Decrease In Carnitine Levels Research Articles

Carnitine functions as an enhancer of NRF2 to inhibit osteoclastogenesis via regulating macrophage polarization in osteoporosis

Osteoporosis, which manifests as reduced bone mass and deteriorated bone quality, is common in the elderly population. It is characterized by persistent elevation of macrophage-associated inflammation and active osteoclast bone resorption. Currently, the roles of intracellular metabolism in regulating these processes remain unclear. In this study, we initially performed bioinformatics analysis and observed a significant increase in the proportion of M1 macrophages in bone marrow with aging. Further metabolomics analysis demonstrated a notable reduction in the expression of carnitine metabolites in aged macrophages, while carnitine was not detected in osteoclasts. During the differentiation process, osteoclasts took up carnitine synthesized by macrophages to regulate their own activity. Mechanistically, carnitine enhanced the function of Nrf2 by inhibiting the Keap1-Nrf2 interaction, reducing the proteasome-dependent ubiquitination and degradation of Nrf2. In silico molecular ligand docking analysis of the interaction between carnitine and Keap1 showed that carnitine binds to Keap1 to stabilize Nrf2 and enhance its function. In this study, we found that the decrease in carnitine levels in aging macrophages causes overactivation of osteoclasts, ultimately leading to osteoporosis. A decrease in serum carnitine levels in patients with osteoporosis was found to have good diagnostic and predictive value. Moreover, supplementation with carnitine was shown to be effective in the treatment of osteoporosis.

Evaluation of the relationship between serum carnitine levels and intradialytic complications in children with kidney failure.

Carnitine plays a crucial role in the metabolism of fatty acids as well as energy production. Previous research has suggested a significant decrease in carnitine levels in patients with kidney failure and those undergoing hemodialysis. Therefore, we designed this study to assess the prevalence and characteristics of carnitine deficiency and its association with hemodialysis complications in the pediatric population. This research was a pilot study of 29 children undergoing hemodialysis. Before hemodialysis, a 5-mL blood sample was drawn from each patient through a peripheral vein to measure serum-free carnitine levels, complete blood count with differential, blood urea nitrogen (BUN), creatinine, and electrolytes. Each patient was observed for intradialytic complications, including muscle cramps and hypotension, during 12 sessions of hemodialysis. We included 26 participants with a mean age of 14.23years undergoing hemodialysis. Carnitine deficiency was revealed in 54.8% of our participants. Also, there was no significant correlation between carnitine deficiency and age, gender, and BUN levels (P = 0.698, P = 0.43, and P > 0.05, respectively). Intradialytic complications, including episodes of hypotension and muscle cramps, were more frequent in patients with carnitine deficiency (P = 0.02, P = 0.01, respectively). Other reasons for muscle cramps, such as fluid overload, nutritional status, dialysis regimen, and other important lab results (phosphorus, magnesium, etc.), were ruled out. In conclusion, we found a higher prevalence of carnitine deficiency in pediatric hemodialysis patients. Carnitine deficiency was significantly associated with increased intradialytic symptoms, including muscle spasms and hypotension. Our results could support a potential role of carnitine supplementation in pediatric patients with kidney failure for controlling intradialytic complications, but this requires further investigation. A higher resolution version of the Graphical abstract is available as Supplementary information.

Primary Carnitine Deficiency and Autism Spectrum Disorder is there a Relationship?

Carnitine plays essential role in energy metabolism .Systemic primary carnitine deficiency is a genetic disorder caused by decreased or absent organic cation transporter type 2 (OCTN2) carnitine transporter activity, resulting in low serum carnitine levels and decreased carnitine accumulation inside cells. The decrease carnitine results in impaired fatty acid oxidation. Primary carnitine deficiency presents a hypoketotic, hypoglycemia and hepatic encephalopathy. Recently, primary carnitine deficiency has been associated with neurodevelopmental disorders including autism spectrum disorders. A seven year-old schoolgirl with intellectual deficit, autistic features and primary carnitine deficiency has been reported. A significant decrease in carnitine levels has been shown in patients with autism and this has been related to the existence of a mitochondrial disease and more severe autism. The early identification of patients with low levels of carnitine or primary carnitine deficiency, with the different methods of measuring free carnitine, including tandem mass spectrometry could help to identify these patients early and achieve an early treatment and better neurological prognosis, because autism spectrum disorders may be preventable in this subgroup. We hope that this paper is useful to neurologists and pediatricians, and may give them more reason to suspect a diagnosis of PCD and autism.

