Role of carnitine in disease

“Based on the evidence that heat-shock proteins (Hsps) can exert neuroprotective effects against oxidative stress-related injury and that nutritional antioxidants are able to upregulate Hsps in neurons, use of nutritional antioxidants such as carnitine/acetyl-L-carnitine has been advocated to counteract the oxidative s…”

“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [77-80].”

“Chronic ingestion of alcohol is known to cause hepatic steatosis [69,70].”

“Dry eye is a common disease of the ocular surface that is associated with corneal surface irregularity and blurred vision [155-158].”

“Several mutations have been described [21,22,25,26, 29 ,31-33].”

“However, this is in contrast with other studies that found CPT-1 inhibition actually stimulated hypophagia [76,77] and weight loss [77].”

“ALCA, together with alpha-lipoic acid, was shown to improve mitochondrial energy metabolism and decrease oxidative stress leading to improved memory in aged rats [ 144 ,145].”

“Patients with secondary carnitine deficiency accumulate organic acids which causes enhanced urinary excretion of carnitine in the form of acyl-carnitines [36,37].”

“This deficiency is often triggered by heavy exercise, and can also manifest as a result of exposure to cold, infection, emotional distress, and/or fasting [132].”

“Dry eye is a common disease of the ocular surface that is associated with corneal surface irregularity and blurred vision [155-158].”

“Bioavailability of oral carnitine dietary supplements is only in the order of 14 to 18% of dose and unabsorbed L-carnitine is mostly degraded by micoorganisims in the large intestine [3].”

“Acetyl-L-carnitine is the principal acylcarnitine ester [12].”

“Adverse effects of aging are, in part, attributed to decreases in mitochondrial function and increases mitochondrial oxidant production [141].”

“The pathway in mammals is unique using protein-bound lysine that is enzymatically methylated to form trimethyllysine as a post-translational modification of protein synthesis [6].”

“Glutaryl-CoA dehydrogenase (GCDH) deficiency is an inborn error of lysine and tryptophan metabolism that results in increased formation and excretion of glutaric acid (GA), 3-hydroxyglutaric acid (3-OH-GA), glutaconic acid and glutarylcarnitine [82].”

“GCDH can be controlled nutritionally and supplementation includes L-carnitine to avoid secondary carnitine depletion [84-87].”

“Dry eye is a common disease of the ocular surface that is associated with corneal surface irregularity and blurred vision [155-158].”

“ALCA, together with alpha-lipoic acid, was shown to improve mitochondrial energy metabolism and decrease oxidative stress leading to improved memory in aged rats [144,145].”

“The authors discuss whether CNS injection of the drug versus systemic treatment may play an important role in the overall effect.”

“As the disease progresses however it becomes increasingly nonresponsive to therapeutic interventions [92,93].”

“Acetyl-L-carnitine (ALCA) fed to aged rats was shown to reverse age-related declines in tissue L-carnitine levels and also reversed a number of age-related changes in liver mitochondrial function; however, high doses of ALCA increased liver mitochondrial oxidant production [ 143 ].”

“In ischemia, L-carnitine reduces myocardial injury mainly through improving carbohydrate metabolism and by reducing the toxicity of high free fatty acid levels [124].”

“In both experimental models and human diabetic subjects, there is an initial metabolic phase that is responsive to metabolic corrections [90,91].”

“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [77-80].”

“Conclusion Carnitine as a nutritional supplement has, since the 1960s, been promoted as beneficial in a number of disorders of human carnitine deficiency of impaired fatty acid oxidation, suggesting that nutritional or pharmacologic supplements of carnitine might be beneficial in some disorders [168].”

“The heart is one of the organs most affected in carnitine-acylcarnitine carrier (CAC) deficiency [120].”

“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [77-80].”

“Carnitine has been trialed in cases of sepsis and found to retard protein loss without affecting protein metabolism in target tissues [94].”

“Several mutations have been described [21,22,25,26,29,31-33].”

“As opposed to PCD, SCD occurs due to, or in association with, other disorders such as liver or kidney disease, defects in fatty acid metabolism, or administration of pharmacological agents such as pivampicillin or valproic acid (discussed below) [27,41,42].”

“The most likely reason for incapacity to synthesize carnitine from lysine and methionine is inability to convert γ-butyrobetaine to carnitine [68].”

“PCD occurs in 1-5 per 10, 000 population and most commonly manifests between ages 1-7 [28,29].”

“L-carnitine therapy could also be valuable in those patients who develop VPA-induced hepatotoxicity or VPA-induced hyperammonaemic encephalopathy [133].”

