Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis
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ABSTRACT:
PROVIDER: PRJNA719096 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR14127803.fastq.gz | Fastqsanger.gz | |||
| SRR14127804.fastq.gz | Fastqsanger.gz | |||
| SRR14127805.fastq.gz | Fastqsanger.gz | |||
| SRR14127806.fastq.gz | Fastqsanger.gz | |||
| SRR14127807.fastq.gz | Fastqsanger.gz |
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Project description:Peroxisomes play an essential role in the β-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. The physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). We performed RNA-seq in WT and Ehhadh KO livers, treated with vehicle or L-aminocarnitine (L-AC), an inhibitor of mitochondrial fatty acid oxidation. We show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA β-oxidation is a regulator of hepatic cholesterol biosynthesis.
2021-04-02 | GSE171292 | GEO
Project description:Peroxisomes play an essential role in the β-oxidation of dicarboxylic acids (DCAs), which are metabolites formed upon ω-oxidation of fatty acids. Genetic evidence linking transporters and enzymes to specific DCA β-oxidation steps is generally lacking. Moreover, the physiological functions of DCA metabolism remain largely unknown. In this study, we aimed to characterize the DCA β-oxidation pathway in human cells, and to evaluate the biological role of DCA metabolism using mice deficient in the peroxisomal L-bifunctional protein (Ehhadh KO mice). In vitro experiments using HEK-293 KO cell lines demonstrate that ABCD3 and ACOX1 are essential in DCA β-oxidation, whereas both the bifunctional proteins (EHHADH and HSD17B4) and the thiolases (ACAA1 and SCPx) have overlapping functions and their contribution may depend on expression level. We also show that medium-chain 3-hydroxydicarboxylic aciduria is a prominent feature of EHHADH deficiency in mice most notably upon inhibition of mitochondrial fatty acid oxidation. Using stable isotope tracing methodology, we confirmed that products of peroxisomal DCA β-oxidation can be transported to mitochondria for further metabolism. Finally, we show that, in liver, Ehhadh KO mice have increased mRNA and protein expression of cholesterol biosynthesis enzymes with decreased (in females) or similar (in males) rate of cholesterol synthesis. We conclude that EHHADH plays an essential role in the metabolism of medium-chain DCAs and postulate that peroxisomal DCA β-oxidation is a regulator of hepatic cholesterol biosynthesis.
| S-EPMC8263512 | biostudies-literature
Project description:L-bifunctional enzyme (Ehhadh) is part of the classical peroxisomal fatty acid ?-oxidation pathway. This pathway is highly inducible via peroxisome proliferator-activated receptor ? (PPAR?) activation. However, no specific substrates or functions for Ehhadh are known, and Ehhadh knockout (KO) mice display no appreciable changes in lipid metabolism. To investigate Ehhadh functions, we used a bioinformatics approach and found that Ehhadh expression covaries with genes involved in the tricarboxylic acid cycle and in mitochondrial and peroxisomal fatty acid oxidation. Based on these findings and the regulation of Ehhadh's expression by PPAR?, we hypothesized that the phenotype of Ehhadh KO mice would become apparent after fasting. Ehhadh mice tolerated fasting well but displayed a marked deficiency in the fasting-induced production of the medium-chain dicarboxylic acids adipic and suberic acid and of the carnitine esters thereof. The decreased levels of adipic and suberic acid were not due to a deficient induction of ?-oxidation upon fasting, as Cyp4a10 protein levels increased in wild-type and Ehhadh KO mice.We conclude that Ehhadh is indispensable for the production of medium-chain dicarboxylic acids, providing an explanation for the coordinated induction of mitochondrial and peroxisomal oxidative pathways during fasting.
| S-EPMC3371241 | biostudies-literature
Project description:Peroxisomal multifunctional protein 2 deficiency perturbs lipid homeostasis in the retina causing visual dysfunction in mice
| PRJNA687498 | ENA
Project description:Patients lacking multifunctional protein 2, the central enzyme of the peroxisomal β-oxidation pathway, develop retinopathy. This metabolic pathway is involved in the metabolism of very long chain (VLCFAs) and polyunsaturated (PUFAs) fatty acids, which are enriched in the photoreceptor outer segments (POS). The molecular mechanisms underlying the retinopathy remain however elusive. Here, we report that Mfp2-/- mice display decreased retinal function already at the age of 3 weeks, which is accompanied by a profound shortening of the photoreceptor outer and inner segments, but with preserved photoreceptor ultrastructure. Furthermore, Mfp2-/- retinas exhibit severe changes in gene expression with downregulation of genes involved in the phototransduction pathway and upregulation of inflammation related genes. Lipid profiling of the retina of Mpf2-/- mice revealed a profound reduction of DHA-containing phospholipids. This was likely due to a hampered systemic supply and retinal traffic of this PUFA, although we cannot exclude that the local defect of peroxisomal β-oxidation contributes to this DHA decrease. Moreover, VLC-PUFAs were also reduced, except those containing ≥34 carbons that accumulated. The latter suggests that there is an uncontrollable elongation of retinal PUFAs. In conclusion, we showed that intact peroxisomal β-oxidation is indispensable for retinal integrity, most likely by maintaining PUFA homeostasis.
