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Communications Biology May 2024Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that...
Propionic acidemia (PA), resulting from Pcca or Pccb gene mutations, impairs propionyl-CoA metabolism and induces metabolic alterations. While speculation exists that fasting might exacerbate metabolic crises in PA patients by accelerating the breakdown of odd-chain fatty acids and amino acids into propionyl-CoA, direct evidence is lacking. Our investigation into the metabolic effects of fasting in Pcca(A138T) mice, a PA model, reveals surprising outcomes. Propionylcarnitine, a PA biomarker, decreases during fasting, along with the C3/C2 (propionylcarnitine/acetylcarnitine) ratio, ammonia, and methylcitrate. Although moderate amino acid catabolism to propionyl-CoA occurs with a 23-h fasting, a significant reduction in microbiome-produced propionate and increased fatty acid oxidation mitigate metabolic alterations by decreasing propionyl-CoA synthesis and enhancing acetyl-CoA synthesis. Fasting-induced gluconeogenesis further facilitates propionyl-CoA catabolism without changing propionyl-CoA carboxylase activity. These findings suggest that fasting may alleviate metabolic alterations in Pcca(A138T) mice, prompting the need for clinical evaluation of its potential impact on PA patients.
Topics: Animals; Mice; Fasting; Methylmalonyl-CoA Decarboxylase; Mutation; Propionic Acidemia; Male; Mice, Knockout; Disease Models, Animal; Mice, Inbred C57BL; Acyl Coenzyme A
PubMed: 38811689
DOI: 10.1038/s42003-024-06362-8 -
Antioxidants (Basel, Switzerland) Apr 2024To investigate the ameliorative effects and mechanism of polysaccharide (LBP) on growth performance, oxidative stress, and lipid deposition in common carp () fed with...
To investigate the ameliorative effects and mechanism of polysaccharide (LBP) on growth performance, oxidative stress, and lipid deposition in common carp () fed with high-fat diets, fish with an initial weight of 5.29 ± 0.12 g were divided into five experimental groups-including normal-fat diets, high-fat diets, and high-fat diets-supplemented with LBP (0.5, 1.0, and 2.0 g/kg) for 8 weeks. The results showed that high-fat diets resulted in significant decreases in final body weight, weight gain rate, and specific growth rate of fish, as well as causing a significant decrease in hepatic total antioxidant capacity, catalase, and glutathione peroxidase activities. These changes were accompanied by a significant decrease in lipase activity and ATP level and a significant increase in malondialdehyde content. The expression levels of lipid metabolism-related genes (acetyl coenzyme A carboxylase 1, stearoyl coenzyme A desaturase 1, fat synthase, peroxisome proliferator-activated receptor-γ, fructofuranose bisphosphatase, and glucose-6-phosphatase) were also markedly elevated by high-fat diets. Supplementation with 0.5-2.0 g/kg LBP in high-fat diets improved the reduced growth performance, increased hepatic total antioxidant enzymes, catalase, and glutathione peroxidase activities, and lowered malondialdehyde level in fish fed with high-fat diets. Additionally, dietary supplementation with LBP significantly downregulated hepatic gene expression levels of acetyl coenzyme A carboxylase 1, stearoyl coenzyme A desaturase 1, fat synthase, sterol regulatory element-binding protein 1, peroxisome proliferator-activated receptor-γ, fructofuranose bisphosphatase, and glucose-6-phosphatase. In conclusion, fish fed with high-fat diets demonstrated impaired growth performance, antioxidant capacity, and lipid metabolism, and dietary supplementation with 0.5-2.0 g/kg LBP ameliorated the impairments induced by high-fat diets.
PubMed: 38790645
DOI: 10.3390/antiox13050540 -
Metabolites May 2024Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in...
