the Medial Cells of Transduced Rabbit Carotid Arteries
by Goren Saenz-Pipaon, Bradley K. Wacker, Lianxiang Bi, Alexis Stamatikos and David A. Dichek
Biology 2024, 13(12), 965; https://doi.org/10.3390/biology13120965 - 24 Nov 2024
Viewed by 605
Abstract
Atherosclerosis is caused by the accumulation of cholesterol within intimal smooth muscle cells (SMCs) and macrophages. However, the transporter ATP-binding cassette subfamily A, member 1 (ABCA1), can remove cholesterol from these intimal, cells reducing atherosclerosis. Antagomir-mediated inhibition of miR-33a-5p, a microRNA that represses [...] Read more.
Atherosclerosis is caused by the accumulation of cholesterol within intimal smooth muscle cells (SMCs) and macrophages. However, the transporter ATP-binding cassette subfamily A, member 1 (ABCA1), can remove cholesterol from these intimal, cells reducing atherosclerosis. Antagomir-mediated inhibition of miR-33a-5p, a microRNA that represses ABCA1 translation, promotes ABCA1-dependent cholesterol efflux and may impede atherosclerosis development. In our previous work, transducing cultured endothelial cells (ECs) with a helper-dependent adenoviral vector (HDAd) that expresses X-motif-tagged anti-miR-33a-5p enhanced antagomir packaging into EC-derived exosomes, which delivered the antagomir to cultured SMCs and macrophages. In this present study, we tested whether in vivo transduction of rabbit carotid artery endothelium can deliver an X-motif-tagged anti-miR-33a-5p to subendothelial cells. Rabbit carotid endothelial cells were transduced in vivo with an HDAd expressing anti-miR-33a-5p either with or without the X-motif (n = 11 arteries per vector). Contralateral carotids received HDAd that express scrambled oligonucleotides. Three days after transduction, the antagomir—without the X-motif—was detected in the intima but not in the media of transduced carotids (p = 0.062). The X-motif antagomir was detected in 82% of the intimal extracts (9 out of 11 carotids) and 27% of medial samples (3 out of 11 carotids, p = 0.031). However, the X-motif did not significantly enhance antagomir delivery to the media (p = 0.214 vs. non-X-motif antagomir). Expression of the antagomirs—with and without the X-motif—was sub-stoichiometric in ECs and SMCs. No antagomir-related changes in miR-33a-5p or ABCA1 expressions were detected. Despite its potential as a therapeutic strategy, our exosome-targeted gene transfer system requires further improvements to enhance antagomir expression and delivery to the subendothelial cells. Full article
(This article belongs to the Special Issue ABCG1 and HDL in Health and Disease)
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Graphical abstract

Graphical abstract
Full article ">Figure 1
<p>Sorting of carotid endothelial and smooth muscle cells. Three days after HDAd treatment, rabbit carotids were harvested and enzymatically digested, and cell suspensions were stained with antibodies targeting CD45 (immune cell marker) and CD31 (endothelial cell marker) or isotype controls. (<b>A</b>,<b>B</b>) Scatter plots of (<b>A</b>) total cells and (<b>B</b>) single cells were used to discard potential cell debris and doublet events. Each dot represents one event; the red color indicates a higher concentration of events, whereas blue represents less event concentration. The graph axes show SSC and FSC (arbitrary units) that represent cellular granularity and size, respectively. (<b>C</b>–<b>F</b>) Histograms show the fluorescence intensity from APC or AF488 fluorochromes (logarithmic scale, arbitrary units) on the X-axis and event count on the Y-axis. Gates for (<b>C</b>) CD45 and (<b>D</b>) CD31 were set using isotype control antibodies. (<b>E</b>) Histogram of CD45 staining allowed for discrimination of CD45-negative cells—primarily endothelial cells and smooth muscle cells—from CD45-positive cells (i.e., immune cells). (<b>F</b>) Histogram of CD31 staining using the previously