Comprehensive Plasma Metabolomic Profile of Patients with Advanced Neuroendocrine Tumors (NETs). Diagnostic and Biological Relevance.

Simple SummaryMetabolic flexibility is one of the key hallmarks of cancer and metabolites are the final products of this adaptation, reflecting the aberrant changes of tumors. However, the metabolic plasticity of each cancer type is still unknown, and specifically to date, there are no data on metabolic profile in neuroendocrine tumors. The aim of our retrospective study was to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. We provided, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use, selecting a reduced set of metabolites of high diagnostic accuracy. We have identified 32 novel enriched metabolic pathways in NETs related with the TCA cycle, and with arginine, pyruvate or glutathione metabolism, which have distinct implications in oncogenesis and may open innovative avenues of clinical research.Purpose: High-throughput “-omic” technologies have enabled the detailed analysis of metabolic networks in several cancers, but NETs have not been explored to date. We aim to assess the metabolomic profile of NET patients to understand metabolic deregulation in these tumors and identify novel biomarkers with clinical potential. Methods: Plasma samples from 77 NETs and 68 controls were profiled by GC−MS, CE−MS and LC−MS untargeted metabolomics. OPLS-DA was performed to evaluate metabolomic differences. Related pathways were explored using Metaboanalyst 4.0. Finally, ROC and OPLS-DA analyses were performed to select metabolites with biomarker potential. Results: We identified 155 differential compounds between NETs and controls. We have detected an increase of bile acids, sugars, oxidized lipids and oxidized products from arachidonic acid and a decrease of carnitine levels in NETs. MPA/MSEA identified 32 enriched metabolic pathways in NETs related with the TCA cycle and amino acid metabolism. Finally, OPLS-DA and ROC analysis revealed 48 metabolites with diagnostic potential. Conclusions: This study provides, for the first time, a comprehensive metabolic profile of NET patients and identifies a distinctive metabolic signature in plasma of potential clinical use. A reduced set of metabolites of high diagnostic accuracy has been identified. Additionally, new enriched metabolic pathways annotated may open innovative avenues of clinical research.

Serum Carnitine Levels in Childhood Leukemia

In patients with malignancies, the system of carnitine seems abnormally expressed. The serum total, free, and acyl carnitine levels in 40 children and adolescents with acute leukemia were determined using electrospray tandem mass spectrometry in 4 different phases of the disease: at the diagnosis, 1 year after the initiation of chemotherapy, at the end of treatment, and 2.4+/-1.668 years after the completion of chemotherapy. The age, sex, hemoglobin values, serum biochemistry, somatometric features of the patients, and the risk group of the disease were examined. Although the carnitine levels were found higher in patients compared with the control group from diagnosis to treatment completion, statistically significant decrease in carnitine levels was observed in patients within different phases of the disease especially during induction and consolidation treatment (phase A to B) for both free and total (P=0.023) carnitine. In addition, a statistically significant recovery in carnitine levels was observed between phase B (end of intensive chemotherapy) and D (some years after the completion of treatment) for free and total carnitine (P=0.054 and 0.035, respectively). No statistical correlation was documented between the carnitine levels and somatometric parameters or other variables studied. In conclusion, a significant transient decrease in the levels of carnitine during the treatment was observed in children with acute leukemia. Further studies are required to clarify the role of carnitine status in patients with malignancies and possibly the necessity of carnitine supplementation during chemotherapy administration.

Gestational diabetes exhibits lack of carnitine deficiency despite relatively low carnitine levels and alterations in ketogenesis

Objective: Previous studies have underlined the importance of the carnitine shuttle system and its dysfunction both in normal pregnancy and in type 1 and 2 diabetes. The objective of this paper was to delineate more systematically the role of the carnitine shuttle system in normal pregnancy and in gestational diabetes.Methods: A total of 119 women matched for age comprised three groups: 40 normal adult non-pregnant women (NNP), 46 normal pregnant women with uncomplicated pregnancy (NP) and 33 women with gestational diabetes (GDM). The latter group was further subdivided into those being managed either by diet alone (25 women, GDM-D) or by insulin (8 women, GDM-I). The following biochemical parameters were assayed: fasting plasma total, free and acyl-carnitine, FFA and β-OH-butyrate, together with several essential anthropometric parameters.Results: Women with GDM, in contrast to the control groups, displayed the biochemical features characteristic of insulin resistance: higher body weight, higher BMI, higher skinfold and higher HbA1c levels. No differences on any parameters were found between the two GDM subgroups. Both NP and GDM groups had low levels of total carnitine compared to NNP control group, but surprisingly, the GDM group did not exhibit any further decrease of carnitine levels, as would have been expected by the combination of pregnancy and diabetes. Both groups, despite these low carnitine levels, had no clinical symptoms of carnitine deficiency. Furthermore, the GDM group displayed higher levels of FFA and β-hydroxybutyrate, which were statistically significant compared to the other two control groups.Conclusions: The data corroborate the negative effect of normal gestation on the carnitine shuttle system, while they document for the first time that GDM does not further affect the efficiency of the carnitine system. The mild effect of GDM on carnitine status could be explained by the concurrent increased gluconeogenesis, a process which does not affect directly carnitine metabolism.