Purines are the building blocks of DNA/RNA, energy substrates, and cofactors. Purine metabolites, including ATP, GTP, NADH, and coenzyme A, are essential molecules in diverse biological processes such as energy metabolism, signal transduction, and enzyme activity. When purine levels increase, excess purines are either recycled to synthesize purine metabolites or catabolized to the end product uric acid. Purine catabolism increases during states of low oxygen tension (hypoxia and ischemia), but this metabolic pathway is incompletely understood in the context of histotoxic hypoxia (i.e., inhibition of oxygen utilization despite normal oxygen tension). In rabbits exposed to cyanide-a classical histotoxic hypoxia agent-we demonstrated significant increases in several concordant metabolites in the purine catabolic pathway (including plasma levels of uric acid, xanthosine, xanthine, hypoxanthine, and inosine) via mass spectrometry-based metabolite profiling. Pharmacological inhibition of the purine catabolic pathway with oxypurinol mitigated the deleterious effects of cyanide on skeletal muscle cytochrome c oxidase redox state, measured by non-invasive diffuse optical spectroscopy. Finally, plasma uric acid levels correlated strongly with those of lactic acid, an established clinical biomarker of cyanide exposure, in addition to a tissue biomarker of cyanide exposure (skeletal muscle cytochrome c oxidase redox state). Cumulatively, these findings not only shed light on the in vivo role(s) of cyanide but also have implications in the field of medical countermeasure (MCM) development.
PubMed: 38786756
DOI: 10.3390/metabo14050279 -
Scientific Reports May 2024Statins, the drugs used for the treatment of hypercholesterolemia, have come into the spotlight not only as chemoadjuvants, but also as potential stem cell modulators in...
Statins, the drugs used for the treatment of hypercholesterolemia, have come into the spotlight not only as chemoadjuvants, but also as potential stem cell modulators in the context of regenerative therapy. In our study, we compared the in vitro effects of all clinically used statins on the viability of human pancreatic cancer (MiaPaCa-2) cells, non-cancerous human embryonic kidney (HEK 293) cells and adipose-derived mesenchymal stem cells (ADMSC). Additionally, the effect of statins on viability of MiaPaCa-2 and ADMSC cells spheroids was tested. Furthermore, we performed a microarray analysis on ADMSCs treated with individual statins (12 μM) and compared the importance of the effects of statins on gene expression between stem cells and pancreatic cancer cells. Concentrations of statins that significantly affected cancer cells viability (< 40 μM) did not affect stem cells viability after 24 h. Moreover, statins that didn´t affect viability of cancer cells grown in a monolayer, induce the disintegration of cancer cell spheroids. The effect of statins on gene expression was significantly less pronounced in stem cells compared to pancreatic cancer cells. In conclusion, the low efficacy of statins on non-tumor and stem cells at concentrations sufficient for cancer cells growth inhibition, support their applicability in chemoadjuvant tumor therapy.
Topics: Humans; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Pancreatic Neoplasms; Cell Survival; Mesenchymal Stem Cells; Cell Line, Tumor; Spheroids, Cellular; HEK293 Cells
PubMed: 38782983
DOI: 10.1038/s41598-024-62615-w -
BioRxiv : the Preprint Server For... May 2024Proliferating cancer cells actively utilize anabolic processes for biomass production, including biosynthesis of amino acids, nucleotides, and fatty acids. The key...
Proliferating cancer cells actively utilize anabolic processes for biomass production, including biosynthesis of amino acids, nucleotides, and fatty acids. The key enzyme of the fatty acid biosynthesis pathway, fatty acid synthase (FASN), is widely recognized as a promising therapeutic target in cancer and other health conditions. Here, we establish a metabolic signature of FASN inhibition using a panel of pharmacological inhibitors (GSK2194069, TVB-2640, TVB-3166, C75, cerulenin, and Fasnall). We find that the activity of commonly used FASN inhibitors is inconsistent with the metabolic signature of FASN inhibition (accumulation of malonate, succinate, malonyl coenzyme A, succinyl coenzyme A, and other metabolic perturbations). Moreover, we show that one of these putative FASN inhibitors, Fasnall, is a respiratory Complex I inhibitor that mimics FASN inhibition through NADH accumulation and consequent depletion of the tricarboxylic acid cycle metabolites. We demonstrate that Fasnall impairs tumor growth in several oxidative phosphorylation-dependent cancer models, including combination therapy-resistant melanoma patient-derived xenografts. Fasnall administration does not reproduce neurological side effects in mice reported for other Complex I inhibitors. Our results have significant implications for understanding the FASN role in human health and disease and provide evidence of therapeutic potential for Complex I inhibitors with fast systemic clearance. Our findings also highlight the continuing need for validation of small molecule inhibitors to distinguish high-quality chemical probes and to expand the understanding of their application.
