Search Results (67)

Background: Adrenoleukodystrophy is a rare, inherited X-linked disease related to mutations in the ABCD1 gene. Peroxisomal β-oxidation is impaired, underpinning the tissue accumulation of very long-chain fatty acids (VLCFAs), especially in the central nervous system (i.e., the white matter and axons), adrenal glands, and testes. VLCFA accumulation contributes to oxidative stress, neuroinflammation, and progressive demyelination, leading to severe neurological sequelae. Though gene therapies and drug development are advancing, dietary management may still play a crucial role in modulating lipid metabolism and mitigating disease progression. Methods: A narrative review of studies published up to May 2025 in major scientific databases was conducted, focusing on biochemical and clinical outcomes, including VLCFA plasma modulation and nutritional status. Results: VLCFA restriction alone has shown limited efficacy due to the counteractive effect of endogenous synthesis. “Lorenzo’s Oil” inhibits VLCFA elongation, yet with inconsistent clinical benefits. Novel dietary strategies, such as the “Bambino Diet” and innovative dietary supplements similar to Lorenzo’s Oil, composed of glyceryl trioleate, glyceryl trierucate, and antioxidants, provide promising biochemical effects, such as reducing VLCFA plasma levels and improving lipid profiles. Malnutrition risk is also increased in X-ALD patients, underscoring the need for personalized nutritional interventions. Conclusions: Dietary strategies are one of the pillars of X-ALD management, to be further combined with pharmacological, gene therapies, and hematopoietic stem cell transplantation. Future research should refine emerging therapies, assess long-term effects, and develop personalized nutritional strategies. Full article

Environmental salinity is a critical factor influencing the physiological and metabolic processes of teleosts. Despite its importance, the molecular mechanisms underlying these responses, particularly those involving specific signaling pathways and gene expression regulation, remain poorly understood. To elucidate the role of lipid metabolism in osmotic regulation, the present study investigated the effects of varying salinity levels (2, 20, 40, and 60 ppt) on growth performance and metabolic status, including the biosynthesis of LC-FAs and VLC-FAs, respectively, in neural tissues (brain and eyes), of the euryhaline fish Fundulus heteroclitus over a 62-day period. The findings revealed multiple physiological adaptations to salinity variation, encompassing both molecular and metabolic responses. Salinity had a significant impact on growth performance, with fish exposed to the highest salinity level (60 ppt) exhibiting reduced growth. At this salinity, plasma levels of lipid-related metabolites, i.e., triglycerides and cholesterol, were decreased, whereas both osmolality and cortisol levels increased. Hepatic glucose and lactate levels increased with rising salinity, while glucose and triglyceride concentrations in muscle tissue declined. Additionally, intestinal lipase activity was significantly higher at 60 ppt. Although no significant differences were observed in the total UFAs content of both tissues, in the brain, significant differences were detected in the levels of 16:1n-7, 18:1n-9, 18:2n-6, 20:3n-3, 20:4n-6, and 20:5n-3, whereas in the eye, differences were observed only for 16:1n-7 and 20:5n-3. Gene expression analysis revealed that salinity exerts a regulatory effect on the expression of fads2b and elovl4a in the eye, with up-regulation observed at 60 ppt. In contrast, no significant changes in the expression of fads or elovl genes were detected in the brain. These findings highlight the contribution of non-osmoregulatory organs, such as the brain and eyes, in the osmotic adaptation of teleosts. Collectively, the results suggest that lipid metabolism plays a key regulatory role in the adaptation of F. heteroclitus to salinity fluctuations. Full article