2021-01-31 | GSE163770 | GEO
Project description:Distinct retrograde signaling pathways have been identified for several cellular organelles. These pathways are important to maintain the function of these organelles in response to organelle-specific stress. Using Caenorhabditis elegans, we show for the first time that such a retrograde signaling also exists for peroxisomes. Analysis of the C. elegans transcriptome revealed that peroxisomal import stress caused by the knock-down of the peroxisomal matrix protein import receptor prx-5/PEX5 induces the compensatory up-regulation of genes involved in defense response and lipid metabolic processes, especially peroxisomal beta oxidation. We, therefore, propose that the peroxisomal retrograde signaling participates in the maintenance of peroxisomal function in response to peroxisomal import stress.
2020-12-19 | GSE156318 | GEO
Project description:Peroxisomal retrograde signaling in C. elegans
| PRJNA657442 | ENA
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana Experimenter phone = 0131 650 5316 Experimenter fax = 0131 650 5392 Experimenter department = Institute of Molecular Plant Sciences Experimenter institute = University of Edinburgh Experimenter address = Daniel Rutherford Building University of Edinburgh Experimenter address = The King's Buildings Experimenter address = Edinburgh Experimenter zip/postal_code = EH9 3JH Experimenter country = UK Keywords: genetic_modification_design
2007-01-08 | GSE5641 | GEO
Project description:The aim is to study the function of peroxisomal NAD-malate dehydrogenase in fatty acid beta-oxidation, glyoxylate cycle and photorespiration. Both peroxisomal MDH genes (At2g22780 and At5g09660) have been knocked out with T-DNA insertions and a double mutant made. Double mutant seedlings are blocked in beta-oxidation - they are 2,4DB resistant and beta-oxidation genes are repressed. They carry out glyoxylate cycle as normal. Plants grow well in soil and produce seed. Microarray analysis will tell us the extent of changes in gene expression in the mutant. For microarray analysis seeds are stratified at 4 C on agar medium with 1/2 strength M&S salts and 1% sucrose for 2 days, then seedlings grown for 2 days at 20 C in the light (100 umol/m2/s). Triplicate samples will be grown for mutant and wild type (col-0) and RNA isolated from each. Experimenter name = Itsara Pracharoenwattana; Experimenter phone = 0131 650 5316; Experimenter fax = 0131 650 5392; Experimenter department = Institute of Molecular Plant Sciences; Experimenter institute = University of Edinburgh; Experimenter address = Daniel Rutherford Building University of Edinburgh; Experimenter address = The King's Buildings; Experimenter address = Edinburgh; Experimenter zip/postal_code = EH9 3JH; Experimenter country = UK Experiment Overall Design: 6 samples were used in this experiment
2008-06-13 | E-GEOD-5641 | biostudies-arrayexpress
Project description:Study of the effect of cadmium on KO and overexpressor mutants of glycolate oxidase-GOX2, which is one of the main sources of H202 from peroxisomes. Reactive oxygen species (ROS) act as secondary messengers that can be sensed by specific redox sensitive proteins responsible for the activation of signal transduction culminating in altered gene expression. ROS, which are involved in different activities, elicit a wide range of protein modifications, which might elicit different gene expressions. The subcellular site, in which modifications in ROS/oxidation state occur, can also act as a specific cellular redox network signal. The chemical identity of ROS and their subcellular origin actually is a specific imprint on the transcriptome response. In recent years, a number of transcriptomic studies related to altered ROS metabolism in plant peroxisomes have been carried out. In this study, we made a meta-analysis of these transcriptomic findings to identify common transcriptional footprints for plant peroxisomal-dependent signaling at early and later time points. These footprints highlight the regulation of various metabolic pathways and gene families, which are also found in plant responses to several abiotic stresses. Major peroxisomal-dependent genes are associated with protein and endoplasmic reticulum (ER) protection at later stages of stress while, at earlier stages, these genes are related to hormone biosynthesis and signaling regulation. Further, in silico analyses allowed us to assign human orthologs to some of the peroxisomal-dependent genes, which are mainly associated with different cancer types pathologies. Peroxisomal footprints provide a valuable resource for assessing and supporting key peroxisomal functions in cellular metabolism under control and stress conditions across species.
2022-09-20 | GSE199325 | GEO