Murine deficiency of peroxisomal L-bifunctional protein (EHHADH) causes medium-chain 3-hydroxydicarboxylic aciduria and perturbs hepatic cholesterol homeostasis
Ontology highlight
ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE171292 | GEO | 2021/04/02
REPOSITORIES: GEO
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Project description:Metabolic reprogramming of glucose and amino acids has been documented to affect early development. Here, we show that peroxisome-mediated β-oxidation is involved in lipids reprogramming to achieve H3K4me3 erasure and then zygotic genome activation (ZGA) in early embryo development. The metabolic patterns of fatty acids (FAs), triglyceride (TG) and phospholipid (PL) are reprogrammed during the oocyte-to-embryo transition. Very long-chain fatty acids (VLCFAs), arachidonic acid (ARA), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (Lyso-PE), lysophosphatidylcholine (Lyso-PC), and methyl donors are stored in oocytes, and after fertilization, they are converted into phosphatidylcholine (PC) at the 2-cell stage. Mitochondrial β-oxidation prevails in oocytes, while peroxisomal β-oxidation plays a critical role in shortening the VLCFA to form TG and synthesize PC and balancing the ratio of saturated and unsaturated FAs, which consumes the methyl donors as conducive to H3K4me3 erasure at the 2-cell stage. Inhibiting the peroxisome-mediated β-oxidation disrupts lipids metabolism remodellingH3K4me3 erasure and subsequent ZGA, leading to embryo arrest at the 2-cell stage. Oocytes from obese mice show I a relatively low level of VLCFAs, defective peroxisomal β-oxidation, and incomplete H3K4me3 erasure and ZGA. Microinjection of two saturated fatty acids, palmitic and myristic acids, rescues 2-cell arrest caused by peroxisome-mediated β-oxidation inhibition and obesity, and overexpressing Pemt to consume the methyl donors has the same rescue effect. These results elucidate a novel link among the peroxisomal-β-oxidation-mediated lipid metabolism reprogramming, H3K4me3 modification and ZGA during oocyte-embryo transition, and may provide a unique approach to improve reproduction in obese women.
2023-09-25 | GSE243450 | GEO
Project description:Metabolic reprogramming of glucose and amino acids has been documented to affect early development. Here, we show that peroxisome-mediated β-oxidation is involved in lipids reprogramming to achieve H3K4me3 erasure and then zygotic genome activation (ZGA) in early embryo development. The metabolic patterns of fatty acids (FAs), triglyceride (TG) and phospholipid (PL) are reprogrammed during the oocyte-to-embryo transition. Very long-chain fatty acids (VLCFAs), arachidonic acid (ARA), phosphatidylethanolamine (PE), lysophosphatidylethanolamine (Lyso-PE), lysophosphatidylcholine (Lyso-PC), and methyl donors are stored in oocytes, and after fertilization, they are converted into phosphatidylcholine (PC) at the 2-cell stage. Mitochondrial β-oxidation prevails in oocytes, while peroxisomal β-oxidation plays a critical role in shortening the VLCFA to form TG and synthesize PC and balancing the ratio of saturated and unsaturated FAs, which consumes the methyl donors as conducive to H3K4me3 erasure at the 2-cell stage. Inhibiting the peroxisome-mediated β-oxidation disrupts lipids metabolism remodellingH3K4me3 erasure and subsequent ZGA, leading to embryo arrest at the 2-cell stage. Oocytes from obese mice show I a relatively low level of VLCFAs, defective peroxisomal β-oxidation, and incomplete H3K4me3 erasure and ZGA. Microinjection of two saturated fatty acids, palmitic and myristic acids, rescues 2-cell arrest caused by peroxisome-mediated β-oxidation inhibition and obesity, and overexpressing Pemt to consume the methyl donors has the same rescue effect. These results elucidate a novel link among the peroxisomal-β-oxidation-mediated lipid metabolism reprogramming, H3K4me3 modification and ZGA during oocyte-embryo transition, and may provide a unique approach to improve reproduction in obese women.
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2015-01-08 | E-GEOD-34730 | biostudies-arrayexpress
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2015-01-08 | GSE34730 | GEO
Project description:Metabolic reprogramming provides transformed cells with proliferative and/or survival advantages. However, capitalizing on this therapeutically has been only moderately successful due to the relatively small magnitude of these differences and because cancers may re-program their metabolism to evade metabolic pathway inhibition. Mice lacking the peroxisomal bi-functional enzyme enoyl-CoA hydratase/3-hydroxyacyl CoA dehydrogenase (Ehhadh) and supplemented with the 12-carbon fatty acid lauric acid (C12) accumulate dodecanedioic acid (DDDA), a toxic C12 metabolite that causes hepatocyte necrosis and acute liver failure. In a murine model of pediatric hepatoblastoma (HB), down-regulation of Ehhadh also occurs in combination with a more general suppression of mitochondrial β- and peroxisomal ω-fatty acid oxidation (FAO) pathways. HB-bearing mice provided with C12 and/or DDDA-supplemented diets survived significantly longer than those on standard diets. The tumors also developed massive necrosis in response to short-term DDDA supplementation. Reduced Ehhadh was noted in murine hepatocellular carcinomas (HCCs) and in substantial subsets of human cancers, including HCCs. Acquired DDDA resistance was not associated with Ehhadh re-expression but was associated with 129 transcript differences ~90% of which were down-regulated in DDDA-resistant tumors and ~two-thirds of which correlated with survival in several human cancers. These transcripts often encoded components of the extracellular matrix suggesting that DDDA resistance arises from its reduced intracellular transport. Our results demonstrate the feasibility of a metabolic intervention that is non-toxic, inexpensive and likely compatible with traditional therapies. C12 and/or DDDA-containing diets could potentially be used to supplement other treatments or as alternative therapeutic choices.