PubMed: 38766222
DOI: 10.1101/2024.05.03.592013 -
BioRxiv : the Preprint Server For... May 2024Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation....
Sub-cellular compartmentalization of metabolism has important implications for the local production of metabolites and redox co-factors, as well as pathway regulation. 4'-phosphopantetheinyl (4'PP) groups are essential co-factors derived from coenzyme A and added to target proteins in both the cytoplasm and mitochondria by p hospho p antetheinyl transferase (PPTase) enzymes. Mammals express only one PPTase, thought to localize to the cytoplasm: aminoadipate semialdehyde dehydrogenase phosphopantetheinyl transferase (AASDHPPT); raising the question of how mitochondrial proteins are 4'PP-modified. We found that AASDHPPT is required for mitochondrial respiration and oxidative metabolism via the mitochondrial fatty acid synthesis (mtFAS) pathway. Moreover, we discovered that a pool of AASDHPPT localizes to the mitochondrial matrix via an N-terminal mitochondrial targeting sequence contained within the first 13 amino acids of the protein. Our data show that mitochondrial localization of AASDHPPT is required to support mtFAS function, and further identify two variants in that are likely pathogenic in humans.
PubMed: 38766035
DOI: 10.1101/2024.05.09.592977 -
BMC Cancer May 2024Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject...
BACKGROUND
Melanoma proliferation is partly attributed to dysregulated lipid metabolism. The effectiveness of lipid-lowering drugs in combating cutaneous melanoma (CM) is a subject of ongoing debate in both in vitro and clinical studies.
METHOD
This study aims to evaluate the causal relationship between various lipid-lowering drug targets, namely 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR, targeted by statins), Proprotein convertase subtilisin/kexin type 9 (PCSK9, targeted by alirocumab and evolocumab), and Niemann-Pick C1-like 1 (NPC1L1, targeted by ezetimibe), and the outcomes of cutaneous melanoma. To mimic the effects of lipid-lowering drugs, we utilized two genetic tools: analysis of polymorphisms affecting the expression levels of drug target genes, and genetic variations linked to low-density lipoprotein cholesterol levels and drug target genes. These variations were sourced from genome-wide association studies (GWAS). We applied Summary-data-based Mendelian Randomization (SMR) and Inverse Variance Weighted Mendelian Randomization (IVW-MR) to gauge the effectiveness of these drugs.
RESULTS
Our findings, with SMR results showing an odds ratio (OR) of 1.44 (95% CI: 1.08-1.92; P = 0.011) and IVW-MR results indicating an OR of 1.56 (95% CI: 1.10-2.23; P = 0.013), demonstrate a positive correlation between PCSK9 expression and increased risk of CM. However, no such correlations were observed in other analyses.
CONCLUSION
The study concludes that PCSK9 plays a significant role in the development of CM, and its inhibition is linked to a reduced risk of the disease.
Topics: Humans; Melanoma; Mendelian Randomization Analysis; Skin Neoplasms; Proprotein Convertase 9; Hydroxymethylglutaryl CoA Reductases; Genome-Wide Association Study; Melanoma, Cutaneous Malignant; Antibodies, Monoclonal, Humanized; Polymorphism, Single Nucleotide; Membrane Transport Proteins; Membrane Proteins; Hydroxymethylglutaryl-CoA Reductase Inhibitors; Ezetimibe; Hypolipidemic Agents
PubMed: 38760735
DOI: 10.1186/s12885-024-12366-8 -
Nature Communications May 2024The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in...
