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L-Carnitine - Metabolic Functions and Meaning in Humans Life

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Abstract

L-Carnitine is an endogenous molecule involved in fatty acid metabolism, biosynthesized within the human body using amino acids: L-lysine and L-methionine, as substrates. L-Carnitine can also be found in many foods, but red meats, such as beef and lamb, are the best choices for adding carnitine into the diet. Good carnitine sources also include fish, poultry and milk. Essentially, L-carnitine transports the chains of fatty acids into the mitochondrial matrix, thus allowing the cells to break down fat and get energy from the stored fat reserves. Recent studies have started to shed light on the beneficial effects of L-carnitine when used in various clinical therapies. Because L-carnitine and its esters help reduce oxidative stress, they have been proposed as a treatment for many conditions, i.e. heart failure, angina and weight loss. For other conditions, such as fatigue or improving exercise performance, L-carnitine appears safe but does not seem to have a significant effect. The presented review of the literature suggests that continued studies are required before L-carnitine administration could be recommended as a routine procedure in the noted disorders. Further research is warranted in order to evaluate the biochemical, pharmacological, and physiological determinants of the response to carnitine supplementation, as well as to determine the potential benefits of carnitine supplements in selected categories of individuals who do not have fatty acid oxidation defects.
... It could be transformed into betaine and γ-butyrobetaine [33]. First, L-carnitine plays a critical role in fat metabolism, transporting the activated longchain fatty acids from the cytosol into the mitochondria and making them available for mitochondrial β-oxidation [48]. Second, carnitine may suppress the accumulation of lactic acid by reacting with acyl-coenzyme A to form acetyl-carnitine and coenzyme A, thereby enhancing high-intensity exercise performance [48]. ...
... First, L-carnitine plays a critical role in fat metabolism, transporting the activated longchain fatty acids from the cytosol into the mitochondria and making them available for mitochondrial β-oxidation [48]. Second, carnitine may suppress the accumulation of lactic acid by reacting with acyl-coenzyme A to form acetyl-carnitine and coenzyme A, thereby enhancing high-intensity exercise performance [48]. Moreover, experimental data illustrated that carnitine administration could increase serum osteocalcin concentrations in animals, which suggested that carnitine might be helpful for the prevention and/or therapeutic treatment of osteoporosis and post-menopause syndrome [49]. ...
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This study aimed to investigate the association between changes in levels of trimethylamine N-oxide (TMAO) and its precursors and the prognosis of patients with acute myocardial infarction (AMI). Patients diagnosed with AMI were prospectively enrolled at Fuwai Hospital between March 2017 and January 2020. TMAO, betaine, choline, and L-carnitine were measured in 1203 patients at their initial admission and 509 patients at their follow-up of one month. Major adverse cardiovascular events (MACE), a composite of all-cause death, recurrence of MI, rehospitalization caused by HF, ischemic stroke, and any revascularization, were followed up. A decision tree by TMAO levels implicated that compared to those with low levels at admission, patients with high TMAO levels at both time points showed an increased risk of MACE (adjusted hazard ratio (HR) 1.59, 95% confidence interval (CI): 1.03–2.46; p = 0.034), while patients with high TMAO levels at admission and low levels at follow-up exhibited a similar MACE risk (adjusted HR 1.20, 95% CI: 0.69–2.06; p = 0.520). Patients with high choline levels at admission and follow-up showed an elevated MACE risk compared to those with low levels at both time points (HR 1.55, 95% CI: 1.03–2.34; p = 0.034). Repeated assessment of TMAO and choline levels helps to identify the dynamic risk of cardiovascular events.
... In a randomized controlled trial carried out on 250 septic shock patients, single infusion doses of 18 g, 12 g, and 6 g of l-carnitine, vs. a saline placebo, had no effects on the 28-mortality rate at any dose [19]. Chronic critically ill ICU patients are at risk for l-carnitine deficiency due to prolonged parenteral nutrition, malnutrition, and renal failure; in addition, studies have revealed that serum carnitine tends to be notably reduced in these patients [7,10,20]. ...
