Dataset Information

Label-free LC-MSMS proteomics for P30 Acox1 WT vs KO

ABSTRACT: Background: Dyslipidemia is a significant contributor to many eye diseases and the lipid processing pathways are not well understood. Peroxisomes oxidize very long-chain, monocarboxylic and dicarboxylic fatty acids. Genetic mutations in peroxisomal proteins may lead to severe neural retinal degeneration. However, there are limited approaches available for peroxisomal disease treatment. Method: In mice with genetic deficiency of ACOX1 (acyl-coenzyme A oxidase 1, the first and key metabolic enzyme in peroxisomal fatty acid oxidation), we characterized the retinal phenotype during development. Retinal function, thickness and photoreceptor structure were examined. Proteomics was utilized for molecular mechanistic investigation. Metabolomics and fatty acid profiling and were conducted to study the metabolic alterations in the retinas. Nutrient intervention was also applied to test if supplementation of lacking nutrients attenuated retinal dysfunction. Results: In one-month-old mice with ACOX1 deficiency, we found reduced neural retinal signaling, accompanied with decrease expression of genes involved in phototransduction. Proteomics identified decreased glucose and mitochondrial metabolism, supported by decreased mitochondrial DNA copy number. Metabolomics showed decreased retinal pyruvate and pyruvate supplementation from one-month old attenuated neural retinal dysfunction in ACOX1-deficient mice at 2 months. Furthermore, there was also a significant decrease in omega-3 fatty acids and a compensatory increase in omega-6 fatty acids. Dietary supplementation of docosahexaenoic acid (omega-3) or docosahexaenoic acid plus arachidonic acid (omega-6) improved neural retinal function in ACOX1-deficient mice. Conclusion: Retinal metabolic imbalance was observed in mice with peroxisomal fatty acid dysfunction. Nutrient intervention is an effective approach to attenuate the disease progression.

INSTRUMENT(S):

ORGANISM(S): Mus Musculus (mouse)

TISSUE(S): Retina

SUBMITTER: Zhongjie Fu

LAB HEAD: Zhongjie Fu

PROVIDER: PXD055240 | Pride | 2025-12-15

REPOSITORIES: Pride

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Publications

Nutrient supplementation mitigates retinal dysfunction in Acox1 knockout mice with impaired peroxisomal fatty acid oxidation.

Boeck Myriam M Yagi Hitomi H Chen Chuck T CT Zeng Yan Y Lee Deokho D Nian Shen S Kasai Taku T Lee Jeff J Hirst Victoria V Wang Chaomei C Neilsen Katherine K Rodrick Tori C TC McCutcheon Andrew A Yu Mathew M Lodhi Irfan J IJ Singh Sasha A SA Aikawa Masanori M Bazinet Richard P RP Fu Zhongjie Z

Journal of advanced research 20250304

<h4>Introduction</h4>Dyslipidemia contributes to many retinal diseases, but underlying lipid processing pathways are not fully understood. Peroxisomes oxidize very long-chain fatty acids and generate docosahexaenoic acid (DHA). Mutations in peroxisomal genes can result in severe neural retinal dysfunction. However, therapeutic approaches for peroxisomal diseases remain scarce, and dietary strategies yield inconsistent results.<h4>Objectives</h4>This study sought to elucidate retinal metabolic ad ...[more]

