Case Report: Carnitine Palmitoyl Transferase II (CPT II) Deficiency

Carnitine Palmitoyl Transferase II (CPTII) is a very important enzyme that helps with the oxidation of long-chain fatty acid to produce energy. Deficiency in CPTII will lead to energy deficiency in the case of fasting and the accumulation of the long chain fatty in the body. There are three types of CPT II deficiency, the myopathic form, the severe infantile hepatocardiomuscular form and the lethal neonatal form. They are all inherited as an autosomal recessive. Diagnosis of the CPTII are 1) tandem mass spectrometry (MS/MS) in adult form and 2) CPTII polymorphism (F352C), which is linked to reducing the activity of CPTII in infantile form [1]. Glucose is the primary management and medium-chain fatty acid is an alternative due to the bypass of the CPTII enzyme in the pathway. For the prevention of CPTII deficiency are to avoid long chain fatty acid (C12-fatty acid), fasting, prolonged exercise, known triggers, and certain medications such as anti-epileptics and general anesthesia. During the rhabdomyolysis and myoglobinuria attack, it is very important to maintain hydration to avoid acute renal failure. If, however, renal failure occurs, dialysis is recommended. We present a case of a 27-year-old African American woman with the significant past medical history of CPT II deficiency leading to recurrent rhabdomyolysis and myoglobinuria. Together with all the research studies from diagnosis to treatment of CPTII deficiency will help in clinical management of patients. And this case report will add to the existing case reports of patients who have CPTII deficiency in terms of how we diagnose, how we treat, and how we prevent symptoms from re-occurring.

Mitochondrial carnitine palmitoyltransferase-Ⅱ dysfunction: A possible novel mechanism for nonalcoholic fatty liver disease in hepatocarcinogenesis

Nonalcoholic fatty liver disease(NAFLD)or metabolic-associated fatty liver disease has been characterized by the lipid accumulation with injury of hepatocytes and has become one of the most common chronic liver diseases in the world.The complex mechanisms of NAFLD formation are still under identification.Carnitine palmitoyltransferase-Ⅱ(CPT-Ⅱ)on inner mitochondrial membrane(IMM)regulates long chain fatty acidβ-oxidation,and its abnormality has had more and more attention paid to it by basic and clinical research in NAFLD.The sequences of its peptide chain and DNA nucleotides have been identified,and the catalytic activity of CPT-Ⅱ is affected on its gene mutations,deficiency,enzymatic thermal instability,circulating carnitine level and so on.Recently,the CPT-Ⅱ dysfunction has been discovered in models of liver lipid accumulation.Meanwhile,the malignant transformation of hepatocyte-related CD44^(+) stem T cell activation,high levels of tumor-related biomarkers(AFP,GPC3)and abnormal activation of Wnt3a expression as a key signal molecule of the Wnt/β-catenin pathway run parallel to the alterations of hepatocyte pathology.This review focuses on some of the progress of CPT-Ⅱ inactivity on IMM with liver fatty accumulation as a possible novel pathogenesis for NAFLD in hepatocarcinogenesis.

Acylcarnitine: Useful biomarker for early diagnosis of hepatocellular carcinoma in non-steatohepatitis patients