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Background Critically ill patients must be monitored constantly in intensive care units (ICUs). Among many laboratory variables, nutritional status indicators are a key role in the prognosis of diseases. We investigated the effects of l-carnitine adjunctive therapy on monitoring variables in critical illness. Method A prospective, double-blind, randomized controlled trial was implemented in a medical ICU. Participants were 54 patients, aged > 18 years, with multiple conditions, randomly assigned to receive 3 g l-carnitine per day or placebo, along with enteral feeding, for 1 week. Primary outcomes included monitoring variables related to nutritional status. Result Of 54 patients randomly assigned, 51 completed the trial. Serum albumin (Alb) (P-value: 0.001), total protein (P-value: 0.003), and calcium (Ca) (0.044) significantly increased in the intervention vs. control group. Alanine transaminase (ALT) (0.022), lactate (<0.001), creatinine (Cr) (0.005), and international normalized ratio (INR) (0.049) decreased meaningfully in the intervention vs. control group. Conclusion l-Carnitine supplementation in critically ill patients can improve several parameters including INR, Cr, ALT, lactate, Ca, Alb, and total protein. Trial registration Iranian Registry of Clinical Trials IRCT 20151108024938N2. This trial was approved by the Research Ethics Committee of Mashhad University of Medical Sciences (registration code: IR.MUMS.fm.REC.1396.671) (available at https://en.irct.ir/trial/30748, May 2018).
... Previous study has demonstrated the importance of carnitine as a coenzyme in lipid metabolism and the role it plays in mitochondrial lipid metabolism. Acylcarnitine, a byproduct of carnitine metabolism, has the potential to reveal the imbalance between fatty acid oxidation and mitochondrial stress conditions in young animals [74]. In the present study, the acylcarnitine content in the cecum was signi cantly increased and the serum acylcarnitine content was signi cantly decreased when OVX mice were supplemented with EB, but the serum acylcarnitine content did not change signi cantly. ...
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Decreased estrogen levels are one of the main causes of lipid metabolism disorders and coronary heart disease in women after menopause. Exogenous estradiol benzoate is effective to some extent in alleviating lipid metabolism disorders caused by estrogen deficiency, but the role of gut microbes in the regulation process is not yet clear. The objective of this 45 days randomized trial was to investigate the effects of estradiol benzoate supplementation on lipid metabolism, gut microbiota and metabolites in ovariectomized (OVX) mice, and revealing the important role of gut microbes and metabolites in the regulation of lipid metabolism disorders. This study found that high doses of estradiol benzoate supplementation effectively attenuated fat accumulation in OVX mice and significantly altered the expression of genes enriched in hepatic cholesterol metabolism and unsaturated fatty acid metabolism pathways. Further screening of the gut for characteristic metabolites associated with improved lipid metabolism disorders revealed that estradiol benzoate supplementation influences major subsets of acylcarnitine metabolites, and ovariectomy significantly increased the abundance of characteristic microbes that were significantly negatively associated with acylcarnitine synthesis, including Lactobacillus and Eubacterium_ruminantium_group bacteria, while estradiol benzoate supplementation significantly increased the abundance of characteristic microbes that were significantly positively associated with acylcarnitine synthesis, including Ileibacterium and Bifidobacterium bacteria. The use of pseudo-sterile mice gut microbial deficiency greatly facilitates the synthesis of acylcarnitine due to estradiol benzoate supplementation and alleviates lipid metabolism disorders to a greater extent in OVX mice. Our findings established a role for gut microbes in the progression of estrogen deficiency-induced lipid metabolism disorders, and screened for key target bacteria that may have the potential to regulate acylcarnitine synthesis. These findings suggest a possible route for the use of microbe or acylcarnitine to regulate estrogen deficiency-induced disorders of lipid metabolism.
... Carnitine can promote the oxidative degradation of fatty acids to provide energy [29]. The energy demand for cellular metabolism could be supplied through the oxidation of fatty acids under ATP limitation. ...