Background: β-ketolipoyl coenzyme A synthase (KCS) is an essential limiting catalyst involved in carbon chain elongation during fatty acid biosynthesis, characterized by strict substrate specificity. C18:1 (oleic acid) plays a vital role in cell membranes and is essential for nutrient storage and stress defense. There are indications of significant accumulation and rapid synthesis of C18:1 during the early growth stages of Ginkgo biloba L. episperm. The KCS gene family in G. biloba has yet to be analyzed, and the role of KCS in oleic acid synthesis remains unexplored. Methods: In this study, this issue was investigated using transcriptomic and metabolomic data, bioinformatics analysis to screen a key gene from the KCS gene family, and dual validation using yeast and Arabidopsis thaliana expression systems to probe its function. Results: A total of 11 members of the GbKCS gene family were identified, and the dynamics of these genes were analyzed during exocarp development in the G. biloba genome. Among them, the gene designated GbKCS7 showed a highly direct association with the content of C18:1. Heterologous expression of GbKCS7 in yeast increased C18:1N12 and C18:1 content by 3.18-fold and 2.07-fold, respectively. Overexpression of GbKCS7 in Arabidopsis showed that C18:1 was increased by 27.70% and 31.43% in GbKCS7-OE-1 and GbKCS7-OE-2 strains, correspondingly, in juxtaposition to the non-transgenic plants. In addition, the content of VLCFAs increased to varying degrees. Conclusions: These outcomes offer important insights for investigating the role of KCS genes in fatty acid synthesis to further improve G.biloba resistance. Full article

Camelina sativa (L.) Crantz, a native European oilseed crop of the Brassicaceae family, is notable for its short life cycle, making it well-suited for crop rotation and diversification. Its seeds contain a high content of oil (36–47%) that is rich in polyunsaturated fatty acids (PUFAs) such as alpha-linolenic acid (ALA, C18:3, Ω-3) and linoleic acid (LA, C18:2, Ω-6). This oil has diverse industrial applications, including low-emission biofuels, animal feed, pharmaceuticals, biolubricants, bioplastics, and cosmetics. We analyzed the expression of seven key enzymes involved in fatty acid biosynthesis across nine C. sativa accessions at three stages of silique development using highly efficient qRT-PCR assays designed for the target genes and a normalizing control. Our detailed expression analysis revealed significant variation across varieties, with only the gene FAB2c exhibiting genotype-independent expression, indicating a constitutive and essential role in monounsaturated fatty acid (MUFA) biosynthesis. Other genes showed significant interactions between the variety and developmental stage, highlighting the combined influences of genetic background and silique maturation on gene regulation. V18 emerges as particularly promising, exhibiting elevated expression of genes linked to PUFA and VLCFA biosynthesis—traits of significance for food, biofuel, and industrial applications. These findings, together with the developed qRT-PCR assays, provide valuable tools for selecting Camelina varieties with optimized genetic profiles, highlighting the potential of harnessing natural transcriptional diversity for crop improvement. Full article

Background: X-ALD is a white matter (WM) disease caused by mutations in the ABCD1 gene encoding the transporter of very-long-chain fatty acids (VLCFAs) into peroxisomes. Strikingly, the same ABCD1 mutation causes either devastating brain inflammatory demyelination during childhood or, more often, progressive spinal cord axonopathy starting in middle-aged adults. The accumulation of undegraded VLCFA in glial cell membranes and myelin has long been thought to be the central mechanism of X-ALD. Methods: This review discusses studies in mouse and drosophila models that have modified our views of X-ALD pathogenesis. Results: In the Abcd1 knockout (KO) mouse that mimics the spinal cord disease, the late manifestations of axonopathy are rapidly reversed by ABCD1 gene transfer into spinal cord oligodendrocytes (OLs). In a peroxin-5 KO mouse model, the selective impairment of peroxisomal biogenesis in OLs achieves an almost perfect phenocopy of cerebral ALD. A drosophila knockout model revealed that VLCFA accumulation in glial myelinating cells causes the production of a toxic lipid able to poison axons and activate inflammatory cells. Other mouse models showed the critical role of OLs in providing energy substrates to axons. In addition, studies on microglial changing substates have improved our understanding of neuroinflammation. Conclusions: Animal models supporting a primary role of OLs and axonal pathology and a secondary role of microglia allow us to revisit of X-ALD mechanisms. Beyond ABCD1 mutations, pathogenesis depends on unidentified contributors, such as genetic background, cell-specific epigenomics, potential environmental triggers, and stochasticity of crosstalk between multiple cell types among billions of glial cells and neurons. Full article