BACKGROUND Early diagnosis of hepatocellular carcinoma(HCC)is necessary to improve the prognosis of patients.However,the currently available tumor biomarkers are insufficient for the early detection of HCC.Acylcarnitine is essential in fatty acid metabolic pathways.A recent study reported that a high level of acylcarnitine may serve as a useful biomarker for the early diagnosis of HCC in steatohepatitis(SH)patients.In contrast,another study reported that the level of acetylcarnitine(AC2)-one of the acylcarnitine species-in non-SH patients with HCC was decreased vs that reported in those without HCC.AIM To investigate the usefulness of acylcarnitine as a biomarker for the early diagnosis of HCC in non-SH patients.METHODS Thirty-three non-SH patients(14 with HCC and 19 without HCC)were enrolled in this study.Blood samples were obtained from patients at the time of admission.The levels of acylcarnitine and AC2 in the serum were determined through tandem mass spectrometry.The levels of vascular endothelial growth factor(VEGF)and VEGF receptor 2(VEGFR-2)were determined by enzymelinked immunosorbent assay.Univariate and multivariate analyses were used to determine early diagnostic factors of HCC.RESULTS The level of acylcarnitine was significantly lower in non-SH patients with HCC vs those without HCC(P<0.05).In contrast,the level of lens culinaris agglutininreactive fraction ofα-fetoprotein(AFP)-AFP-L3%-was significantly higher in non-SH patients with HCC vs those without HCC(P<0.05).However,the levels of total carnitine,free carnitine,AFP,des-γ-carboxy prothrombin,VEGF,and VEGFR-2 were not different between patients with and without HCC.The multivariate analysis showed that a low level of acylcarnitine was the only independent factor for the early diagnosis of HCC.The patients with a low level of AC2 had a significantly higher level of VEGF vs those with a high level of AC2(P<0.05).CONCLUSION The metabolic pathways of fatty acids may differ between SH HCC and non-SH HCC.Further studies are warranted to investigate these differences.

A study of the ameliorating effects of carnitine on hepatic steatosis induced by total parenteral nutrition in rats

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Mitochondrial carnitine palmitoyl transferase-Ⅱ inactivity aggravates lipid accumulation in rat hepatocarcinogenesis

AIM To investigate the dynamic alteration of mitochondrial carnitine palmitoyl transferase Ⅱ(CPT-Ⅱ) expression during malignant transformation of rat hepatocytes.METHODS Sprague-Dawley male rats were fed with normal, high fat(HF), and HF containing 2-fluorenylacetamide(2-FAA) diet, respectively. According to the Hematoxylin and Eosin staining of livers, rats were divided into control, fatty liver, degeneration, pre-cancerous, and cancerous groups. Liver lipids were dyed with Oil Red O, CPT-Ⅱ alterations were analyzed by immunohistochemistry, and compared with CPT-Ⅱ specific concentration(μg/mg protein). Levels of total cholesterol(Tch), triglyceride(TG), and aminotransferases [alanine aminotransferase(ALT), aspartate aminotransferase(AST)] were determined by the routine methods.RESULTS After intake of HF and/or HF+2-FAA diets, the rat livers showed mass lipid accumulation. The lipid level in the control group was significantly lower than that in other groups. The changes of serum TG and Tch levels were abnormally increasing, 2-3 times more than those in the controls(P < 0.05). During the rat liver morphological changes from normal to cancer development process with hepatocyte injury, serum AST and ALT levels were significantly higher(4-8 times, P < 0.05) than those in the control group. The specific concentration of CPT-Ⅱ in liver tissues progressively decreased during hepatocyte malignant transformation, with the lowest CPT-Ⅱ levels in the cancer group than in any of the other groups(P < 0.05).CONCLUSION Low CPT-Ⅱ expression might lead to abnormal hepatic lipid accumulation, which should promote the malignant transformation of hepatocytes.

Autism and carnitine: A possible link

Patients with autism spectrum disorders(ASD) present deficits in social interactions and communication, they also show limited and stereotypical patterns of behaviors and interests. The pathophysiological bases of ASD have not been defined yet. Many factors seem to be involved in the onset of this disorder. These include genetic and environmental factors, but autism is not linked to a single origin, only. Autism onset can be connected with various factors such as metabolic disorders: including carnitine deficiency. Carnitine is a derivative of two amino acid lysine and methionine. Carnitine is a cofactor for a large family of enzymes: the carnitine acyltransferases. Through their action these enzymes(and L-carnitine) are involved in energy production and metabolic homeostasis. Some people with autism(less than 20%) seem to have L-carnitine metabolism disorders and for these patients, a dietary supplementation with Lcarnitine is beneficial. This review summarizes the available information on this topic.

