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Brain : a Journal of Neurology Apr 2024Acyl-CoA binding domain containing 5 (ACBD5) is a critical player in handling very long chain fatty acids (VLCFA) en route for peroxisomal β-oxidation. Mutations in...
Acyl-CoA binding domain containing 5 (ACBD5) is a critical player in handling very long chain fatty acids (VLCFA) en route for peroxisomal β-oxidation. Mutations in ACBD5 lead to the accumulation of VLCFA and patients present retinal dystrophy, ataxia, psychomotor delay and a severe leukodystrophy. Using CRISPR/Cas9, we generated and characterized an Acbd5 Gly357* mutant allele. Gly357* mutant mice recapitulated key features of the human disorder, including reduced survival, impaired locomotion and reflexes, loss of photoreceptors, and demyelination. The ataxic presentation of Gly357* mice involved the loss of cerebellar Purkinje cells and a giant axonopathy throughout the CNS. Lipidomic studies provided evidence for the extensive lipid dysregulation caused by VLCFA accumulation. Following a proteomic survey, functional studies in neurons treated with VLCFA unravelled a deregulated cytoskeleton with reduced actin dynamics and increased neuronal filopodia. We also show that an adeno-associated virus-mediated gene delivery ameliorated the gait phenotypes and the giant axonopathy, also improving myelination and astrocyte reactivity. Collectively, we established a mouse model with significance for VLCFA-related disorders. The development of relevant neuropathological outcomes enabled the understanding of mechanisms modulated by VLCFA and the evaluation of the efficacy of preclinical therapeutic interventions.
Topics: Humans; Mice; Animals; Fatty Acids; Dependovirus; Proteomics; Ataxia; Genetic Therapy; Adrenoleukodystrophy
PubMed: 38066620
DOI: 10.1093/brain/awad407 -
Journal of Human Nutrition and... Aug 2023Adrenoleukodystrophy (ALD) is a rare X-linked metabolic disorder that causes the accumulation of very-long-chain fatty acids (VLCFAs) (C26:0) and the subsequent variety...
BACKGROUND
Adrenoleukodystrophy (ALD) is a rare X-linked metabolic disorder that causes the accumulation of very-long-chain fatty acids (VLCFAs) (C26:0) and the subsequent variety of clinical and neurological symptoms. Little is known about nutritional status and dietary habits of children affected by ALD, and so the present study aimed to assess nutritional status and food intake in children with ALD, also exploring the relationship between food intake and the consumption of disease-specific dietary supplements to reduce blood C26:0 concentrations and increase monounsaturated fatty acids (C26:1).
METHODS
All patients underwent a clinical and neurological evaluation and a comprehensive nutritional assessment. The association of VLCFA concentrations with dietary lipids was assessed.
RESULTS
Nine boys (11.49 ± 3.61 years) were enrolled in a cross-sectional study. All patients were normal weight, with normal resting energy expenditure. Only six of nine patients followed the low-fat diet and dietary supplements. An inverse association was found between the food intake of polyunsaturated lipids and C26:0; conversely, the C26:0 was positively associated with the dietary saturated lipids. When consumed, dietary supplement consumption correlated positively with C26:1 (ρ = 0.917, p = 0.029) and no correlation was found with C26:0 (ρ = 0.410, p = 0,493).
CONCLUSIONS
No children were found to be malnourished or overweight or obese; however, half of the children reported excessive body fat, probably as a result of the pharmacotherapies. A low-fat diet could be adjuvant in the management of the accumulation of VLCFAs, but poor dietary compliance to disease-specific nutritional guidelines appears to be a major problem of this condition and underlines the need for a structured and personalised nutritional management in ALD disease.