The Agrobacterium fabrum C58 is a phytopathogen able to infect numerous species of cultivated and ornamental plants. During infection, bacteria genetically transform plant cells and induce the formation of tumours at the site of invasion. Bacterial cell wall components play a crucial role in the infection process. Lipopolysaccharide is the main component of Gram-negative bacteria’s outer leaflet of outer membrane. Its lipophilic part, called lipid A, is built of di-glucosamine backbone substituted with a specific set of 3-hydroxyl fatty acids. A. fabrum incorporates a very long chain hydroxylated fatty acid (VLCFA), namely 27-hydroxyoctacosanoic acid (28:0-(27OH)), into its lipid A. A. fabrum C58 mutants deprived of this component due to mutation in the VLCFA’s genomic region, have been characterised. High-resolution mass spectrometry was used to establish acylation patterns in the mutant’s lipid A preparations. The physiological properties of mutants, as well as their motility, ability to biofilm formation and plant infectivity, were tested. The results obtained showed that the investigated mutants were more sensitive to environmental stress conditions, formed a weakened biofilm, exhibited impaired swimming motility and were less effective in infecting tomato seedlings compared to the wild strain. Full article

This article represents the first consideration of the peculiarities of the fatty acid (FAs) composition and structure of storage triacylglycerols (TAGs) of the relict plant Lunaria rediviva L. The composition of storage TAGs was found to comprise 21 individual FAs, with an unsaturated FA content of 96.8%. Additionally, monounsaturated acids with a very long chain (VLCFAs), specifically C20:1–C24:1, constituted over 60% of the total FAs. The ethylene bond position isomers of unsaturated FAs were accurately identified and the presence of unusual isomers, including 20:1$\Delta$13, 22:1$\Delta$15, and 24:1$\Delta$17 acids. Furthermore, the unusual minor 24:2$\Delta$15,18 acid was identified and characterised for the first time. The pathways of the mentioned VLCFA’s biosynthesis have been proposed. The distribution of FA acyls between the sn positions of triacylglycerols was found to be highly specific. Thus, VLCFAs exclusively acylate the $\alpha$ positions of the carbon atoms of the glycerol residue of the TAG molecule (sn-1 and sn-3 positions), while unsaturated C18 acids exclusively acylate the $\beta$-carbon atom (sn-2 position). The composition of the molecular species of TAGs was analysed using a calculation method based on the Vander Wal model and by RP-HPLC-ESI-MS. A significant discrepancy from the statistical model was observed, indicating a preference for the formation of symmetrical TAGs, such as sn-1,3-dierucoyl-2-oleoyl-glycerol and related molecular species. This observation led to the formulation of a hypothesis regarding the potential existence of at least two specialised enzyme isoforms involved in the biosynthesis of such TAGs via the Kennedy pathway, exhibiting unusual substrate specificity. Consequently, this plant can be regarded not only as a producer of unusual molecular types of triacylglycerols but also as a source of genetic material for the search of genes encoding the aforementioned enzymes with unusual substrate specificity. Full article

