カルニチン回路異常症

Nutritional peripheral neuropathy is a clinically important condition associated with inadequate intake, malabsorption, bariatric surgery, aging, metabolic disease, and chronic medication exposure. B vitamins serve as essential coenzymes in mitochondrial energy metabolism, one-carbon metabolism, neurotransmitter synthesis, redox regulation, and myelin maintenance. This narrative review synthesizes mechanistic and clinical evidence linking B vitamin-dependent coenzyme systems to nutritional neuropathy and selected neuropsychiatric manifestations. Particular emphasis is placed on the tricarboxylic acid cycle, electron transport chain, urea cycle, folate-methionine cycle, and MTHFR-dependent one-carbon metabolism. The proposed "dynamic coenzyme network" is intended as an integrative mechanistic framework rather than a stand-alone therapeutic recommendation. Although biochemical interdependence among B vitamins supports evaluation for combined or functional deficiencies in selected patients, mechanistic plausibility should not be equated with clinical efficacy. Clinical consideration of B vitamin repletion should be guided by documented deficiency, dietary and gastrointestinal risk factors, medication exposure, neurological phenotype, and functional biomarkers such as homocysteine and methylmalonic acid. Adjunctive nutrients, including alpha-lipoic acid and acetyl-L-carnitine, may have context-specific relevance, particularly in metabolic neuropathies, but evidence for fixed multi-nutrient combinations remains heterogeneous. Further well-designed clinical studies are needed to determine whether this mechanistic framework translates into meaningful neurological or neuropsychiatric benefit beyond established deficiency states.

Background/Objectives: Ovarian cancer (OC) is a leading cause of cancer-related mortality in women, largely driven by late-stage diagnosis. Five-year survival is just 30% for advanced-stage (III-IV) disease but exceeds 90% for early-stage disease, underscoring the critical need for effective early detection tools. Current standard-of-care biomarkers show limited sensitivity for early-stage OC and lack specificity in symptomatic populations. Most biomarker studies in OC serum evaluate single molecular classes or compare OC to healthy controls, limiting understanding of coordinated biological alterations in circulating proteins, lipids, and metabolites in clinically relevant populations. Methods: We performed integrated multi-omics profiling of serum from a retrospective, case-control cohort of women presenting with vague abdominal symptoms (VAS), including early- and late-stage OC, borderline tumors, benign gynecologic conditions including adnexal masses, GI disorders, and healthy controls. Protein biomarkers were quantified by ELISA, lipidomic profiling was performed by untargeted LC-MS, and ganglioside and metabolomic profiling were performed by semi-targeted LC-MS with metabolite annotation performed against a curated reference library. Results: Consistent with known limitations for early-stage OC detection, CA125 and HE4 levels overlapped substantially with benign gynecologic conditions. Additional proteins also showed limited separation in their expression between early-stage OC and symptomatic controls. In contrast, OC showed unique lipid and metabolite profiles: phospholipids and glycerolipids were decreased, and sphingolipid composition was altered. Borderline and benign conditions exhibited lipid profiles that fall between healthy and OC groups, suggesting a continuum of metabolic changes rather than distinct states between OC and non-OC controls. Sphingolipid alterations included changes in ceramides and sphingomyelins, along with broader dysregulation of ganglioside profiles, including an elevated GD2;O2-to-GD1;O2 ratio. Metabolic profiling showed decreased amino acids and enriched cysteine metabolism in OC, consistent with altered redox balance, along with changes in fatty acids and acyl-carnitines, suggesting altered lipid metabolism and inflammatory mechanisms. Lower levels of glycolytic and TCA cycle intermediates in OC suggested altered mitochondrial metabolism and energetic reprogramming. Pairwise comparisons revealed a gradient of significance between groups, with differences between OC and healthy controls across lipid classes (LPC, PC, PE, TG, SM), gangliosides (GD1, GD2, GD2/GD1 ratio), and metabolites (amino acids, Cys/CySS, TCA cycle); borderlines occupied an intermediate space. Integration of these datasets revealed coordinated cross-omics relationships, identifying links between metabolite, lipid, and protein features. Together, these connections highlight structured, system-level alterations related to lipid remodeling, redox balance, immune signaling, and energy metabolism that no single modality would have revealed in isolation. Conclusions: This study presents an integrated analysis of the lipidome, gangliosome, metabolome, and protein biomarkers within a single clinically relevant symptomatic cohort enriched with multiple stages and subtypes of OC. This multi-omics framework demonstrates that molecular alterations in OC are biologically interconnected across molecular classes. While these findings are discovery-based and require independent validation prior to clinical application, they support the development of clinically deployable multi-omics biomarker strategies for early detection and potential pathways for therapeutic intervention.