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S-adenosyl-methionine (SAM) is crucial for organisms to maintain some physiological functions. However, the inconsistency between high L-methionine feeding rate and yield during SAM production at an industrial scale and its metabolic mechanism have not been elucidated. Here, the cellular metabolic mechanism of feeding sodium citrate to the Pichia pastoris (P. pastoris) G12’/AOX-acs2 strain to enhance SAM production was investigated using untargeted metabolomics and metabolic flux analysis. The results indicated that the addition of sodium citrate has a facilitative effect on SAM production. In addition, 25 metabolites, such as citrate, cis-aconitate, and L-glutamine, were significantly up-regulated, and 16 metabolites, such as glutathione, were significantly down-regulated. Furthermore, these significantly differential metabolites were mainly distributed in 13 metabolic pathways, such as the tricarboxylic acid (TCA) cycle. In addition, the metabolic fluxes of the glycolysis pathway, pentose phosphate pathway, TCA cycle, and glyoxylate pathway were increased by 20.45–29.32%, respectively, under the condition of feeding sodium citrate compared with the control. Finally, it was speculated that the upregulation of dihydroxyacetone level might increase the activity of alcohol oxidase AOX1 to promote methanol metabolism by combining metabolomics and fluxomics. Meanwhile, acetyl coenzyme A might enhance the activity of citrate synthase through allosteric activation to promote the flux of the TCA cycle and increase the level of intracellular oxidative phosphorylation, thus contributing to SAM production. These new insights into the L-methionine utilization for SAM biosynthesis by systematic biology in P. pastoris provides a novel vision for increasing its industrial production.
... In addition, another enriched pathway was carnitine synthesis, which is essential for transportation of fatty acids into the mitochondria for fatty acid oxidation. 54 Previous research has linked fatty acid oxidation to the development of various cancers, via increased ATP production driving tumor growth. 55 Similar to our study, both pyrimidine metabolism and carnitine synthesis were highlighted as pathways that may play pivotal roles in adenomyosis in a previous study utilizing myometrial tissues, 21 thus supporting the cervicovaginal signatures identified in our study. ...
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Adenomyosis is a burdensome gynaecologic condition that is associated with pelvic pain, dysmenorrhea, and abnormal uterine bleeding, leading to a negative impact on quality of life; and yet is often left undiagnosed. We recruited 108 women undergoing hysterectomy for benign gynaecologic conditions and collected non-invasive cervicovaginal lavage samples for immunometabolic profiling. Patients were grouped according to adenomyosis status. We investigated the levels of 72 soluble immune proteins and >900 metabolites using multiplex immunoassays and an untargeted global metabolomics platform. There were statistically significant alterations in the levels of several immune proteins and a large quantity of metabolites, particularly cytokines related to type II immunity and amino acids, respectively. Enrichment analysis revealed that pyrimidine metabolism, carnitine synthesis, and histidine/histamine metabolism were significantly upregulated pathways in adenomyosis. This study demonstrates utility of non-invasive sampling combined with immunometabolic profiling for adenomyosis detection and a greater pathophysiological understanding of this enigmatic condition.
... [31][32][33] Carnitine deficiency has been shown to correlate with cardiomyopathy. [34] Therefore, decreased carnitine levels may impair myocardial function. [33,35] It has been suggested that L-carnitine, especially with its antioxidant and lipid-lowering effects, may be able to reduce atherosclerotic lesions. ...
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Diabetes mellitus is one of the most prevalent metabolic diseases in existence. With more than 536.6 million cases having been diagnosed globally, its prevalence is reported to be 10.5% in 2021. In individuals with diabetes, plasma L-carnitine is low and metabolized abnormally. In this review, we aimed to assess whether L-carnitine supplementation is correlated with a reduction of the risk of cardiovascular diseases in individuals with diabetes by improving the compositions of lipid profiles, indicators of oxidative stress, glycemic control, and anthropometric indices. A literature search in major databases such as Web of Science, PubMed, Google Scholar, Scopus, and Scientific Information Database was conducted until November 2021. This was done in conjunction with a search in Elsevier and SpringerLink databases, resulting in the inclusion of relevant articles in this review. To construct the search strategy, “Carnitine” OR “glycine propionyl carnitine” OR “Acetylcarnitine” in combination with “Diabetes Mellitus” OR “Diabetes Complications” OR “Lipid Profile” and all of its components were used to search for and within the articles and databases. After screening, 10 articles published between 1998 and 2017 were identified. They evaluated the effect of L-carnitine on lipid profile metabolism, glycemic control, anthropometric indices, and oxidative stress markers in individuals with diabetes. In this systematic review, we concluded that L-carnitine had no notable effect on lipid profile as well as glycemic control and anthropometric indices. Therefore, using L-carnitine probably has no notable effect on metabolic status in individuals with diabetes. Meanwhile, some articles suggested that L-carnitine may have positive effects on some oxidative stress indicators.
