| 1997 |
ABCD2 (ALDRP) encodes a 740-amino-acid peroxisomal membrane protein that is a half-ABC transporter with 62.8% identity to ABCD1 (ALDP), predicted to form homodimers or heterodimers with other peroxisomal ABC transporters. mRNA is expressed predominantly in brain and heart. |
cDNA cloning, sequence analysis, tissue expression profiling |
Biochemical and biophysical research communications |
Medium |
9345306
|
| 1999 |
Human ABCD2 (ALDRP) localizes exclusively to peroxisomes. The gene spans 33 kb on chromosome 12q12, consists of 10 exons, and its promoter contains a novel motif conserved among peroxisomal ABC transporters. ALDRP transfection into X-ALD cells complements the VLCFA oxidation defect. |
Subcellular fractionation, immunolocalization, genomic sequencing, functional complementation in ABCD1-deficient cells |
Biochemical and biophysical research communications |
Medium |
10329405
|
| 2000 |
The ABCD2 promoter (1.3 kb of human and mouse 5'-upstream region) has functional promoter activity and is upregulated by 9-cis-retinoic acid and forskolin. No PPARα response element was detected in the promoter by transfection assays. |
Luciferase reporter assays, promoter deletion/transfection in cell lines |
Genomics |
Medium |
11087670
|
| 2001 |
Fibrate induction of ABCD2 is PPARα-dependent in vivo (absent in PPARα-knockout mice), but no functional PPRE motif could be identified in the ABCD2 promoter by gel-shift assay and transfection of COS-7 cells, indicating a non-canonical PPARα-dependent regulatory mechanism. |
PPARα knockout mice treated with fenofibrate, gel-shift assay, promoter transfection in COS-7 cells |
European journal of biochemistry |
Medium |
11422379
|
| 2002 |
ABCD2 is transcriptionally induced by sterol depletion via activation of sterol regulatory element-binding proteins (SREBPs). A functional sterol regulatory element (SRE) was identified in the proximal ABCD2 promoter by reporter gene studies, site-directed mutagenesis, and gel-shift assays. ABCD2 induction by sterol depletion significantly reduced VLCFA accumulation in X-ALD fibroblasts. |
Real-time PCR, reporter gene assays, site-directed mutagenesis, gel-shift assay (EMSA), functional VLCFA measurement in patient fibroblasts |
Human molecular genetics |
High |
12374760
|
| 2003 |
ABCD2 is induced by thyroid hormone (T3) via TRβ. The ABCD2 promoter contains a functional thyroid hormone response element that binds RXR/TRβ heterodimer, mediating T3 responsiveness. T3 induces ABCD2 in liver of normal rats but not TRβ-knockout mice, and in differentiated oligodendrocytes (CG4 cells) but not astrocytes. T3 induction in ABCD1-deficient fibroblasts normalized VLCFA β-oxidation. |
Gel-shift assay (RXR/TRβ binding), TRβ-knockout mice, liver induction in vivo, cell-type specific induction, β-oxidation assay in ABCD1-deficient fibroblasts |
Molecular pharmacology |
High |
12761339
|
| 2004 |
ABCD2 functionally overlaps with ABCD1 in vivo: overexpression of ABCD2 in Abcd1-knockout mice prevents VLCFA accumulation and neurodegenerative pathology (axonal damage followed by myelin degeneration). Double Abcd1/Abcd2 knockout mice display earlier onset and more severe disease, including inflammatory reaction, demonstrating functional redundancy between the two transporters. |
Transgenic overexpression of ABCD2 in Abcd1-KO mice, Abcd1/Abcd2 double knockout generation, histopathology, VLCFA measurement |
Human molecular genetics |
High |
15489218
|
| 2005 |
Abcd2-knockout mice develop late-onset cerebellar and sensory ataxia with loss of Purkinje cells and dorsal root ganglia degeneration, correlating with VLCFA accumulation in those cells. The underlying pathological mechanism involves mitochondrial, Golgi, and endoplasmic reticulum damage, demonstrating disturbed organelle cross-talk as a downstream consequence of ABCD2 loss. |