L-carnitine protects C2C12 cells against mitochondrial superoxide overproduction and cell death

AIM To identify and characterize the protective effect that L-carnitine exerted against an oxidative stress in C2C12 cells.METHODS Myoblastic C2C12 cells were treated with menadione, a vitamin K analog that engenders oxidative stress, and the protective effect of L-carnitine(a nutrient involved in fatty acid metabolism and the control of the oxidative process), was assessed by monitoring various parameters related to the oxidative stress, autophagy and cell death. RESULTS Associated with its physiological function, a muscle cell metabolism is highly dependent on oxygen and may produce reactive oxygen species(ROS), especially under pathological conditions. High levels of ROS are known to induce injuries in cell structure as they interact at many levels in cell function. In C2C12 cells, a treatment with menadione induced a loss of transmembrane mitochondrial potential, an increase in mitochondrial production of ROS; it also induces autophagy and was able to provoke cell death. Pre-treatment of the cells with L-carnitine reduced ROS production, diminished autophagy and protected C2C12 cells against menadione-induced deleterious effects. CONCLUSION In conclusion, L-carnitine limits the oxidative stress in these cells and prevents cell death.

Diabetic Cardiovascular Risk and Carnitine Deficiency <br/>—Carnitine Deficiency in Clinical Diabetes Mellitus

Background: Type 1 diabetes mellitus increases the risk of coronary heart disease. The Pittsburgh IDDM morbidity and mortality study reported greater than 10 fold coronary heart disease mortality compared with US national data?[1]. Adults with diabetes have heart disease death rates 2 to 4 times higher than adults without diabetes [2]. Diabetic cardiomyopathy explains much of this survival difference and carnitine deficiency is a cause of cardiomyopathy. Research Design and Methods: Adult subjects (40) with type 1 diabetes mellitus were seen for a routine annual visit having no clinical complaints. Fasting serum samples were collected for annual chemistries and the measurement of carnitine. Results: The mean total (40.8 ± 8.8) [40 - 80 nmol/ml] and free (32.9 ± 7.9) [30 - 60 nmol/ml] carnitine levels for this group included 43% low total and 28% low free carnitine. The mean esterified/free (E/F) carnitine ratio (0.25 ± 0.09) for this group was elevated indicating carnitine insufficiency. Conclusions: Fatty acids are the primary energy source for diabetic heart muscle, and carnitine is essential for intracellular fatty acid transport and ATP production. Therefore, mild carnitine deficiency can compromise fatty acid energy production in a failing heart. Carnitine deficiency in subjects at high risk for cardiovascular failure is a possible unrecognized reason for the 4 fold increased death rate in patients with type 1 diabetes. Supplementation with oral carnitine could reduce that increased risk of heart failure, in patients with type 1 diabetes. Intravenous carnitine may be life saving when managing acute cardiac failure in patients with diabetes mellitus. Normal carnitine levels in patients with type 1 diabetes may provide a biochemical environment that prevents the long recognized idiopathic heart failure that occurs in insulin requiring diabetics as first reported in the 1974 Framingham Study.

Carnitine Deficiency and Improvement of Muscle Cramp by Administration of Carnitine in Patients with Liver Cirrhosis