X-adrenoleukodystrophy (X-ALD) is a peroxisomal metabolic disorder caused by mutations in the ABCD1 gene encoding the peroxisomal ABC transporter adrenoleukodystrophy protein (ALDP). Similar mutations in ABCD1 may result in a spectrum of phenotypes in males with slow progressing adrenomyeloneuropathy (AMN) and fatal cerebral adrenoleukodystrophy (cALD) dominating most cases. Mouse models of X-ALD do not capture the phenotype differences and an appropriate model to investigate the mechanism of disease onset and progress remains a critical need. Here, we generated induced pluripotent stem cell (iPSC) lines from skin fibroblasts of two each of apparently healthy control, AMN, and cALD patients with non-integrating mRNA-based reprogramming. iPSC lines expanded normally and expressed pluripotency markers Oct4, SOX2, NANOG, SSEA, and TRA-1–60. Expression of markers SOX17, Brachyury, Desmin, OXT2, and beta tubulin III demonstrated the ability of the iPSCs to differentiate into all three germ layers. iPSC-derived lines from CTL, AMN, and cALD male patients were differentiated into astrocytes. Differentiated AMN and cALD astrocytes lacked ABCD1 expression and accumulated saturated very long chain fatty acids (VLCFAs), a hallmark of X-ALD, and demonstrated differential mitochondrial bioenergetics, cytokine gene expression, and differences in STAT3 and AMPK signaling between AMN and cALD astrocytes. These patient astrocytes provide disease-relevant tools to investigate the mechanism of differential neuroinflammatory response in X-ALD and will be valuable cell models for testing new therapeutics. Full article

β-ketoacyl-CoA synthase (KCS) enzymes play a pivotal role in plants by catalyzing the first step of very long-chain fatty acid (VLCFA) biosynthesis. This process is crucial for plant development and stress responses. However, the understanding of KCS genes in maize remains limited. In this study, we present a comprehensive analysis of ZmKCS genes, identifying 29 KCS genes that are unevenly distributed across nine maize chromosomes through bioinformatics approaches. These ZmKCS proteins varied in length and molecular weight, suggesting functional diversity. Phylogenetic analysis categorized 182 KCS proteins from seven species into six subgroups, with maize showing a closer evolutionary relationship to other monocots. Collinearity analysis revealed 102 gene pairs between maize and three other monocots, whereas only five gene pairs were identified between maize and three dicots, underscoring the evolutionary divergence of KCS genes between monocotyledonous and dicotyledonous plants. Structural analysis revealed that 20 out of 29 ZmKCS genes are intronless. Subcellular localization prediction and experimental validation suggest that most ZmKCS proteins are likely localized at the plasma membrane, with some also present in mitochondria and chloroplasts. Analysis of the cis-acting elements within the ZmKCS promoters suggested their potential involvement in abiotic stress responses. Notably, expression analysis under abiotic stresses highlighted ZmKCS17 as a potential key gene in the stress response of maize, which presented an over 10-fold decrease in expression under salt and drought stresses within 48 h. This study provides a fundamental understanding of ZmKCS genes, paving the way for further functional characterization and their potential application in maize breeding for enhanced stress tolerance. Full article

Obesity and type 2 diabetes (T2D) are widespread metabolic disorders that significantly impact global health today, affecting approximately 17% of adults worldwide with obesity and 9.3% with T2D. Both conditions are closely linked to disruptions in lipid metabolism, where peroxisomes play a pivotal role. Mitochondria and peroxisomes are vital organelles responsible for lipid and energy regulation, including the β-oxidation and oxidation of very long-chain fatty acids (VLCFAs), cholesterol biosynthesis, and bile acid metabolism. These processes are significantly influenced by estrogens, highlighting the interplay between these organelles’ function and hormonal regulation in the development and progression of metabolic diseases, such as obesity, metabolic dysfunction-associated fatty liver disease (MAFLD), and T2D. Estrogens modulate lipid metabolism through interactions with nuclear receptors, like peroxisome proliferator-activated receptors (PPARs), which are crucial for maintaining metabolic balance. Estrogen deficiency, such as in postmenopausal women, impairs PPAR regulation, leading to lipid accumulation and increased risk of metabolic disorders. The disruption of peroxisomal–mitochondrial function and estrogen regulation exacerbates lipid imbalances, contributing to insulin resistance and ROS accumulation. This review emphasizes the critical role of these organelles and estrogens in lipid metabolism and their implications for metabolic health, suggesting that therapeutic strategies, including hormone replacement therapy, may offer potential benefits in treating and preventing metabolic diseases. Full article