gated (<b>E</b>) CD45-negative cell population. The CD45−CD31+ endothelial cells (shown with red background) and CD45−CD31− smooth muscle cells (green background) were sorted for downstream RNA analysis. To minimize the potential sorting of EC (with lower CD31 expression than the established CD31+ threshold) into the SMC-enriched CD45−CD31− population, the gate for CD45−CD31− cells (green background) was set at the lowest AF488 signal of the peak of CD45−CD31− cells. Gate range of EC population (AF488, arbitrary units): 2 × 10<sup>3</sup> to 2 × 10<sup>5</sup>. Gate range of SMC population (AF488, arbitrary units): 5 × 10<sup>1</sup> to 1 × 10<sup>2</sup>. SSC-A: side scatter area; FSC-A: forward scatter area; FSC-H: forward scatter height; APC: allophycocyanin; AF488: Alexa Fluor 488.</p> Full article ">Figure 2
<p>Fluorescence images of a representative rabbit carotid section used for laser microdissection of the intima and media. (<b>A</b>) Non-dissected carotid, (<b>B</b>) dissection of the intima, and (<b>C</b>) dissection of the media. The dotted red line represents the trace followed by the laser. The lumen of the artery is indicated. The scale bar corresponds to 100 µm.</p> Full article ">Figure 3
<p>Expression of anti-miR-33a-5p, miR-33a-5p, and ABCA1 mRNA in the intima and media. Arteries were harvested 3 days after treatment with HDAdScr (Scr) or HDAdAntimiR (AntimiR). Intima and media were microdissected and the antagomir, miR-33a-5p, and ABCA1 mRNA were quantified by real-time quantitative PCR. (<b>A</b>) Percentage of carotid intima and media samples in which anti-miR-33a-5p was detected. The percentage of detected samples is shown in black and non-detected samples in gray. Each intima and media sample is from one artery. <span class="html-italic">n</span> = 11 intima and media. <span class="html-italic">p</span> value from McNemar’s exact test. (<b>B</b>,<b>C</b>) Expression of miR-33a-5p in the (<b>B</b>) intima and (<b>C</b>) media of HDAdScr-infused arteries compared to HDAdAntimiR treatment. (<b>D</b>,<b>E</b>) Expression of ABCA1 mRNA in the (<b>D</b>) intima and (<b>E</b>) media of HDAdScr- or HDAdAntimiR-treated arteries. Each data point is from the intima or media of one carotid; data points from the same rabbit are connected by a line. <span class="html-italic">n</span> = 11 carotid intima and media per HDAd vector. <span class="html-italic">p</span> values are from paired <span class="html-italic">t</span>-tests. * <span class="html-italic">p</span> &lt; 0.05 vs. Scr. HDAd: helper-dependent adenovirus; AUs: arbitrary units.</p> Full article ">Figure 4
<p>Expression of X-motif anti-miR-33a-5p in the intima and media. Arteries were harvested 3 days after treatment with HDAdAntimiR or HDAdXMoAntimiR. Intima and media were microdissected and the antagomirs, without or with the X-motif, were quantified by real-time quantitative PCR. (<b>A</b>) Percentage of carotid intima and media samples in which XMo-anti-miR-33a-5p was detected. The percentage of detected samples is shown in black and non-detected samples in gray. Each intima and media sample is from one artery. <span class="html-italic">n</span> = 11 intima and media. <span class="html-italic">p</span> value from McNemar’s exact test. * <span class="html-italic">p</span> &lt; 0.05 vs. intima. (<b>B</b>,<b>C</b>) Percentage of carotid (<b>B</b>) intima and (<b>C</b>) media in which the antagomir was detected, either without (−) or with (+) the X-motif. <span class="html-italic">n</span> = 11 intima and media per HDAd vector. <span class="html-italic">p</span> values from Fisher’s exact test. (<b>D</b>,<b>E</b>) Expression of the antagomir, without and with the X-motif, in the (<b>D</b>) intima and (<b>E</b>) media of HDAd-treated vessels. Target expression was normalized to the snU6 reference gene. Data points represent individual arteries. Bars and whiskers are group medians and interquartile ranges, respectively. The dotted line is the PCR assay’s limit of detection (see <a href="#app1-biology-13-00965" class="html-app">Figure S3</a>); data points below the detection limit are shown in gray. <span class="html-italic">n</span> = 11 intima and media per HDAd vector. <span class="html-italic">p</span> values are from the Wilcoxon rank-sum test. HDAd: helper-dependent adenovirus; AUs: arbitrary units.</p> Full article ">Figure 5