Topics: Male; Humans; Adrenoleukodystrophy; Nutritional Status; Cross-Sectional Studies; Dietary Fats; Fatty Acids
PubMed: 36991579
DOI: 10.1111/jhn.13173 -
Biology Direct Feb 2024Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast,... (Meta-Analysis)
Meta-Analysis
Peroxisomes are primarily studied in the brain, kidney, and liver due to the conspicuous tissue-specific pathology of peroxisomal biogenesis disorders. In contrast, little is known about the role of peroxisomes in other tissues such as the heart. In this meta-analysis, we explore mitochondrial and peroxisomal gene expression on RNA and protein levels in the brain, heart, kidney, and liver, focusing on lipid metabolism. Further, we evaluate a potential developmental and heart region-dependent specificity of our gene set. We find marginal expression of the enzymes for peroxisomal fatty acid oxidation in cardiac tissue in comparison to the liver or cardiac mitochondrial β-oxidation. However, the expression of peroxisome biogenesis proteins in the heart is similar to other tissues despite low levels of peroxisomal fatty acid oxidation. Strikingly, peroxisomal targeting signal type 2-containing factors and plasmalogen biosynthesis appear to play a fundamental role in explaining the essential protective and supporting functions of cardiac peroxisomes.
Topics: Humans; Peroxisomes; Fatty Acids; Peroxisomal Disorders; Mitochondria; Oxidation-Reduction
PubMed: 38365851
DOI: 10.1186/s13062-024-00458-1 -
JNMA; Journal of the Nepal Medical... Feb 2024Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction...
UNLABELLED
Zellweger syndrome is an autosomal recessive disease within the spectrum of peroxisome biogenesis disorder manifesting in the neonatal period with profound dysfunction of the central nervous system, liver and kidney. Common clinical presentations include hypotonia, seizure, hepatomegaly, craniofacial dysmorphism and early death. Mutation in one of the PEX genes coding for a peroxisome assembly protein creates a functionally incompetent organelle causing accumulation of very long chain fatty acids in various organs. Here we report the case of a 5-month-old male presented at birth with hypotonia, poor feeding, gross congenital anomalies and later during early infancy with failure to thrive, several episodes of seizures, aspiration due to feeding difficulties and recurrent severe pneumonia. A whole genomic sequencing brought us to the final diagnosis of Zellweger syndrome. Despite an absence of treatment options, prompt diagnosis of Zellweger syndrome is important for providing appropriate symptomatic care, definitive genetic testing and prenatal counselling.
KEYWORDS
case reports; mutation; neonate; Zellweger syndrome.
Topics: Infant, Newborn; Humans; Male; Infant; Zellweger Syndrome; Muscle Hypotonia; Peroxisomal Disorders; Genetic Testing; Mutation
PubMed: 38409970
DOI: 10.31729/jnma.8467 -
Molecular Neurobiology Feb 2024Phytanic acid (PA) (3,7,11,15-tetramethylhexadecanoic acid) is a methyl-branched fatty acid that enters the body through food consumption, primarily through red meat,... (Review)
Review
Phytanic acid (PA) (3,7,11,15-tetramethylhexadecanoic acid) is a methyl-branched fatty acid that enters the body through food consumption, primarily through red meat, dairy products, and fatty marine foods. The metabolic byproduct of phytol is PA, which is then oxidized by the ruminal microbiota and some marine species. The first methyl group at the 3-position prevents the β-oxidation of branched-chain fatty acid (BCFA). Instead, α-oxidation of PA results in the production of pristanic acid (2,10,14-tetramethylpentadecanoic acid) with CO. This fatty acid (FA) builds up in individuals with certain peroxisomal disorders and is historically linked to neurological impairment. It also causes oxidative stress in synaptosomes, as demonstrated by an increase in the production of reactive oxygen species (ROS), which is a sign of oxidative stress. This review concludes that the nutraceuticals (melatonin, piperine, quercetin, curcumin, resveratrol, epigallocatechin-3-gallate (EGCG), coenzyme Q10, ω-3 FA) can reduce oxidative stress and enhanced the activity of mitochondria. Furthermore, the use of nutraceuticals completely reversed the neurotoxic effects of PA on NO level and membrane potential. Additionally, the review further emphasizes the urgent need for more research into dairy-derived BCFAs and their impact on human health.
