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Nature Communications May 2024The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in...
The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
Topics: Animals; Liver; Mice, Knockout; Mice; Acyl-CoA Oxidase; Obesity; Male; Insulin Resistance; Mice, Inbred C57BL; Oxidation-Reduction; Lipid Metabolism; Adipose Tissue; Diet, High-Fat; Energy Metabolism; Fatty Acids; Receptors, G-Protein-Coupled
PubMed: 38760332
DOI: 10.1038/s41467-024-48471-2 -
Brain : a Journal of Neurology Jun 2024The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts...
The peroxisomal disease adrenoleukodystrophy (X-ALD) is caused by loss of the transporter of very-long-chain fatty acids (VLCFAs), ABCD1. An excess of VLCFAs disrupts essential homeostatic functions crucial for axonal maintenance, including redox metabolism, glycolysis and mitochondrial respiration. As mitochondrial function and morphology are intertwined, we set out to investigate the role of mitochondrial dynamics in X-ALD models. Using quantitative 3D transmission electron microscopy, we revealed mitochondrial fragmentation in corticospinal axons in Abcd1- mice. In patient fibroblasts, an excess of VLCFAs triggers mitochondrial fragmentation through the redox-dependent phosphorylation of DRP1 (DRP1S616). The blockade of DRP1-driven fission by the peptide P110 effectively preserved mitochondrial morphology. Furthermore, mRNA inhibition of DRP1 not only prevented mitochondrial fragmentation but also protected axonal health in a Caenorhabditis elegans model of X-ALD, underscoring DRP1 as a potential therapeutic target. Elevated levels of circulating cell-free mtDNA in patients' CSF align this leukodystrophy with primary mitochondrial disorders. Our findings underscore the intricate interplay between peroxisomal dysfunction, mitochondrial dynamics and axonal integrity in X-ALD, shedding light on potential avenues for therapeutic intervention.
Topics: Adrenoleukodystrophy; Animals; Mitochondrial Dynamics; Humans; Mice; Dynamins; ATP Binding Cassette Transporter, Subfamily D, Member 1; Caenorhabditis elegans; Mitochondria; Axons; Fibroblasts; Male; DNA, Mitochondrial; Disease Models, Animal; Pyramidal Tracts; Peptide Fragments; GTP Phosphohydrolases
PubMed: 38763511
DOI: 10.1093/brain/awae038 -
Advances in Experimental Medicine and... May 2024One of the functions of peroxisomes is the oxidation of fatty acids (FAs). The importance of this function in our lives is evidenced by the presence of peroxisomal...
One of the functions of peroxisomes is the oxidation of fatty acids (FAs). The importance of this function in our lives is evidenced by the presence of peroxisomal disorders caused by the genetic deletion of proteins involved in these processes. Unlike mitochondrial oxidation, peroxisomal oxidation is not directly linked to ATP production. What is the role of FA oxidation in peroxisomes? Recent studies have revealed that peroxisomes supply the building blocks for lipid synthesis in the endoplasmic reticulum and facilitate intracellular carbon recycling for membrane quality control. Accumulation of very long-chain fatty acids (VLCFAs), which are peroxisomal substrates, is a diagnostic marker in many types of peroxisomal disorders. However, the relationship between VLCFA accumulation and various symptoms of these disorders remains unclear. Recently, we developed a method for solubilizing VLCFAs in aqueous media and found that VLCFA toxicity could be mitigated by oleic acid replenishment. In this chapter, we present the physiological role of peroxisomal FA oxidation and the knowledge obtained from VLCFA-accumulating peroxisome-deficient cells.
PubMed: 38811487
DOI: 10.1007/5584_2024_802 -
Orphanet Journal of Rare Diseases Mar 2024Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of...
BACKGROUND
Adrenoleukodystrophy (ALD) is a multifaceted, X-linked, neurodegenerative disorder that comprises several clinical phenotypes. ALD affects patients through a variety of physical, emotional, social, and other disease-specific factors that collectively contribute to disease burden. To facilitate clinical care and research, it is important to identify which symptoms are most common and relevant to individuals with any subtype of ALD.
METHODS
We conducted semi-structured qualitative interviews and an international cross-sectional study to determine the most prevalent and important symptoms of ALD. Our study included adult participants with a diagnosis of ALD who were recruited from national and international patient registries. Responses were categorized by age, sex, disease phenotype, functional status, and other demographic and clinical features.