Aim: We measured carnitine levels in patients with carnitine including dialysis patients, and examined whether administration of L-carnitine improved muscle symptoms. Methods: We measured carnitine levels in 27 patients with liver cirrhosis who were receiving treatment in our hospital, and administered L-carnitine (600 mg - 1800 mg) to patients having muscle cramps for approximately one month and examined the presence/absence of the symptom. We measured carnitine concentration before and after dialysis, before dialysis after the administration to eight dialysis patients, before and after the administration to 19 nondialytic patients. Results: The total carnitine levels before the dialysis of dialysis patients were an average of 42.2 μmol/L and fell to 17.7 μmol/L after more dialysis, but it was increased to 155 μmol/L after the administration of L-carnitine. In the nondialytic patients, the total carnitine levels were significantly increased from 71.7 μmol/L to 101.7 μmol/L after the administration of L-carnitine (P = 0.038). For symptomatic patients, significant improvement of muscle clamps was observed in the L-carnitine administrated group when compared with the non-administrated group (P = 0.0002). Conclusions: Total carnitine levels were low even before dialysis in the dialysis patients with liver cirrhosis in particular and they further decreased after the dialysis. Administration of L-carnitine increased the total carnitine levels and improved the symptom. Based on these results, we conclude that L-carnitine is useful for carnitine deficiency in patients with liver cirrhosis.

Quality Evaluation of Carnitine for Proper Use of Supplement

In recent years, consumers are becoming more health-conscious. Supplements are becoming popular as they can be purchased easily. In Japan, the “Food with Function Claims” system began in 2015;the market for supplements is expected to continue to expand. However, the use of some supplements has not been supported with sufficient scientific evidence;some products have even caused health problems. In addition, consumers may not be able to make correct decisions based on the information from the Internet. Unlike medicine, the instruction on the usage of supplements is not precise. Therefore, improving the quality of the information on the supplements will become more necessary in the future. This study aims to improve the quality of the information on supplements by surveying the disintegration and dissolution behavior of the carnitine-containing supplements and evaluated their quality. The products tested here were supplements containing commercial carnitine. Disintegration test and dissolution test were conducted according to the Japanese Pharmacopoeia. Carnitine was quantified by high-performance liquid chromatography. The disintegration tests revealed that the products had different disintegration times, varying from 35 to 100 minutes;some products took more than 5 hours to disintegrate. Thus, some products had a slow rise in their dissolution rate. These results suggest that the carnitine-containing supplements used in this study may affect the absorption process. Therefore, in the case of oral administration, the expected effect might not be achieved depending on the product.

Carnitine palmitoyl transferase 1C regulates tumor cell senescence

OBJECTIVE Passage-dependent cel ular senescence is a complex process limiting the proliferative lifespan of tumor cells but the mechanism of this process is not understood.METHODS Replicative senescenceof pancreatic carcinoma-derived PANC-1 cells wasanalyzed.Metabolomics and transcriptomic analyses were performed to find endogenous metabolites changed andassociated genes.Mitochondrial function,cell survival andtumorigenesis of replicative senescent PANC-1 cellswere analyzed.PANC-1 cells were transfected with RNAi CPT1C to specifically knockdown CPT1C expressions,then mitochondrial function,cellular senescence,cell survival and tumorigenesis were investigated.MDA-MB-231,HCT116,A549,MCF7,and He Lacells werealso transfected with si RNA CPT1C and cellular senescence were monitored.RESULTS Replicative senescenceof PANC-1 cells was confirmed.Metabolomic and transcriptomicanalyses revealed that acylcarnitines and their upstream regulator carnitine palmitoyltransferase 1C(CPT1C),an enzyme that catalyzes the initiating step of fatty acidβ-oxidation,were markedly decreased in senescent PANC-1 cells.Furthermore,low CPT1C expression caused abnormal energy metabolism and mitochondrial dysfunction of PANC-1 cells,resulting in decreased cell survival and a suppressed tumorigenesis.Most importantly,loss of CPT1C triggered mitochondrial dysfunction,leading to senescence-like growth suppression and cellular senescence,suppressed cell survival under metabolic stress,and lower tumorigenesis in a mouse xenograft model.Silencing of CPT1C also induced cellular senescence in five other tumor cell lines.CONCLUSION Low CPT1C expression is a novel biomarker and key regulator of cellular senescence in tumor cell lines.Inhibition of CPT1C may be a new cancer therapeutic target impacting cellular senescence and tumorigenesis through modulation of mitochondrial function.