“Bubblegum” acyl-CoA synthetase (ACSBG1) is a pivotal player in lipid metabolism during mouse brain development, facilitating the activation of long-chain fatty acids (LCFA) and their incorporation into lipid species that are crucial for brain function. ACSBG1 converts LCFA into acyl-CoA derivatives, supporting vital metabolic processes. Fruit fly mutants lacking ACSBG1 exhibited neurodegeneration and had elevated levels of very long-chain fatty acids (VLCFA), characteristics of human X-linked adrenoleukodystrophy (XALD). To explore ACSBG1’s function and potential as a therapeutic target in XALD, we created an ACSBG1 knockout (Acsbg1^−/−) mouse and examined the effects on brain FA metabolism during development. Phenotypically, Acsbg1^−/− mice resembled wild type (w.t.) mice. ACSBG1 expression was found mainly in tissue affected pathologically in XALD, namely the brain, adrenal gland and testis. ACSBG1 depletion did not significantly reduce the total ACS enzyme activity in these tissue types. In adult mouse brain, ACSBG1 expression was highest in the cerebellum; the low levels detected during the first week of life dramatically increased thereafter. Unexpectedly, lower, rather than higher, saturated VLCFA levels were found in cerebella from Acsbg1^−/− vs. w.t. mice, especially after one week of age. Developmental changes in monounsaturated ω9 FA and polyunsaturated ω3 FA levels also differed between w.t. and Acsbg1^−/− mice. ACSBG1 deficiency impacted the developmental expression of several cerebellar FA metabolism enzymes, including those required for the synthesis of ω3 polyunsaturated FA, precursors of bioactive signaling molecules like eicosanoids and docosanoids. These changes in membrane lipid FA composition likely affect membrane fluidity and may thus influence the body’s response to inflammation. We conclude that, despite compelling circumstantial evidence, it is unlikely that ACSBG1 directly contributes to the pathology of XALD, decreasing its potential as a therapeutic target. Instead, the effects of ACSBG1 knockout on processes regulated by eicosanoids and/or docosanoids should be further investigated. Full article

Peroxisomes are organelles involved in many cellular metabolic functions, including the degradation of very-long-chain fatty acids (VLCFAs; C ≥ 22), the initiation of ether-phospholipid synthesis, and the metabolism of reactive oxygen species. All of these processes are essential for the maintenance of cellular lipid and redox homeostasis, and their perturbation can trigger inflammatory response in immune cells, including in the central nervous system (CNS) resident microglia and astrocytes. Consistently, peroxisomal disorders, a group of congenital diseases caused by a block in peroxisomal biogenesis or the impairment of one of the peroxisomal enzymes, are associated with neuroinflammation. Peroxisomal function is also dysregulated in many neurodegenerative diseases and during brain aging, both of which are associated with neuroinflammation. This suggests that deciphering the role of peroxisomes in neuroinflammation may be important for understanding both congenital and age-related brain dysfunction. In this review, we discuss the current advances in understanding the role and function of peroxisomes in neuroinflammation. Full article