RESULTS
Seventeen individuals with ALD participated in qualitative interviews, providing 1709 direct quotes regarding their symptomatic burden. One hundred and nine individuals participated in the cross-sectional survey study, which inquired about 182 unique symptoms representing 24 distinct symptomatic themes. The symptomatic themes with the highest prevalence in the overall ALD sample cohort were problems with balance (90.9%), limitations with mobility or walking (87.3%), fatigue (86.4%), and leg weakness (86.4%). The symptomatic themes with the highest impact scores (on a 0-4 scale with 4 being the most severe) were trouble getting around (2.35), leg weakness (2.25), and problems with balance (2.21). A higher prevalence of symptomatic themes was associated with functional disability, employment disruption, and speech impairment.
CONCLUSIONS
There are many patient-relevant symptoms and themes that contribute to disease burden in individuals with ALD. These symptoms, identified by those having ALD, present key targets for further research and therapeutic development.
Topics: Adult; Humans; Cross-Sectional Studies; Adrenoleukodystrophy; Phenotype; Surveys and Questionnaires; Patient Reported Outcome Measures
PubMed: 38504253
DOI: 10.1186/s13023-024-03129-6 -
Biomolecules Nov 2023Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore,...
Elevated levels of saturated very long-chain fatty acids (VLCFAs) in cell membranes and secreted lipoparticles have been associated with neurotoxicity and, therefore, require tight regulation. Excessive VLCFAs are imported into peroxisomes for degradation by β-oxidation. Impaired VLCFA catabolism due to primary or secondary peroxisomal alterations is featured in neurodegenerative and neuroinflammatory disorders such as X-linked adrenoleukodystrophy and multiple sclerosis (MS). Here, we identified that healthy human macrophages upregulate the peroxisomal genes involved in β-oxidation during myelin phagocytosis and pro-inflammatory activation, and that this response is impaired in peripheral macrophages and phagocytes in brain white matter lesions in MS patients. The pharmacological targeting of VLCFA metabolism and peroxisomes in innate immune cells could be favorable in the context of neuroinflammation and neurodegeneration. We previously identified the epigenetic histone deacetylase (HDAC) inhibitors entinostat and vorinostat to enhance VLCFA degradation and pro-regenerative macrophage polarization. However, adverse side effects currently limit their use in chronic neuroinflammation. Here, we focused on tefinostat, a monocyte/macrophage-selective HDAC inhibitor that has shown reduced toxicity in clinical trials. By using a gene expression analysis, peroxisomal β-oxidation assay, and live imaging of primary human macrophages, we assessed the efficacy of tefinostat in modulating VLCFA metabolism, phagocytosis, chemotaxis, and immune function. Our results revealed the significant stimulation of VLCFA degradation with the upregulation of genes involved in peroxisomal β-oxidation and interference with immune cell recruitment; however, tefinostat was less potent than the class I HDAC-selective inhibitor entinostat in promoting a regenerative macrophage phenotype. Further research is needed to fully explore the potential of class I HDAC inhibition and downstream targets in the context of neuroinflammation.
Topics: Humans; Histone Deacetylase Inhibitors; ATP-Binding Cassette Transporters; Neuroinflammatory Diseases; Fatty Acids; ATP Binding Cassette Transporter, Subfamily D, Member 1; Fatty Acids, Nonesterified; Macrophages; Immunity
PubMed: 38136568
DOI: 10.3390/biom13121696 -
Neurogenetics Oct 2023Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous...