Effect of Acupuncture on Carnitine for Skeletal Muscle Fatigue

Skeletal muscle fatigue is a common symptom in various diseases, works and exercises. These were generally induced by neuron, metabolic conditions, overused muscle, and stress. But, there have been few principles about it. Many researchers have reported that acupuncture therapy has been useful to skeletal muscle fatigue on various diseases and conditions. However, it has never been shown why acupuncture therapy has the effect on skeletal muscle fatigue. The deficiency of carnitine induces fatigue, weakness, and disorder of skeletal muscle. It has showed that acupuncture induces the increase of carnitine in skeletal muscle. These findings demonstrated that acupuncture on skeletal muscle fatigue could increase carnitine as a possible affection mechanism.

Rethinking neurodegenerative diseases:neurometabolic concept linking lipid oxidation to diseases in the central nervous system

Currently,there is a lack of effective medicines capable of halting or reve rsing the progression of neurodegenerative disorde rs,including amyotrophic lateral sclerosis,Parkinson s disease,multiple sclerosis,or Alzheimer s disease.Given the unmet medical need,it is necessary to reevaluate the existing para digms of how to to rget these diseases.When considering neurodegenerative diseases from a systemic neurometabolic perspective,it becomes possible to explain the shared pathological features.This innovative approach presented in this paper draws upon exte nsive research conducted by the authors and researchers worldwide.In this review,we highlight the importance of metabolic mitochondrial dysfunction in the context of neurodegenerative diseases.We provide an overview of the risk factors associated with developing neurodegenerative disorders,including genetic,epigenetic,and environmental fa ctors.Additionally,we examine pathological mechanisms implicated in these diseases such as oxidative stress,accumulation of misfolded proteins,inflammation,demyelination,death of neurons,insulin resistance,dysbiosis,and neurotransmitter disturbances.Finally,we outline a proposal for the restoration of mitochondrial metabolism,a crucial aspect that may hold the key to facilitating curative therapeutic interventions for neurodegenerative disorders in forthcoming advancements.

左卡尼汀在新生儿的临床应用

肉碱（carnitine）音译为＂卡尼汀＂,其有生物活性的异构体为左卡尼汀（levocarnitine）,是哺乳动物能量代谢必需的体内天然物质。研究表明,左卡尼汀是新生儿一种条件性必需营养素[1-2]。左卡尼汀最重要的代谢功能是能协助长链脂肪酸（long-chain fatty aicds,LCFAs）转运至线粒体内进行β-氧化和产能[3]。

A simplified LC-MS/MS method for the quantification of the cardiovascular disease biomarker trimethylamine-N-oxide and its precursors

Trimethylamine-N-oxide(TMAO)has emerged as a potential biomarker for atherosclerosis and the development of cardiovascular diseases(CVDs).Although several clinical studies have shown striking associations of TMAO levels with atherosclerosis and CVDs,TMAO determinations are not clinical routine yet.The current methodology relies on isotope-labeled internal standards,which adds to pre-analytical complexity and costs for the quantification of TMAO and its precursors carnitine,betaine or choline.Here,we report a liquid chromatography-tandem mass spectrometry based method that is fast(throughput up to 240 samples/day),consumes low sample volumes(e.g.,from a finger prick),and does not require isotope-labeled standards.We circumvented the analytical problem posed by the presence of endogenous TMAO and its precursors in human plasma by using an artificial plasma matrix for calibration.We cross-validated the results obtained using an artificial matrix with those using mouse plasma matrix and demonstrated that TMAO,carnitine,betaine and choline were accurately quantified in’reallife’human plasma samples from healthy volunteers,obtained either from a finger prick or from venous puncture.Additionally,we assessed the stability of samples stored at-20℃and room temperature.Whereas all metabolites were stable at-20℃,increasing concentrations of choline were determined when stored at room temperature.Our method will facilitate the establishment of TMAO as a routine clinical biomarker in hematology in order to assess the risk for CVDs development,or to monitor disease progression and intervention effects.