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Project description:Dietary polyunsaturated fatty acids (PUFA) act as potent natural hypolipidemics and are linked to many health benefits in humans and in animal models. Mice fed long-term a high fat diet, in which medium-chain alpha linoleic acid (ALA) was partially replaced by long-chain docosahexaenoic (DHA) and eicosapentaenoic (EPA) fatty acids, showed reduced accumulation of body fat and prevention of insulin resistance, besides increased mitochondrial beta-oxidation in white adipose tissue and decreased plasma lipids. ALA, EPA and DHA all belong to PUFA of n-3 series. The intestine is a gatekeeper organ for ingested lipids. To examine the potential contribution of the intestine in the beneficial effects of EPA and DHA, this study assessed gene expression changes using whole genome microarray analysis on small intestinal scrapings. The main biological process affected was lipid metabolism. Fatty acid uptake, peroxisomal and mitochondrial beta-oxidation, and omega-oxidation of fatty acids were all increased. Quantitative real time PCR and intestinal fatty acid oxidation measurements ([14C(U)]-palmitate) confirmed significant gene expression differences in a dose-dependent manner. Furthermore, no major changes in the expression of lipid metabolism genes were observed in colonic scrapings. In conclusion, we show that marine n-3 fatty acids regulate small intestinal gene expression patterns. Since this organ contributes significantly to whole organism energy use, this adaptation of the small intestine may contribute to the complex and observed beneficial physiological effects of these natural compounds under conditions that will normally lead to development of obesity and diabetes.
2009-04-01 | GSE11936 | GEO
Project description:Apolipoprotein E-knock out (apoE-KO) mouse is known as a model animal for atherosclerosis accompanied by spontaneous hypercholesterolemia. When apoE-KO mice were fed a chow supplemented with 1.25% cholesterol (high-Chol diet), cholesterol and bile acids were highly increased in the liver within a week. However, the amount of triacylglycerol (TG) in very low-density lipoprotein (VLDL), but not in the liver, was reduced by 78%. The epididymal adipose tissue was almost diminished in the long term. Cholesterol metabolism is tightly regulated by both cholesterol and its metabolites in the mammalian liver, but the regulatory mechanism of TG synthesis remains to be elucidated. To evaluate the impact of high-Chol diet for 1 week on gene expression in the liver of apoE-KO mice, DNA microarray analysis was performed with comparison to apoE-KO mice fed a normal chow. We found that mRNA expression related to lipid metabolism was suppressed by the high-Chol diet in the liver of apoE-KO mice, which includes beta-oxidation and glycerol-3-phosphate (G3P) pathway for TG synthesis. In particular, the mRNA and protein expression of lipin-1 and lipin-2 was markedly decreased. PGC-1?, which up-regulates the transcription of lipin-1, was also suppressed. Lipin is reported to function as a coactivator of PGC-1? and is an inducible amplifier of PPAR?, indicating that the suppression of genes involved in beta-oxidation could be induced by suppression of the lipins. These data using apoE-KO mice indicate that cholesterol and its metabolites are involved in regulating TG metabolism through a suppression of lipin-1 and lipin-2 in the liver. This research provides evidence for the mechanism of lipin expression in the liver. Apo E-KO mice at 10 weeks of age were fed normal chow (control) or high-Chol diet containing 1.25% cholesterol for 1 week. Three independent experiments were performed at each diet.
2011-08-07 | E-GEOD-27457 | biostudies-arrayexpress
Project description:Solid evidence indicates that intake of marine n-3 fatty acids lower serum triglycerides, and that replacing saturated fatty acids (SFA) with polyunsaturated fatty acids (PUFA) reduces plasma total cholesterol and LDL-cholesterol. The molecular mechanisms underlying these health beneficial effects are however not completely elucidated. The aim of this study was to investigate the expression of genes related to lipid metabolism in peripheral blood mononuclear cells (PBMC) depending on the plasma levels of n-6 and n-3 fatty acids and the SFA to PUFA ratio.
2019-03-08 | GSE111567 | GEO