Abcd2-knockout mouse generation and characterization, histopathology, electron microscopy of organelles, VLCFA measurement |
Human molecular genetics |
High |
16223892
|
| 2005 |
LXRα acts as a negative modulator of Abcd2 expression by competing with SREBP1c at overlapping SRE/DR-4 binding sites in the Abcd2 promoter. SREBP1c induces adipose Abcd2, while concurrent LXRα activation suppresses hepatic Abcd2. LXRα/β-deficient mice show greatly elevated Abcd2 induction, confirming LXRα as a repressor. |
EMSA with nuclear extracts, LXRα/β-knockout mice, fasting-refeeding and cholesterol loading paradigms, cell culture reporter assays |
The Journal of biological chemistry |
High |
16249184
|
| 2006 |
ABCD2 (ALDRP) expressed in Sf21 insect cells via baculovirus shows ATPase activity in membrane fractions and nucleotide-binding capacity. Unlike ABCD1 which binds both ADP and ATP, ABCD2 binds ADP but has negligible affinity for ATP, suggesting functional differences in nucleotide binding between the two paralogs. |
Baculovirus-mediated overexpression in Sf21 cells, ATPase activity assay, ATP/ADP-agarose binding, immunoelectron microscopy, subcellular fractionation |
Biological & pharmaceutical bulletin |
Medium |
16946495
|
| 2007 |
Loss of Abcd2 (not Abcd1) causes oxidative damage in the mouse adrenal gland: Abcd2 knockout mice show increased mitochondrial manganese superoxide dismutase immunoreactivity and spontaneous premature ceroid deposition (a marker of oxidative damage) predominantly in adrenal medullary cells, indicating a specific role for ABCD2 in limiting oxidative stress in adrenal tissue. |
Abcd1 and Abcd2 single/double knockout mice, immunohistochemistry for oxidative stress markers (MnSOD, ceroid), comparative genotype analysis |
Laboratory investigation |
Medium |
17260006
|
| 2007 |
DHEA induces Abcd2 and Abcd3 expression in rodent liver in vivo and in primary rat hepatocytes in vitro, but this induction of Abcd2 is independent of PPARα (unlike Abcd3), revealing a PPARα-independent pathway for ABCD2 regulation. |
In vivo DHEA treatment, primary hepatocyte cultures, PPARα-knockout mice comparison, RT-PCR |
Biochimie |
Medium |
17686565
|
| 2008 |
ABCD2 plays a role in degradation of long-chain saturated and omega-9 monounsaturated fatty acids and in the synthesis of docosahexaenoic acid (DHA). Abcd2-knockout mouse brain slices show defective VLCFA β-oxidation ex vivo using radiolabeled hexacosanoic acid and DHA precursor, distinct from the substrate profile of Abcd1-knockout. |
Fatty acid profiling in knockout mouse organs and primary neurons, radiolabeled β-oxidation assay in brain slices, dietary challenge experiments |
American journal of physiology. Endocrinology and metabolism |
High |
18854420
|
| 2008 |
TRα and TRβ bind the overlapping SRE/DR-4 motif in the ABCD2 promoter and differentially modulate SREBP1-dependent ABCD2 activation: unliganded TRβ (but not TRα) represses ABCD2 independently of DNA binding, while T3-dependent activation requires TRα and intact SRE/DR-4 motifs. EMSA with nuclear extracts supports direct TR-SREBP1 interaction at this element. |
EMSA, TRα and TRβ knockout mice, T3 manipulation (fasting/refeeding), reporter gene assays, RT-PCR in liver |
European journal of cell biology |
High |
18834645
|
| 2008 |
Silencing of Abcd1 and Abcd2 by siRNA in mouse primary astrocytes causes VLCFA accumulation and induces an inflammatory response (iNOS, inflammatory cytokines) mediated by NF-κB, AP-1, and C/EBP transcription factors, establishing a direct link between peroxisomal VLCFA accumulation (mediated by ABCD2 deficiency) and neuroinflammatory signaling. |
siRNA knockdown of Abcd1/Abcd2 in primary astrocytes, VLCFA measurement, inflammatory marker expression, transcription factor activity assays |
Journal of lipid research |
Medium |
18723473
|
| 2009 |