The liver gene expression of the peroxisomal β-oxidation enzyme acyl-coenzyme A oxidase 1 (ACOX1), which catabolizes very long chain fatty acids (VLCFA), increases in the context of obesity, but how this pathway impacts systemic energy metabolism remains unknown. Here, we show that hepatic ACOX1-mediated β-oxidation regulates inter-organ communication involved in metabolic homeostasis. Liver-specific knockout of Acox1 (Acox1-LKO) protects mice from diet-induced obesity, adipose tissue inflammation, and systemic insulin resistance. Serum from Acox1-LKO mice promotes browning in cultured white adipocytes. Global serum lipidomics show increased circulating levels of several species of ω-3 VLCFAs (C24-C28) with previously uncharacterized physiological role that promote browning, mitochondrial biogenesis and Glut4 translocation through activation of the lipid sensor GPR120 in adipocytes. This work identifies hepatic peroxisomal β-oxidation as an important regulator of metabolic homeostasis and suggests that manipulation of ACOX1 or its substrates may treat obesity-associated metabolic disorders.
Topics: Animals; Liver; Mice, Knockout; Mice; Acyl-CoA Oxidase; Obesity; Male; Insulin Resistance; Mice, Inbred C57BL; Oxidation-Reduction; Lipid Metabolism; Adipose Tissue; Diet, High-Fat; Energy Metabolism; Fatty Acids; Receptors, G-Protein-Coupled
PubMed: 38760332
DOI: 10.1038/s41467-024-48471-2 -
Science Advances May 2024Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated...
Acetyl-CoA synthetase short-chain family member 1 (ACSS1) uses acetate to generate mitochondrial acetyl-CoA and is regulated by deacetylation by sirtuin 3. We generated an ACSS1-acetylation (Ac) mimic mouse, where lysine-635 was mutated to glutamine (K635Q). Male mice were smaller with higher metabolic rate and blood acetate and decreased liver/serum ATP and lactate levels. After a 48-hour fast, mice presented hypothermia and liver aberrations, including enlargement, discoloration, lipid droplet accumulation, and microsteatosis, consistent with nonalcoholic fatty liver disease (NAFLD). RNA sequencing analysis suggested dysregulation of fatty acid metabolism, cellular senescence, and hepatic steatosis networks, consistent with NAFLD. Fasted mouse livers showed increased fatty acid synthase (FASN) and stearoyl-CoA desaturase 1 (SCD1), both associated with NAFLD, and increased carbohydrate response element-binding protein binding to and enhancer regions. Last, liver lipidomics showed elevated ceramide, lysophosphatidylethanolamine, and lysophosphatidylcholine, all associated with NAFLD. Thus, we propose that ACSS1-K635-Ac dysregulation leads to aberrant lipid metabolism, cellular senescence, and NAFLD.
Topics: Animals; Non-alcoholic Fatty Liver Disease; Mice; Cellular Senescence; Acetylation; Mitochondria; Stearoyl-CoA Desaturase; Male; Acetate-CoA Ligase; Gene Knock-In Techniques; Liver; Lipid Metabolism; Sirtuin 3; Disease Models, Animal; Coenzyme A Ligases; Fatty Acid Synthase, Type I
PubMed: 38758779
DOI: 10.1126/sciadv.adj5942 -
Food Chemistry: X Jun 2024Changes in physio-biochemical metabolism, phenolics and antioxidant capacity during germination were studied in eight different wheat varieties. Results showed that...
Changes in physio-biochemical metabolism, phenolics and antioxidant capacity during germination were studied in eight different wheat varieties. Results showed that germination enhanced sprout growth, and caused oxidative damage, but enhanced phenolics accumulation. Ferulic acid and -coumaric acid were the main phenolic acids in wheat sprouts, and dihydroquercetin, quercetin and vitexin were the main flavonoids. The phenolic acid content of Jimai 44 was the highest on the 2th and 4th day of germination, and that of Bainong 307 was the highest on the 6th day. The flavonoid content of Hei jingang was the highest during whole germination. The enzymes activities of phenylalanine ammonia lyase (PAL), cinnamic acid 4-hydroxylase (C4H) and 4-coumarate coenzyme A ligase (4CL) were up-regulated. The activities of catalase, polyphenol oxidase and peroxidase were also activated. Antioxidant capacity of wheat sprouts was enhanced. The results provided new ideas for the production of naturally sourced phenolic rich foods.
PubMed: 38756466
DOI: 10.1016/j.fochx.2024.101429