SERUM CARNITINE LEVELS OF PEDIATRIC CANCER PATIENTS

Secondary carnitine deficiency may occur in some diseases including malnutrition. The present study examined the serum carnitine levels of children with cancer and their relationship with nutritional status. Fifty-one (mean age: 104 - 23 months) patients with cancer were evaluated at diagnosis and 3 months after the initiation of the treatment. There were significant differences between the mean carnitine levels of patients before and during the treatment ( p : .004). Although initial carnitine levels of patients were similar to those in control groups, there was a significant difference between the mean carnitine levels of patients and those of the control group at the third month ( p : .02). The prevalence of malnutrition at the third month of the treatment (43%) was higher from the prevalence at diagnosis (33%) but this was not significant. No significant relationship was found between carnitine levels and nutritional status of patients either at diagnosis or during treatment. These results showed that inadequate intake of carnitine or its precursors could not be responsible for decrease in carnitine levels. Metabolic changes that result from therapy and/or from neoplastic process may be responsible for the decrease in carnitine levels. Detailed studies, including measurements of fractions of carnitine and urinary carnitine excretion according to individual drug, are necessary to determine real cause of this decrease.

Weight gain associated with valproate in childhood

Weight gain is a common side effect of valproate treatment. Several mechanisms have been suggested for its pathophysiology; of these, impairment of beta-oxidation of fatty acids and increased insulin secretion have been supported by clinical studies. To investigate whether changes in carnitine and insulin levels had a role in the weight gain occurring with valproate treatment in children, 20 patients with epilepsy were randomly assigned to receive either carnitine or placebo supplementation in addition to valproate. After a follow-up period of 3 months, weight gain was observed in both groups. The mean insulin concentration and insulin/glucose ratios increased. Weight gain did not correlate with carnitine levels. These results suggest that weight gain during valproate treatment is not related to a decrease in carnitine levels. However, an increase in insulin levels together with a decrease in glucose levels may cause weight gain, possibly by stimulating appetite.

Effects of carnitine on preconditioned latissimus dorsi muscle at different burst frequencies.

Exercise and electrical stimulation may result in a decrease in carnitine levels associated with preconditioned latissimus dorsi muscles. Therefore, the effects of exogenous carnitine were studied in a model of latissimus dorsi muscle contraction. Twelve dogs were studied. Under anesthesia, the latissimus dorsi was placed around an implantable mock circulation system. The muscle was made fatigue-resistant with the aid of chronic low-frequency electrical stimulation. Six animals received carnitine 0.15 mmol/kg; the other six served as control. The muscles were stimulated with 20, 43, and 85 Hz pulse training. During the 90-minute stimulation period, the pressure that developed in the mock circulation was measured at 15 minute intervals. The changes in ATP and lactate levels were measured every 30 minutes. Stimulations at 20 and 43 Hz did not result in any change in pressure or metabolic data over the course of 90 minutes of stimulation. When the 85 Hz burst was applied, ATP levels decreased, while lactate levels increased, with an associated drop in pressure in the control group. ATP and lactate levels were, respectively, 13.8 +/- 1.4 mumol/g and 15.0 +/- 4.0 mumol/g in the carnitine group and 10.3 +/- 1.1 mumol/g and 23.0 +/- 3.0 mumol/g in the control group at the end of 90 minutes (p < 0.06). The pressure at the same time interval was 74 +/- 4 mmHg in the control group, and 85 +/- 3 mmHg in the carnitine group (p < 0.05). In this study, we demonstrated that carnitine administration enhances muscle performance in terms of metabolic and pressure changes during high-frequency electrical stimulation at 85 Hz.