Background/Objectives: Exposure to high and sustained levels of non-esterified fatty acids (NEFA) in the peripartal period is the main cause of fatty liver disease in dairy cows. Rumen-protected choline is often fed as part of the nutritional management of peripartal cows, with in vivo and in vitro data indicating positive effects of this nutrient on alleviating liver lipid accumulation. Although hepatic molecular mechanisms associated with choline supply have been studied using a target gene, protein, or metabolite approach, application of high-throughput technologies could vastly enhance fundamental knowledge on the functional role of choline. The main objective was to challenge isolated hepatocytes with a mixture of NEFA and determine proteome- and metabolome-wide effects in response to choline supply. Methods: Three healthy female calves (1 d old, 30-45 kg) were sacrificed to harvest hepatocytes. During a 12 h incubation, isolated hepatocytes were challenged without NEFA (control), 1.2 mM NEFA (c9-18:1, 18:2, 16:0, 18:0, and c9-16:1 at 43.5%, 4.9%, 31.9%, 14.4%, and 5.3% of total NEFA, respectively), or NEFA for 6 h followed by 10 μM choline chloride for another 6 h (NEFA + Chol). iTRAQ labeling-based protein profiling and GC/MS-based metabolomics profiling were used to determine changes in proteins and metabolites. Differentially abundant proteins for each group comparison were determined at a threshold of 1.4-fold change. Differences in metabolite profiles were assessed via pairwise comparisons. A subset of differentially abundant proteins was validated via qRT-PCR and Western blotting. Results: Compared with the control, there were 90 proteins and 22 metabolites in the NEFA group, and 83 proteins and 29 metabolites in the NEFA + Chol. Compared with NEFA, there were 49 proteins and 17 metabolites in the NEFA + Chol group. Greater abundance of hexokinase-1 (HK1), fructose-bisphosphate aldolase (ALDOA), mitochondrial pyruvate carrier 1 (MPC1), and increased concentrations of lactate with high NEFA treatment alone suggested greater glycolytic and TCA cycle activity. Accumulation of triacylglycerol in the NEFA group was associated with lipotoxicity and markers of inflammation, such as greater abundance of prostaglandin reductase 1 (PTGR1), serious cell autophagy processes, such as greater abundance of cell division cycle 42 (CDC42), and NFκB-related proteins. Choline supplementation reduced TAG partly due to greater VLDL secretion driven by greater abundance of diacylglycerol acyltransferase (DGAT1), perilipin 3 (PLIN3), and apolipoprotein C-III (APOC3). In addition, a greater abundance of carnitine O-palmitoyltransferase 1b (CPT1B) with choline suggested enhanced mitochondrial β-oxidation. Activation of the CDC42/JNK pathway and ROS/NFκB axis-related proteins, along with depressed PI3K/AKT/RAC-related proteins, indicated enhanced mitochondrial autophagy in response to NEFA. Conclusions: Overall, data confirmed published effects of choline on TAG accumulation, VLDL secretion, and fatty acid oxidation, while highlighting negative effects of NEFA on the respiratory electron transport chain, autophagy, and inflammatory processes.

Methylmalonic acidemia (MMA) is one of the rare inherited metabolic disorders, and the affected patients usually suffer from repeated life-threatening metabolic crises in which hyperammonemia and acidosis are observed. Although continuous venovenous hemodialysis is considered the first choice for extracorporeal detoxification in neonates and infants, the available experience regarding peritoneal dialysis in this group of patients is still limited, and how to optimally manage the complications of dialysis has not been clearly described. We report the case of a three-month-old female infant with isolated MMA who was brought in with vomiting for four days, cough for seven days, and fever for one day. Even after she was started on sodium benzoate, L-carnitine, and sodium bicarbonate, encephalopathy gradually became worse, plasma ammonia level increased from 188 μmol/L to 332 μmol/L, and severe metabolic acidosis was observed (bicarbonate: 9 mEq/L). Peritoneal dialysis was then started, and the metabolic response was found to be excellent: ammonia level came down to 86 μmol/L after eight cycles of dialysis and further to 61 μmol/L on hospital day four. After completion of 17 cycles of dialysis, culture-negative peritonitis was noted in the patient (150 cells/mm³ with 57% neutrophils), and this was managed by escalation of antibiotics together with removal of the catheter. The infant was finally discharged on day 23 in stable condition, with the ammonia level back to normal (49 μmol/L) and the metabolic acidosis showing resolution. From the present case, it can be stated that peritoneal dialysis is effective for the management of severe hyperammonemia in infants suffering from MMA, and rapid correction of the metabolic disturbance was achieved even though the course was complicated by peritonitis. The outcome obtained in our patient supports the expert consensus that, in this age group, peritoneal dialysis can be used as a reasonable alternative to continuous renal replacement therapy, especially at centers where pediatric peritoneal dialysis experience is available.

Acetyl-CoA is a central metabolite that links energy status to transcriptional regulation through protein acetylation, yet its functions in skeletal biology depend strongly on subcellular compartmentalization. Because acetyl-CoA does not freely traverse biological membranes, its mitochondrial, cytosolic, and nuclear pools are maintained through compartment-specific synthesis and exchange routes, including the citrate-SLC25A1-ACLY axis, acetylcarnitine/carnitine cycling, acetate-dependent ACSS2 activity, and local nuclear enzyme activity. This review synthesizes current evidence that three conserved modules, including glycolytic/PDC-driven mitochondrial production, CIC/ACLY-mediated citrate export, and HAT-dependent acetylation, connect carbon flux with skeletal cell fate. However, lineage-specific outcomes are shaped by local acetyl-CoA availability, acetyltransferase context, and the transcription-factor landscape, including RUNX2 (osteogenesis), SOX9 (chondrogenesis) and NFATc1 (osteoclastogenesis). Critically, compartmentalized acetyl-CoA dysregulation can contribute to different pathological states: excess acetyl-CoA supply is linked to ACLY/FAO-driven cartilage catabolism and osteoclast resorption, whereas insufficient nucleocytosolic supply is associated with impaired regenerative programs in aged or inflamed bone. This duality argues for context-specific therapeutic strategies that either restrain excess acetyl-CoA flux or restore deficient pools. We propose that the translational bottleneck is not target identification but delivery precision, advocating for localized metabolite supplementation, cell-selective ACLY/FAO inhibitors, and spatial acetylome mapping to deconvolute cell-type-specific fluxes. Moving beyond broad HDAC/HAT modulation toward compartment-resolved strategies will be essential for translating acetyl-CoA biology into effective skeletal therapies.