<p>Effect of X-motif antagomir on miR-33a-5p and ABCA1 mRNA expression. Intima and media were microdissected 3 days after treating rabbit carotids with HDAdXMoScr (XMo-Scr) or HDAdXMoAntimiR (XMo-AntimiR). The expression of miR-33a-5p and ABCA1 mRNA was measured by qPCR. (<b>A</b>,<b>B</b>) Expression of miR-33a-5p in the (<b>A</b>) intima and (<b>B</b>) media of HDAdXMoScr-treated arteries compared to HDAdXMoAntimiR. (<b>C</b>,<b>D</b>) Expression of ABCA1 mRNA in the (<b>C</b>) intima and (<b>D</b>) media of HDAdXMoScr-treated or HDAdXMoAntimiR-infused arteries. Each data point is from the intima or media of one carotid; data points from the same rabbit are connected by a line. <span class="html-italic">n</span> = 11 carotid intima and media per HDAd vector. <span class="html-italic">p</span> values are from (<b>A,D</b>) Wilcoxon signed-rank tests and (<b>B</b>,<b>C</b>) paired <span class="html-italic">t</span>-tests. HDAd: helper-dependent adenovirus; qPCR: real-time quantitative PCR; AUs: arbitrary units.</p> Full article ">Figure 6
<p>Distribution of antagomirs in the endothelial cells (ECs) and smooth muscle cells (SMCs). Three days after treatment with HDAdAntimiR or HDAdXMoAntimiR, rabbit arteries were removed and enzymatically digested. Cell suspensions were stained with fluorescently labeled antibodies and EC-enriched (CD45−CD31+) and SMC-enriched (CD45−CD31−) populations were sorted for subsequent RNA analysis. (<b>A</b>,<b>B</b>) Percentage of carotid EC and SMC samples in which (<b>A</b>) anti-miR-33a-5p and (<b>B</b>) XMo-anti-miR-33a-5p were detected. The percentage of detected samples is shown in black and non-detected samples in gray. Each EC and SMC sample is from one artery. <span class="html-italic">n</span> = 9 samples of ECs and SMCs per HDAd vector. <span class="html-italic">p</span> values from McNemar’s exact test. (<b>C</b>,<b>D</b>) Expression of (<b>C</b>) anti-miR-33a-5p and (<b>D</b>) XMo-anti-miR-33a-5p (transcripts per cell) in the sorted ECs and SMCs. Data points are from individual arteries; points from the same artery are connected by lines. The dotted line is the PCR assay’s limit of detection (see <a href="#app1-biology-13-00965" class="html-app">Figure S3</a>); gray data points are below the detection limit. <span class="html-italic">n</span> = 9 samples of ECs and SMCs per HDAd vector. <span class="html-italic">p</span> values are from (<b>C</b>) Wilcoxon signed-rank test and (<b>D</b>) paired <span class="html-italic">t</span>-test. HDAd: helper-dependent adenovirus.</p> Full article ">Figure 7
<p>Stoichiometry of the antagomir and miR-33a-5p in the endothelial cells (ECs) and smooth muscle cells (SMCs). Rabbit arteries were harvested 3 days after treatment with HDAdAntimiR or HDAdXMoAntimiR. Vessels were enzymatically digested, and cell suspensions were stained with antibodies. The EC-enriched (CD45−CD31+) and SMC-enriched (CD45−CD31−) populations were sorted for RNA analysis. (<b>A</b>,<b>B</b>) Quantification of the miR-33a-5p and anti-miR-33a-5p (molecules per cell) in the sorted (<b>A</b>) EC and (<b>B</b>) SMC extracts. (<b>C</b>,<b>D</b>) Expression of the miR-33a-5p and XMo-anti-miR-33a-5p (molecules per cell) in the sorted (<b>C</b>) EC and (<b>D</b>) SMC samples. Data points represent individual arteries; points from the same artery are connected by lines. The dotted line is the PCR assay’s limit of detection (see <a href="#app1-biology-13-00965" class="html-app">Figure S3</a>); data points below the detection limit are shown in gray. <span class="html-italic">n</span> = 9 samples of ECs and SMCs per HDAd vector. <span class="html-italic">p</span> values are from (<b>A</b>,<b>C</b>) Wilcoxon signed-rank tests and (<b>B,D</b>) paired <span class="html-italic">t</span>-tests. * <span class="html-italic">p</span> &lt; 0.05, ** <span class="html-italic">p</span> &lt; 0.01, and *** <span class="html-italic">p</span> &lt; 0.001 vs. miR-33a-5p. HDAd: helper-dependent adenovirus.</p> Full article ">Figure 8