Leukodystrophies (LDs) are a heterogeneous group of progressive neurological disorders and characterized by primary involvement of white matter of the central nervous system (CNS). This is the first report of the Iranian LD Registry database to describe the clinical, radiological, and genomic data of Persian patients with leukodystrophies. From 2016 to 2019, patients suspicious of LDs were examined followed by a brain magnetic resonance imaging (MRI). A single gene testing or whole-exome sequencing (WES) was used depending on the neuroradiologic phenotypes. In a few cases, the diagnosis was made by metabolic studies. Based on the MRI pattern, diagnosed patients were divided into cohorts A (hypomyelinating LDs) versus cohort B (Other LDs). The most recent LD classification was utilized for classification of diagnosed patients. For novel variants, in silico analyses were performed to verify their pathogenicity. Out of 680 registered patients, 342 completed the diagnostic evaluations. In total, 245 patients met a diagnosis which in turn 24.5% were categorized in cohort A and the remaining in cohort B. Genetic tests revealed causal variants in 228 patients consisting of 213 variants in 110 genes with 78 novel variants. WES and single gene testing identified a causal variant in 65.5% and 34.5% cases, respectively. The total diagnostic rate of WES was 60.7%. Lysosomal disorders (27.3%; GM2-gangliosidosis-9.8%, MLD-6.1%, KD-4.5%), amino and organic acid disorders (17.15%; Canavan disease-4.5%, L-2-HGA-3.6%), mitochondrial leukodystrophies (12.6%), ion and water homeostasis disorders (7.3%; MLC-4.5%), peroxisomal disorders (6.5%; X-ALD-3.6%), and myelin protein disorders (3.6%; PMLD-3.6%) were the most commonly diagnosed disorders. Thirty-seven percent of cases had a pathogenic variant in nine genes (ARSA, HEXA, ASPA, MLC1, GALC, GJC2, ABCD1, L2HGDH, GCDH). This study highlights the most common types as well as the genetic heterogeneity of LDs in Iranian children.
Topics: Humans; Child; Iran; Genetic Heterogeneity; Demyelinating Diseases; Magnetic Resonance Imaging; Brain; Neurodegenerative Diseases; Alcohol Oxidoreductases
PubMed: 37597066
DOI: 10.1007/s10048-023-00730-y -
The Journal of Clinical Investigation Apr 2024Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an...
Dicarboxylic fatty acids are generated in the liver and kidney in a minor pathway called fatty acid ω-oxidation. The effects of consuming dicarboxylic fatty acids as an alternative source of dietary fat have not been explored. Here, we fed dodecanedioic acid, a 12-carbon dicarboxylic (DC12), to mice at 20% of daily caloric intake for nine weeks. DC12 increased metabolic rate, reduced body fat, reduced liver fat, and improved glucose tolerance. We observed DC12-specific breakdown products in liver, kidney, muscle, heart, and brain, indicating that oral DC12 escaped first-pass liver metabolism and was utilized by many tissues. In tissues expressing the "a" isoform of acyl-CoA oxidase-1 (ACOX1), a key peroxisomal fatty acid oxidation enzyme, DC12 was chain shortened to the TCA cycle intermediate succinyl-CoA. In tissues with low peroxisomal fatty acid oxidation capacity, DC12 was oxidized by mitochondria. In vitro, DC12 was catabolized even by adipose tissue and was not stored intracellularly. We conclude that DC12 and other dicarboxylic acids may be useful for combatting obesity and for treating metabolic disorders.
PubMed: 38687608
DOI: 10.1172/JCI174186 -
Pharmacological Research Mar 2024Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of...
Chronic interstitial fibrosis presents a significant challenge to the long-term survival of transplanted kidneys. Our research has shown that reduced expression of acyl-coenzyme A oxidase 1 (ACOX1), which is the rate-limiting enzyme in the peroxisomal fatty acid β-oxidation pathway, contributes to the development of fibrosis in renal allografts. ACOX1 deficiency leads to lipid accumulation and excessive oxidation of polyunsaturated fatty acids (PUFAs), which mediate epithelial-mesenchymal transition (EMT) and extracellular matrix (ECM) reorganization respectively, thus causing fibrosis in renal allografts. Furthermore, activation of Toll-like receptor 4 (TLR4)-nuclear factor kappa-B (NF-κB) signaling induced ACOX1 downregulation in a DNA methyltransferase 1 (DNMT1)-dependent manner. Overconsumption of PUFA resulted in endoplasmic reticulum (ER) stress, which played a vital role in facilitating ECM reorganization. Supplementation with PUFAs contributed to delayed fibrosis in a rat model of renal transplantation. The study provides a novel therapeutic approach that can delay chronic interstitial fibrosis in renal allografts by targeting the disorder of lipid metabolism.