PubMed: 38374317
DOI: 10.1007/s12035-024-03985-0 -
American Journal of Physiology.... May 2024Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs... (Review)
Review
Fatty acid oxidation (FAO) releases the energy stored in fat to maintain basic biological processes. Dehydrogenation is a major way to oxidize fatty acids, which needs NAD to accept the released H from fatty acids and form NADH, which increases the ratio of NADH/NAD and consequently inhibits FAO leading to the deposition of fat in the liver, which is termed fatty liver or steatosis. Consumption of alcohol (ethanol) initiates simple steatosis that progresses to alcoholic steatohepatitis, which constitutes a spectrum of liver disorders called alcohol-associated liver disease (ALD). ALD is linked to ethanol metabolism. Ethanol is metabolized by alcohol dehydrogenase (ADH), microsomal ethanol oxidation system (MEOS), mainly cytochrome P450 2E1 (CYP2E1), and catalase. ADH also requires NAD to accept the released H from ethanol. Thus, ethanol metabolism by ADH leads to increased ratio of NADH/NAD, which inhibits FAO and induces steatosis. CYP2E1 directly consumes reducing equivalent NADPH to oxidize ethanol, which generates reactive oxygen species (ROS) that lead to cellular injury. Catalase is mainly present in peroxisomes, where very long-chain fatty acids and branched-chain fatty acids are oxidized, and the resultant short-chain fatty acids will be further oxidized in mitochondria. Peroxisomal FAO generates hydrogen peroxide (HO), which is locally decomposed by catalase. When ethanol is present, catalase uses HO to oxidize ethanol. In this review, we introduce FAO (including α-, β-, and ω-oxidation) and ethanol metabolism (by ADH, CYP2E1, and catalase) followed by the interaction between FAO and ethanol metabolism in the liver and its pathophysiological significance.
Topics: Humans; Catalase; NAD; Cytochrome P-450 CYP2E1; Hydrogen Peroxide; Fatty Liver; Ethanol; Liver Diseases, Alcoholic; Fatty Acids
PubMed: 38573193
DOI: 10.1152/ajpgi.00281.2023 -
Indian Journal of Pediatrics May 2024Zellweger syndrome or cerebrohepatorenal syndrome is a rare, multisystem disorder occurring due to defect in metabolic pathway within the peroxisomes. Cirrhosis with...
Zellweger syndrome or cerebrohepatorenal syndrome is a rare, multisystem disorder occurring due to defect in metabolic pathway within the peroxisomes. Cirrhosis with portal hypertension is an important presentation of these patients. Given its progressive, multisystem nature, the role of liver transplantation (LT) in Zellweger syndrome remains undefined and controversial. An 11-y-old boy diagnosed with Zellweger syndrome presented to the authors with decompensated cirrhosis along with bilateral proptosis. After a meticulous evaluation, he was offered an ABO incompatible liver transplantation with his mother being the donor. He had an uneventful post operative period. After a follow up of 24 mo, he has normal graft function, normal cognition along with resolution of proptosis. Therefore, in a group of carefully selected patients with Zellweger syndrome, a liver transplantation can be offered successfully with an excellent prognosis.
Topics: Male; Humans; Zellweger Syndrome; Liver Transplantation; Liver Cirrhosis; Hypertension, Portal; Exophthalmos; Liver
PubMed: 38117438
DOI: 10.1007/s12098-023-04937-7 -
International Ophthalmology Apr 2024This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and... (Review)
Review
PURPOSE
This review examined existing literature to determine various ocular manifestations of liver pathologies, with a focus on metabolic deficiencies as well as viral and immune liver conditions.
METHODS
Recent data were compiled from PubMed from 2000 to 2020 using keywords that were relevant to the assessed pathologies. Ocular presentations of several liver pathologies were researched and then summarized in a comprehensive form.
RESULTS
Several ocular manifestations of liver disease were related to vitamin A deficiency, as liver disease is associated with impaired vitamin A homeostasis. Alcoholic liver cirrhosis can result in vitamin A deficiency, presenting with Bitot spots, xerosis, and corneal necrosis. Congenital liver diseases such as mucopolysaccharidoses and peroxisomal disorders are also linked with ocular signs. Viral causes of liver disease have associations with conditions like retinal vasculitis, keratoconjunctivitis sicca, retinopathies, Mooren's ulcer, and Sjogren's syndrome. Autoimmune hepatitis has been linked to peripheral ulcerative keratitis and uveitis.