<p>Lack of off-target downstream effects of antagomirs in the liver. Rabbit livers were collected from non-HDAd-treated (−) and HDAd-treated (+) rabbits. The HDAd vectors encoded the anti-miR-33a-5p or a scrambled antagomir, either without (−) or with (+) the X-motif. Livers were harvested 3 days after HDAd treatment and RNA was extracted from pooled left, right, and middle lobules. (<b>A</b>,<b>B</b>) Liver expression of (<b>A</b>) miR-33a-5p and (<b>B</b>) ABCA1 mRNA; target expression was normalized with the snU6 and GAPDH mRNA, respectively. Data points represent individual livers. Bars and whiskers are group medians and interquartile ranges, respectively. <span class="html-italic">n</span> = 6 livers from non-HDAd-treated rabbits. <span class="html-italic">n</span> = 22 livers from HDAd-treated rabbits, either without (<span class="html-italic">n</span> = 11) or with (<span class="html-italic">n</span> = 11) the X-motif. <span class="html-italic">p</span> values are from Dunn’s test adjusted by Bonferroni. HDAd: helper-dependent adenovirus; AUs: arbitrary units.</p> Full article ">

Review

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23 pages, 1162 KiB  
Review
Biological Functions and Clinical Significance of the ABCG1 Transporter
by Stanislav Kotlyarov and Anna Kotlyarova
Biology 2025, 14(1), 8; https://doi.org/10.3390/biology14010008 - 25 Dec 2024
Viewed by 405
Abstract
ATP-binding cassette (ABC) transporters are a large family of proteins that transport various substances across cell membranes using energy from ATP hydrolysis. ATP-binding cassette sub-family G member 1 (ABCG1) is a member of the ABCG subfamily of transporters and performs many important functions, [...] Read more.
ATP-binding cassette (ABC) transporters are a large family of proteins that transport various substances across cell membranes using energy from ATP hydrolysis. ATP-binding cassette sub-family G member 1 (ABCG1) is a member of the ABCG subfamily of transporters and performs many important functions, such as the export of cholesterol and some other lipids across the membranes of various cells. Cholesterol transport is the mechanism that links metabolism and the innate immune system. Due to its lipid transport function, ABCG1 may contribute to the prevention of atherosclerosis and is involved in the functioning of the lung, pancreas, and other organs and systems. However, the full clinical significance of ABCG1 is still unknown and is a promising area for future research. Full article
(This article belongs to the Special Issue ABCG1 and HDL in Health and Disease)
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Figure 1

Figure 1
<p>Structure of «half» transporter ABCG1 and «full» ABC transporters (<b>A</b>) and the ABCG1 transport function (<b>B</b>). Note: Unlike classical «full» ABC transporters, which consist of two repeating modules, ABCG1 is a «half» transporter containing one intracellular ATP-binding nucleotide-binding domain (NBD) and one transmembrane domain (TMD).</p> Full article ">Figure 2
<p>Biological and potential clinical significance of the ABCG1 transporter. Through the regulation of cholesterol transport, ABCG1 is involved in the regulation of inflammation involving macrophages (<b>A</b>), with potential clinical relevance to atherosclerosis, tumor progression, pancreatic, adrenal, brain, and breast function (<b>B</b>).</p> Full article ">
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