TRβ-selective thyromimetics (GC-1, CGS 23425) induce ABCD2 expression dose-dependently via the ABCD2 promoter thyroid hormone response element, and maintain prolonged induction (up to 10 days) in X-ALD fibroblasts compared to T3 alone, demonstrating that the TRβ pathway can be selectively targeted for sustained ABCD2 upregulation. |
Reporter gene assay, RT-qPCR in HepG2 cells and X-ALD fibroblasts, dose-response with selective TRβ agonists |
The Journal of steroid biochemistry and molecular biology |
Medium |
19406244
|
| 2010 |
ABCD2 is highly abundant in adipose tissue (>50-fold higher than brain/adrenal) and is upregulated during adipogenesis. In Abcd2-knockout mice, adipose tissue accumulates 20:1 and 22:1 fatty acids, and dietary erucic acid (C22:1) accumulates in adipose in a gene-dosage-dependent manner, demonstrating that ABCD2 opposes accumulation of monounsaturated very-long-chain fatty acids in fat. |
Immunoblotting (quantitative), adipogenesis assay in D2-deficient MEFs, dietary erucic acid challenge with fatty acid profiling in knockout mice |
Journal of lipid research |
High |
19556607
|
| 2010 |
Human ABCD1 and ABCD2 can both function as homodimers when expressed in pxa1/pxa2Δ yeast lacking peroxisomal fatty acid import. They have distinct substrate specificities: ABCD2 rescues β-oxidation best with C22:0, C24:6, and especially C22:6 (DHA), while ABCD1 rescues best with C24:0 and C26:0, demonstrating differential substrate specificity between the two paralogs. |
Functional complementation of S. cerevisiae pxa1/pxa2Δ mutant with human ABCD1 or ABCD2, β-oxidation assays with specific radiolabeled fatty acid substrates, growth assays on oleate |
Biochimica et biophysica acta |
High |
21145416
|
| 2011 |
ABCD2 (ALDRP) physically interacts with ABCD1 (ALDP): proximity ligation assays and co-immunoprecipitation demonstrate a direct physical interaction. Expression of a non-functional ALDRP-EGFP fusion exerts a transdominant-negative effect on ABCD1 function. ABCD2 has redundant substrate activity for saturated VLCFA (C26:0, C24:0) and monounsaturated VLCFA, but a specific role in DHA (C22:6n-3) metabolism. |
Proximity ligation assay, co-immunoprecipitation, inducible dose-dependent expression of wild-type vs. mutant ALDRP-EGFP, fatty acid profiling in phospholipids, β-oxidation assays with C26:0, C24:0, and DHA |
The Journal of biological chemistry |
High |
21209459
|
| 2013 |
ABCD2 is a direct transcriptional target of the β-catenin/TCF-4 (Wnt signaling) pathway. Two functional TCF-4 binding elements were identified in the ABCD2 promoter (positions -360 to -260); mutation of either or both reduced promoter activity. Chromatin immunoprecipitation confirmed direct β-catenin binding to the ABCD2 promoter. Ectopic β-catenin/TCF-4 expression increased ABCD2 mRNA and reduced VLCFA levels. |
In silico promoter analysis, luciferase reporter assays, site-directed mutagenesis, chromatin immunoprecipitation (ChIP), RT-PCR, VLCFA measurement |
PloS one |
High |
23437103
|
| 2014 |
Abcd2 acts as a strong modifier of VLCFA metabolism in peritoneal macrophages: Abcd1/Abcd2 double-deficient macrophages accumulate VLCFA ~6-fold compared to wild-type (vs. ~2-fold for Abcd1-single deficiency), and show peroxisomal β-oxidation reduced to 29% of wild-type (vs. 62% for Abcd1-single deficiency). Single Abcd2 deficiency alone does not compromise β-oxidation of C26:0, demonstrating ABCD2 functions as a compensatory transporter for VLCFA import in macrophages. |
Thioglycollate-elicited peritoneal macrophages from single and double knockout mice, GC-MS VLCFA quantification, peroxisomal β-oxidation assay, RT-PCR |
PloS one |
High |
25255441
|
| 2014 |
ABCD2 localizes to a distinct subclass of microperoxisomes (~200 nm) in mouse adipose tissue that lack classical peroxisome markers (catalase, PEX19, ABCD3). Immunoisolation and proteomic profiling of D2-containing organelles revealed associated proteins from peroxisome, ER, and mitochondria, suggesting physical association of this ABCD2-containing compartment with mitochondria and ER. |