Intestinal OCTN2-and MCT1-targeted drug delivery to improve oral bioavailability

Various drug transporters are widely expressed throughout the intestine and play important roles in absorbing nutrients and drugs,thus providing high quality targets for the design of prodrugs or nanoparticles to facilitate oral drug delivery.In particular,intestinal carnitine/organic cation transporter 2(OCTN2)and mono-carboxylate transporter protein 1(MCT1)possess high transport capacities and complementary distributions.Therefore,we outline recent developments in transporter-targeted oral drug delivery with regard to the OCTN2 and MCT1 proteins in this review.First,basic information of the two transporters is reviewed,including their topological structures,characteristics and functions,expression and key features of their substrates.Furthermore,progress in transporter-targeting prodrugs and nanoparticles to increase oral drug delivery is discussed,including improvements in the oral absorption of anti-inflammatory drugs,antiepileptic drugs and anticancer drugs.Finally,the potential of a dual transporter-targeting strategy is discussed.

Late-onset multiple acyl-CoA dehydrogenase deficiency with cardiac syncope: A case report

BACKGROUND Multiple acyl-CoA dehydrogenase deficiency(MADD)is an uncommon autosomal recessive disorder of mitochondrial fatty acid beta-oxidation.Syncope is a transient loss of consciousness due to acute global cerebral hypoperfusion.Late-onset MADD with syncope has not been reported previously.CASE SUMMARY We report a 17-year-old girl with exercise intolerance and muscle weakness.She felt palpitation and shortness of breath after short bouts of exercise.She also suffered from a transient loss of consciousness many times.Muscle biopsy showed lipid storage.Genetic mutation analysis indicated a compound heterozygous mutation c.250G>A(p.A84T)and c.872T>G(p.V291G)in the ETFDH gene.The results of Holter electrocardiogram monitoring showed supraventricular tachycardia when the patient experienced a loss of consciousness.After treatment with riboflavin and carnitine,muscle weakness and palpitation symptoms improved rapidly.No loss of consciousness occurred,and the Holter electrocardiogram monitoring was normal.CONCLUSION Late-onset MADD with supraventricular tachycardia can cause cardiac syncope.Carnitine and riboflavin supplement were beneficial for treating the late-onset MADD with cardiac syncope.Attention should be paid to the prevention of cardiac syncope when diagnosing late-onset MADD.

左旋肉碱的减肥功效

左旋肉碱（L-carnitine）又称肉毒碱或维生素B7,是一种促使脂肪转化为能量的类氨基酸,对于左旋肉碱的研究始于20世纪初。1905年两位俄国研究者Gulewitsch和Krimberg从肉汁提取物中发现了L-肉碱,自此以后,各国科学家进行了深入的研究。20世纪80年代以来,国外已有含L-肉碱的商品,已列入美国药典。我国卫生部也将其列入营养强化剂。

Exploratory metabolomics of metabolic syndrome: A status report

Metabolic syndrome(MetS) is as a cluster of cardio-metabolic factors that greatly increase the risk of chronic diseases such as type II diabetes mellitus and atherosclerotic cardiovascular disease. In the United States, obesity, physical inactivity, aging, and genetics(to a minor extent) have arisen as risk factors for developing MetS. Although 35% of American adults suffer from MetS, its pathogenesis largely remains unknown. Worse, there is a lack of screening and optimum therapy for this disease. Researchers have consequently turned towards metabolomics to identify biomarkers to better understand MetS. The purpose of this review is to characterize various metabolites and their potential connections to MetS. Numerous studies have also characterized MetS as a disease of increased inflammation, and therefore this review also explores how metabolites play a role in various inflammatory pathways. Our review explores a broad range of metabolites including biogenic amines, branched chain amino acids, aromatic amines, phosphatidylcholines, as well as a variety of other molecules. We will explore their biochemical pathways and their potential role in serving as biomarkers.