Background/Objectives: Adrenoleukodystrophy (X-ALD) is a metabolic disorder caused by dysfunctional peroxisomal beta-oxidation of very-long-chain fatty acids (VLCFAs). A VLCFA-restricted Mediterranean diet has been proposed for patients and carriers to reduce daily VLCFA intake. Methods: We retrospectively evaluated plasma VLCFAs in a cohort of 36 patients and 20 carriers at baseline and after 1 year of restricted diet. Results: At T1, compliant adult patients had significantly lower C26:0 levels [1.7 (1.2) vs. 2.5 µmol/L (1.7), p < 0.05], C26:0/C22:0 ratio [0.04 (0.02) vs. 0.06 (0.03), p < 0.05], and triglycerides [93 (56.5) vs. 128 mg/dL (109.5), p < 0.05] than non-compliant ones. C26:0 [2.4 (1.7) vs. 1.7 (1.2) µmol/L, p < 0.05], the C26:0/C22:0 ratio [0.06 (0.04) vs. 0.04 (0.02), p < 0.05], and cholesterol [173.5 (68.3) mg/dL vs. 157 (54) mg/dL, p < 0.05] were significantly reduced in compliant adult patients at T1 vs. baseline. As for carriers, the C26:0/C22:0 ratio was lower [0.02 (0.01) vs. 0.04 (0.009), p < 0.05] at T1 in compliant carriers, as compared to non-compliant ones. The C26:0/C22:0 [0.03 (0.02) vs. 0.02 (0.01) p < 0.05] and C24:0/C22:0 [1.0 (0.2) vs. 0.9 (0.3), p < 0.05] ratios were significantly decreased at T1 vs. T0. Conclusions: A VLCFA-restricted diet is effective in reducing plasma VLCFA levels and their ratios and must be strongly encouraged as support to therapy. Full article

Cotton fiber is the leading natural textile material, and fiber elongation plays an essential role in the formation of cotton yield and quality. Although a number of components in the molecular network controlling cotton fiber elongation have been reported, a lot of players still need to be functionally dissected to understand the regulatory mechanism of fiber elongation comprehensively. In the present study, an R2R3-MYB transcription factor gene, GhMYB201, was characterized and functionally verified via CRISPR/Cas9-mediated gene editing. GhMYB201 was homologous to Arabidopsis AtMYB60, and both coding genes (GhMYB201At and GhMYB201Dt) were preferentially expressed in elongating cotton fibers. Knocking-out of GhMYB201 significantly reduced the rate and duration of fiber elongation, resulting in shorter and coarser mature fibers. It was found that GhMYB201 could bind and activate the transcription of cell wall loosening genes (GhRDLs) and also β-ketoacyl-CoA synthase genes (GhKCSs) to enhance very-long-chain fatty acid (VLCFA) levels in elongating fibers. Taken together, our data demonstrated that the transcription factor GhMYB201s plays an essential role in promoting fiber elongation via activating genes related to cell wall loosening and VLCFA biosynthesis. Full article

The bHLH (basic helix–loop–helix) transcription factor AtCFLAP2 regulates epidermal wax accumulation, but the underlying molecular mechanism remains unknown. We obtained BnUC1^mut (BnaA05g18250D homologous to AtCFLAP2) from a Brassica napus mutant with up-curling leaves (Bnuc1) and epidermal wax deficiency via map-based cloning. BnUC1^mut contains a point mutation (N200S) in the conserved dimerization domain. Overexpressing BnUC1^mut in ZS11 (Zhongshuang11) significantly decreased the leaf epidermal wax content, resulting in up-curled and glossy leaves. In contrast, knocking out BnUC1^mut in ZS11-NIL (Zhongshuang11-near-isogenic line) restored the normal leaf phenotype (i.e., flat) and significantly increased the leaf epidermal wax content. The point mutation weakens the ability of BnUC1^mut to bind to the promoters of VLCFA (very-long-chain fatty acids) synthesis-related genes, including KCS (β-ketoacyl coenzyme synthase) and LACS (long-chain acyl CoA synthetase), as well as lipid transport-related genes, including LTP (non-specific lipid transfer protein). The resulting sharp decrease in the transcription of genes affecting VLCFA biosynthesis and lipid transport disrupts the normal accumulation of leaf epidermal wax. Thus, BnUC1 influences epidermal wax formation by regulating the expression of LTP and genes associated with VLCFA biosynthesis. Our findings provide a foundation for future investigations on the mechanism mediating plant epidermal wax accumulation. Full article