Subcellular fractionation, electron microscopy, immunoisolation, proteomics/mass spectrometry, immunofluorescence with PEX19 and D2 antibodies |
Biochemical and biophysical research communications |
Medium |
25446110
|
| 2014 |
LXR antagonists (GSK17, 22S-hydroxycholesterol) induce ABCD2 expression in human hepatoma cells and X-ALD fibroblasts, accompanied by decreased oxidative stress. In vivo, 22S-HC treatment of rats induces hepatic Abcd2. This confirms that LXR acts as a repressor of ABCD2 and that its antagonism can upregulate ABCD2 expression with functional consequences. |
Cell treatment with LXR antagonists/agonists, RT-PCR, oxidative stress assays, in vivo rat treatment, multiple tissue expression array |
Biochimica et biophysica acta |
Medium |
24239766
|
| 2014 |
ABCD2 modulates PPARα signaling: D2-deficient mice show altered gene expression clusters associated with lipid metabolism including PPARα signaling. Knockdown of D2 in 3T3-L1 adipocytes (which express high D2 levels) modifies genomic responses to fibrate treatment, though these effects are not sufficient to alter fibrate effects on diet-induced obesity phenotypes in vivo. |
D2-knockout mice with fenofibrate treatment, gene expression profiling, siRNA knockdown in 3T3-L1 adipocytes, dietary obesity model |
Molecular pharmacology |
Medium |
25123288
|
| 2016 |
ABCD2 upregulation by metformin is dependent on AMPKα1: metformin activates AMPKα1 in X-ALD fibroblasts and induces ABCD2 protein levels in vitro and in vivo (brain and spinal cord of Abcd1-KO mice). Metformin-induced ABCD2 induction is abrogated in AMPKα1-KO mouse primary glial cells, establishing AMPKα1 as a required mediator of metformin-induced ABCD2 expression. |
Pharmacological AMPK activation, AMPKα1-knockout mouse glial cells, western blotting, in vivo metformin treatment, VLCFA measurement |
Journal of neurochemistry |
Medium |
26849413
|
| 2018 |
ABCD2 knockdown in human OA chondrocytes causes VLCFA accumulation, apoptotic cell death, altered miRNA profiles, and decreased ACSL4 expression. The regulatory network ABCD2→miR-141→ACSL4 serves as a novel regulator of cartilage lipid homeostasis, and ACSL4 loss promotes MMP-13 expression and cartilage degradation. |
ABCD2 siRNA knockdown in human chondrocytes, VLCFA profiling, miRNA array, ACSL4 knockdown (in vitro and in vivo in mouse OA model), zebrafish morpholino knockdown of ACSL4 homolog |
Cell biochemistry and function |
Medium |
30264402
|
| 2019 |
CRISPR/Cas9-mediated double knockout of Abcd1 and Abcd2 in BV-2 microglial cells results in VLCFA accumulation and lipid inclusions similar to brain macrophages of X-ALD patients. Single Abcd2 knockout alone does not cause VLCFA accumulation, while double deficiency markedly increases cholesterol and neutral lipids and alters expression of microglial function genes (Trem2), demonstrating functional redundancy in microglia. |
CRISPR/Cas9 double knockout in murine BV-2 microglia, electron microscopy, lipid profiling (cholesterol, neutral lipids, VLCFA), RT-PCR for microglial gene expression |
Biochimica et biophysica acta. Molecular and cell biology of lipids |
Medium |
30769094
|
| 2025 |
ABCD2 participates in an ABCD2/PEX2/ATGL axis regulating hepatocellular fatty acid metabolic reprogramming in MASLD. Gene overexpression validated that the herbal formula JTTZF downregulates peroxisomal ABCD2, and ABCD2 overexpression independently reduces lipid droplets and ROS in oleic/palmitic acid-treated HepG2 cells. |
Multi-omics (transcriptomics, proteomics) in HFD mouse model, ABCD2 overexpression in HepG2 cells, ROS flow cytometry, DHE staining, western blotting, immunohistochemistry |
Phytomedicine |
Low |
40674914
|