Topics: Animals; Rats; Acyl-CoA Oxidase; Allografts; Fibrosis; Kidney; Kidney Transplantation; Lipids; Metabolic Diseases
PubMed: 38367917
DOI: 10.1016/j.phrs.2024.107105 -
Orphanet Journal of Rare Diseases Aug 2023X-linked adrenoleukodystrophy (ALD) is a rare metabolic and neurodegenerative disorder belonging to the group of leukodystrophies, with an estimated incidence around...
BACKGROUND
X-linked adrenoleukodystrophy (ALD) is a rare metabolic and neurodegenerative disorder belonging to the group of leukodystrophies, with an estimated incidence around 1:25 000 newborns worldwide, mostly among men. Childhood Cerebral ALD (CCALD) is the most severe form with a poor prognosis if not properly treated during the first years of life. Currently, only allogeneic hematopoietic stem cell transplantation (allo-HSCT) is widely available for CCALD treatment. To date, there is a lack of data regarding CCALD epidemiology, natural history, and current management in France. This knowledge is crucial for the development of new therapies such as gene therapies. In this context, the French National Health Data System (SNDS) is a particularly indicated database to collect information meeting these needs. A non-interventional, national, real-life, retrospective study was performed using secondary data from the national ALD registry (LEUKOFRANCE) and SNDS. CCALD patients detected between 2009 and 2018 and successfully matched between LEUKOFRANCE and SNDS were included in this study. Index date was defined as the first CCALD event detected during study period. Subgroups of patients with sufficient follow-up (6 months) and history (1 year) available around index date were analyzed to assess CCALD burden and natural history.
RESULTS
52 patients were included into the matched cohort. Median annual incidence of CCALD was estimated at 4 patients. Median age at CCALD diagnosis was 7.0 years. Among patients without allo-HSCT, five-year overall survival was 66.6%, with 93.3% of them presenting at least one CCALD symptom and 62.1% presenting a least one major functional disability (MFD). Among patients with allo-HSCT, five-year overall survival was 94.4%, with only 11.1% of patients presenting CCALD symptoms, and 16.7% of presenting a MFD. Mean annualized costs were almost twice as important among patients without allo-HSCT, with 49,211€, 23,117€, respectively. Costs were almost exclusively represented by hospitalizations.
CONCLUSIONS
To the best of our knowledge, this is the most up to date study analyzing CCALD epidemiology, clinical and economic burden in France. The necessity of a precocious management with HSCT highlight the potential benefits of including an expanded screening program among newborns, coupled with family screenings when a mutation is detected.
Topics: Male; Humans; Child; Infant, Newborn; Adrenoleukodystrophy; Retrospective Studies; Hematopoietic Stem Cell Transplantation; France; Cost of Illness
PubMed: 37563635
DOI: 10.1186/s13023-023-02843-x -
Journal of Pediatric Nursing 2023Adrenoleukodystrophy (ALD) is an x-linked genetic condition with a high risk of adrenal dysfunction recommended for newborn screening. This review aims to critically... (Review)
Review
PROBLEM
Adrenoleukodystrophy (ALD) is an x-linked genetic condition with a high risk of adrenal dysfunction recommended for newborn screening. This review aims to critically appraise and synthesize existing literature identifying the impacts of ALD newborn screening in the United States on the evaluation and treatment of adrenal dysfunction in male children.
ELIGIBILITYCRITERIA
An integrative literature review was conducted using the Embase, PubMed, and CINAHL databases. English-language primary source studies published in the past decade and seminal studies were included.
SAMPLE
Twenty primary sources met the inclusion criteria, including five seminal studies.
RESULTS
Three major themes emerged from the review: 1) prevention of adrenal crisis, 2) unexpected outcomes, and 3) ethical impacts.
CONCLUSIONS
ALD screening increases disease identification. Serial adrenal evaluation prevents adrenal crisis and death; data is needed to establish predictive outcomes in ALD prognosis. Disease incidence and prognosis will become more apparent as states increasingly add ALD screening to their newborn panel.
IMPLICATIONS FOR PRACTICE
Clinicians need awareness of ALD newborn screening and state screening protocols. Families first learning of ALD through newborn screening results will require education, support, and timely referrals for appropriate care.
Topics: Infant, Newborn; Humans; Male; Child; Adrenoleukodystrophy; Neonatal Screening; Adrenal Insufficiency
PubMed: 37331834
DOI: 10.1016/j.pedn.2023.06.005