PMID: 40049514

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Project description:Introduction: Retinopathy of prematurity (ROP) with early vessel loss (Phase I) followed by uncontrolled vessel growth (Phase II) causes visual impairment in premature infants. Although supplementation with n-3 docosahexaenoic acid (DHA) alone has mixed results to prevent ROP, combined supplementation with DHA and n-6 arachidonic acid (ARA) in early postnatal life reduces severe ROP by 50% (Mega Donna Mega study). The underlying mechanisms are unknown. Objectives: To evaluate protective effects and mechanism of combined dietary n-3 DHA and n-6 ARA in a neonatal mouse model of Phase I ROP. Methods: In the Mega Donna Mega study, most preterm infants had early postnatal hyperglycemia episodes, a strong risk factor for severe ROP. We used a neonatal mouse model of hyperglycemia-induced suppression of retinal vascular development (Phase I ROP). Dams were fed diets enriched with 3%DHA or 1%DHA+2%ARA. In P10 milk-fed pups, we assessed retinal vascularization, and proteome, and fatty acid profiles in retina, retinal pigment epithelium (RPE) complex and plasma. In vivo, oligomycin A, a mitochondrial ATP synthase inhibitor, was used to assess mitochondrial participation in the combined lipid protective effects. Results: In 201 (97.6%) of 206 randomized infants there was at least one elevated glucose measurement during the first 14 days. In a neonatal mouse model of hyperglycemia-induced suppression of vascular development, maternal DHA+ARA vs. DHA diet promoted pup retinal vessel growth. Fatty acid profiling confirmed lipid changes in pup plasma and RPE complex in accord with DHA and ARA levels in the maternal diets. Proteomic retinal analysis revealed increased abundance of proteins related to mitochondrial respiration and glucose metabolism in the combined diet. Inhibition of mitochondrial ATP synthase negated the protective effects of the combined diet on retinal vascularization. Conclusion: Combined DHA+ARA oral supplementation in the early postnatal period protects against Phase I ROP in mouse neonates, through enhanced retinal metabolism suggesting the potential of balanced lipid supplementation for preventing ROP.

Project description:Elevated circulating lipid levels are known risk factors for cardiovascular diseases (CVD). In order to examine the effects of quercetin on hepatic lipid metabolism and detailed serum lipid profiles, mice received a mild-high-fat diet without (control) or with supplementation of 0.33% (w/w) quercetin for 12 weeks. Gas chromatography and 1H nuclear magnetic resonance were used to measure quantitatively serum lipid profiles and whole genome microarray analysis was used to identify the responsible mechanisms in liver. There were no significant differences found in mean body weight, energy intake and hepatic lipid accumulation between the quercetin and control group. In serum of quercetin-fed mice, TG levels were decreased with 15%, poly unsaturated fatty acids (PUFA) were increased with 14% and saturated fatty acids were decreased. Palmitic acid, oleic acid, and linoleic acid were all decreased in quercetin-fed mice by 9-15%. Both palmitic acid and oleic acid can be oxidized by omega-oxidation. Indeed, gene expression profiling showed that quercetin increased hepatic lipid metabolism, especially omega-oxidation. At the gene level, this was reflected by the up regulation of cytochrome P450 (Cyp) 4a10, Cyp4a14, Cyp4a31 and Acyl-CoA thioesterase 3 (Acot3). Two relevant regulators, Cytochrome P450 oxidoreductase (Por, rate limiting for cytochrome P450s) and the transcription factor Constitutive androstane receptor (Car; official symbol Nr1i3) were also up regulated in the quercetin-fed mice. We conclude that quercetin intake increased hepatic lipid omega-oxidation and lowered corresponding circulating lipid levels, a process that may involve Por and Car, and results in a potential beneficial CVD preventive effect. Liver samples were obtained from 36 C57BL/6J male adult mice. All mice started with a three week adaptation phase, in which they were fed a mild-high-fat diet. 12 mice were sacrificed immediately after the adaptation phase (t=0). The other 24 mice received the mild-high-fat diet without (HF) or with supplementation of 0.33% (w/w) quercetin (HF-Q) for 12 weeks.

			Action	DRS
	41_MB_P30_Acox1.csv	Csv
	41_MB_P30_Acox1.mzML	Mzml
	41_MB_P30_Acox1.mzid.gz	Mzid
	41_MB_P30_Acox1.pdResult	Other
	41_MB_P30_Acox1_KO_1.raw	Raw