CONCLUSIONS
Building strong associations between ocular and liver pathology will allow for early detection of such conditions, leading to the early implementation of management strategies. While this review outlines several of the existing connections between hepatic and ophthalmic disease, further research is needed in the area in order to strengthen these associations.
Topics: Humans; Vitamin A Deficiency; Keratoconjunctivitis Sicca; Corneal Ulcer; Sjogren's Syndrome; Dry Eye Syndromes; Liver Diseases; Retinal Vasculitis
PubMed: 38622271
DOI: 10.1007/s10792-024-03103-y -
Journal of Biomedical Research Dec 2023Peroxisomes are organelles enclosed by a single membrane and are present in various species. The abruption of peroxisomes is correlated with peroxisome biogenesis...
Peroxisomes are organelles enclosed by a single membrane and are present in various species. The abruption of peroxisomes is correlated with peroxisome biogenesis disorders and single peroxisomal enzyme deficiencies that induce diverse diseases in different organs. However, little is known about the protein compositions and corresponding roles of heterogeneous peroxisomes in various organs. Through transcriptomic and proteomic analyses, we observed heterogenous peroxisomal components among different organs, as well as between testicular somatic cells and different developmental stages of germ cells. As is expressed in both germ cells and Sertoli cells, we generated germ cell- and Sertoli cell-specific knockout mice. While deletion in Sertoli cells did not affect spermatogenesis, the deletion in germ cells resulted in male sterility, manifested as the destruction of intercellular bridges between spermatids and the formation of multinucleated giant cells. Proteomic analysis of the -deleted spermatids revealed defective expressions of peroxisomal proteins and spermiogenesis-related proteins. These findings provide new insights that PEX3-dependent peroxisomes are essential for germ cells undergoing spermiogenesis, but not for Sertoli cells.
PubMed: 38062668
DOI: 10.7555/JBR.37.20230055 -
Acta Neuropathologica Aug 2023Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain fatty acids...
Spinocerebellar ataxia 34 (SCA34) is a late-onset progressive ataxia caused by a mutation in ELOVL4, a gene involved in the biosynthesis of very long-chain fatty acids (VLCFAs). We performed post-mortem neuropathological examinations on four SCA34 patients with the ELOVL4 L168F mutation and compared the findings to age-matched controls. Specific gross findings of SCA34 were limited to pontocerebellar atrophy. On light microscopy, pontine base showed neuronal loss and storage of an autofluorescent lipopigment positive on oil red O, PAS and Hale's colloidal iron and negative on Alcian blue and Luxol fast blue (LFB). Among the swollen neurons were abundant CD68+ /CD163+ /IBA1- macrophages laden with a material with similar histochemical profile as in neurons except for the lack of autofluorescence and oil red O positivity and the presence of needle-like birefringent inclusions. Normal resting IBA1 + microglia were generally absent from pontine base nuclei but present in normal numbers elsewhere in the pons. In dentate nucleus neurons, atrophy was milder than in the pontine base and the coarser storage material was LFB-positive, closely resembling lipofuscin. On electron microscopy, dentate nucleus neurons showed neuronal storage of tridimensionally organized trilaminar spicules within otherwise normal lipofuscin, while in the more affected pontine base neurons, lipofuscin was almost completely replaced by the storage material. Storage macrophages were tightly packed with stacks of unorganized trilaminar spicules, reminiscent of the storage material seen in peroxisomal disorders and thought to represent VLCFAs incorporated in complex polar lipids. In summary, we provide histochemical and ultrastructural evidence that SCA34 is a lipid storage disease, the first among the currently known SCAs, and that the storage lipid is accumulating within neuronal lipofuscin. Our findings suggest that the storage lipid is similar to the one accumulating in non-neuronal cells in peroxisomal disorders and provide the first ultrastructural description of this type of material within neurons.
Topics: Humans; Neuronal Ceroid-Lipofuscinoses; Lipofuscin; Ataxia; Lysosomal Storage Diseases; Lipids; Mutation; Peroxisomal Disorders; Eye Proteins; Membrane Proteins
PubMed: 37184663
DOI: 10.1007/s00401-023-02582-0