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Background: Non-transfusion-dependent β-thalassaemia (NTDβT) is a subset of inherited haemoglobin disorders characterised by reduced production of the β-globin chain of haemoglobin leading to anaemia of varying severity. Although blood transfusion is not a necessity for survival, it may be required to prevent complications of chronic anaemia, such as impaired growth and hypercoagulability. People with NTDβT also experience iron overload due to increased iron absorption from food sources which becomes more pronounced in those requiring blood transfusion. People with a higher foetal haemoglobin (HbF) level have been found to require fewer blood transfusions, thus leading to the emergence of treatments that could increase its level. HbF inducers stimulate HbF production without altering any gene structures. Evidence for the possible benefits and harms of these inducers is important for making an informed decision on their use. Objectives: To compare the effectiveness and safety of the following for reducing blood transfusion for people with NTDβT: 1. HbF inducers versus usual care or placebo; 2. single HbF inducer with another HbF inducer, and single dose with another dose; and 3. combination of HbF inducers versus usual care or placebo, or single HbF inducer. Search methods: We used standard, extensive Cochrane search methods. The latest search date was 21 August 2022. Selection criteria: We included randomised controlled trials (RCTs) or quasi-RCTs comparing single HbF inducer with placebo or usual care, with another single HbF inducer or with a combination of HbF inducers; or comparing different doses of the same HbF inducer. Data collection and analysis: We used standard Cochrane methods. Our primary outcomes were blood transfusion and haemoglobin levels. Our secondary outcomes were HbF levels, the long-term sequelae of NTDβT, quality of life and adverse events. Main results: We included seven RCTs involving 291 people with NTDβT, aged two to 49 years, from five countries. We reported 10 comparisons using eight different HbF inducers (four pharmacological and four natural): three RCTs compared a single HbF inducer to placebo and seven to another HbF inducer. The duration of the intervention lasted from 56 days to six months. Most studies did not adequately report the randomisation procedures or whether and how blinding was achieved. HbF inducer against placebo or usual care Three HbF inducers, HQK-1001, Radix Astragali or a 3-in-1 combined natural preparation (CNP), were compared with a placebo. None of the comparisons reported the frequency of blood transfusion. We are uncertain whether Radix Astragali and CNP increase haemoglobin at three months (mean difference (MD) 1.33 g/dL, 95% confidence interval (CI) 0.54 to 2.11; 1 study, 2 interventions, 35 participants; very low-certainty evidence). We are uncertain whether Radix Astragali and CNP have any effect on HbF (MD 12%, 95% CI -0.74% to 24.75%; 1 study, 2 interventions, 35 participants; very low-certainty evidence). Only medians on haemoglobin and HbF levels were reported for HQK-1001. Adverse effects reported for HQK-1001 were nausea, vomiting, dizziness and suprapubic pain. There were no prespecified adverse effects for Radix Astragali and CNP. HbF inducer versus another HbF inducer Four studies compared a single inducer with another over three to six months. Comparisons included hydroxyurea versus resveratrol, hydroxyurea versus thalidomide, hydroxyurea versus decitabine and Radix Astragali versus CNP. No study reported our prespecified outcomes on blood transfusion. Haemoglobin and HbF were reported for the comparison Radix Astragali versus CNP, but we are uncertain whether there were any differences (1 study, 24 participants; low-certainty evidence). Different doses of the same HbF inducer Two studies compared two different types of HbF inducers at different doses over two to six months. Comparisons included hydroxyurea 20 mg/kg/day versus 10 mg/kg/day and HQK-1001 10 mg/kg/day, 20 mg/kg/day, 30 mg/kg/day and 40 mg/kg/day. Blood transfusion, as prespecified, was not reported. In one study (61 participants) we are uncertain whether the lower levels of both haemoglobin and HbF at 24 weeks were due to the higher dose of hydroxyurea (haemoglobin: MD -2.39 g/dL, 95% CI -2.80 to -1.98; very low-certainty evidence; HbF: MD -10.20%, 95% CI -16.28% to -4.12%; very low-certainty evidence). The study of the four different doses of HQK-1001 did not report results for either haemoglobin or HbF. We are not certain if major adverse effects may be more common with higher hydroxyurea doses (neutropenia: risk ratio (RR) 9.93, 95% CI 1.34 to 73.97; thrombocytopenia: RR 3.68, 95% CI 1.12 to 12.07; very low-certainty evidence). Taking HQK-1001 20 mg/kg/day may result in the fewest adverse effects. A combination of HbF inducers versus a single HbF inducer Two studies compared three combinations of two inducers with a single inducer over six months: hydroxyurea plus resveratrol versus resveratrol or hydroxyurea alone, and hydroxyurea plus l-carnitine versus hydroxyurea alone. Blood transfusion was not reported. Hydroxyurea plus resveratrol may reduce haemoglobin compared with either resveratrol or hydroxyurea alone (MD -0.74 g/dL, 95% CI -1.45 to -0.03; 1 study, 54 participants; low-certainty evidence). We are not certain whether the gastrointestinal disturbances, headache and malaise more commonly reported with hydroxyurea plus resveratrol than resveratrol alone were due to the interventions. We are uncertain whether hydroxyurea plus l-carnitine compared with hydroxyurea alone may increase mean haemoglobin, and reduce pulmonary hypertension (1 study, 60 participants; very low-certainty evidence). Adverse events were reported but not in the intervention group. None of the comparisons reported the outcome of HbF. Authors' conclusions: We are uncertain whether any of the eight HbF inducers in this review have a beneficial effect on people with NTDβT. For each of these HbF inducers, we found only one or at the most two small studies. There is no information on whether any of these HbF inducers have an effect on our primary outcome, blood transfusion. For the second primary outcome, haemoglobin, there may be small differences between intervention groups, but these may not be clinically meaningful and are of low- to very low-certainty evidence. Data on adverse effects and optimal doses are limited. Five studies are awaiting classification, but none are ongoing.
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The ability of the rat liver to synthesize camitine from γ-butyrobetaine increases from low values in the fetus to adult values on the 8th day after birth. The rate of synthesis of camitine is greater when determined in the high-speed supernatant than in the low-speed supernatant of the liver. No synthesis could be shown to occur in neonatal rat kidney or neonatal brown adipose tissue.
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We have previously described apparent active transport of carnitine into rat intestinal mucosa with intracellular accumulation against a concentration gradient in a process dependent upon the presence of sodium ions, oxygen, and energy. In the work described here, we sought to define the interaction between carnitine and the brush border membrane, which we presumed contained the transport mechanism. Using isolated rat jejunal brush border microvillous membrane vesicles, we found evidence of passive diffusion alone. We found no evidence of carrier-mediated transport—in particular no saturation over a concentration range, inhibition by structural analogs, transstimulation phenomenon, and no influence of sodium ions, potential difference or proton gradients. We conclude that a carnitine transporter does not exist in the brush border membrane of enterocytes and that other cellular mechanisms are responsible for the apparent active transport observed.
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The review begins with brief introductory remarks about the significance of carnitine. This is followed by a historical section on its discovery and function, ending with a listing of carnitine-dependent enzymes. Carnitine acetyltransferase then becomes the entire focus of the review. The ubiquity of the protein in tissues and organelles is emphasized in an initial section. A discussion of its enzymology follows, beginning with physical properties and kinetics and ending with substrate and inhibitor specificities. The review concludes with a discussion of proposed molecular mechanisms.