“Ascorbic acid, ferrous iron, pyroxidine and niacin are also necessary cofactors [1] and deficiencies of any of these can lead to carnitine deficiency.”

“In patients with chronic heart disease, administration of L-carnitine over 12 months led to attenuation of left ventricular dilatation and prevented ventricular remodeling while reducing incidence of chronic heart failure and death [125].”

“have suggested that there may be mechanisms beyond antioxidant activities playing a neuroprotective role [118].”

“There have been reported at least 15 syndromes in which carnitine deficiency seems to be secondary to genetic defects of intermediary metabolism or to other conditions [40].”

“Several mutations have been described [21,22,25,26,29,31-33].”

“Bioavailability of L-carnitine in individuals such as vegetarians who are adapted to low-carnitine diets is higher (66% to 86% of available carnitine) than regular red-meat eaters adapted to high-carnitine diets (54% to 72% of available carnitine) [4].”

“VPA is used to treat psychiatric disorders and as such there is an association with accidental or deliberate overdose, the incidence of which is increasing [135,136].”

“2 μmol/kg of body weight/day [7].”

“Benefits of oral L-carnitine in relation to VPA-associated deficiency and related adverse effects have been reported [137-139].”

“Myoglobinuria, the traditional hallmark of this disease was not present in 21% patients in one study [48].”

“There is some debate in the literature regarding whether satiety depends on the cytosolic concentration of long-chain fatty acids, with the suggestion that an increased concentration correlates with satiety and decreased feeding and body weight [ 77-80 ].”

“Increased tear osmolarity in dry eye disease has been found to stimulate production of inflammatory cytokines and matrix metalloproteinases by ocular surface epithelial cells [155].”

“Chronic ingestion of alcohol is known to cause hepatic steatosis [69,70].”

“L-carnitine has been shown to have favorable effects in patients with severe cardiovascular disorders, such as coronary heart disease, chronic heart failure and peripheral vascular disease [123-125].”

“GCDH can be controlled nutritionally and supplementation includes L-carnitine to avoid secondary carnitine depletion [84-87].”

“Tears of patients with dry eye show significantly increased osmolarity, with a mean value of 343 mOsm compared with 302 mOsm in healthy controls [162].”

“Secondary carnitine depletion due to increased formation and urinary excretion of glutarylcarnitine is suggested to play an important role in the neuropathogenesis of GCDH deficiency, inducing excitotoxic neuronal damage and mitochondrial dysfunction [83].”

“The nucleotide sequences of cDNA and genomic DNA encoding human CPTI have been characterized [45,46].”

“It is known that dietary absorption of amino acids is impaired by ethanol so this could also contribute to carnitine deficiency overall [73].”

“Al-Majed and colleagues [ 140 ] found that carnitine deficiency and oxidative stress are risk factors during development of cisplatin (CDDP)-induced cardiomyopathy and that carnitine supplementation, using propionyll-carnitine, prevents the progression of CDDP-induced”

“The perinatal disease is the most severe form and is invariably fatal [34].”

“Finally, incremental growth was seen in 22 of 33 carnitine-administered patients who presented with failure to thrive [110] and this was attributed to the role of carnitine as a muscle growth factor.”

“Minimal hepatic encephalopathy (MHE) is a serious and common complication that occurs in the majority of cirrhotic patients [ 59 ].”

“One suggested mechanism of carnitine action is its reduction of serum ammonia levels leading to improved psychometric measures [63-65].”

“Carnitine transporter mutations in Crohn's disease consists of missense mutation(s) in the gene coding plasma membrane transporter OCTN1 (SLC22A4) and/ or mutation(s) in the promoter of the gene encoding OCTN2 (SLC22A5) [14,35].”

“Uptake in skeletal and cardiac muscle is a saturable active transport process against a concentration gradient [ 16 ].”

“Chorioretinopathy emerges during early childhood as granular pigmentation of the central fundus with or without pigment clumping which may progress to chorioretinal atrophy, high myopia, posterior staphyloma and low vision [165].”

“L-carnitine levels in tissues have been found to decline with age [142].”

“Supplementation of the diet with lysine can restore carnitine levels, however, there appeared to be impairment of carnitine biosynthesis in ethanol-compromised livers in the rat study [71].”

“Benefits of oral L-carnitine in relation to VPA-associated deficiency and related adverse effects have been reported [137-139].”

“Impairment of excretion of AC occurs with deteriorating renal function leading to decreased carnitine clearance and resulting in elevated plasma levels of carnitine [13].”

“[121] demonstrated in a rat model that chronic administration of LC reduces blood pressure and attenuates the inflammatory process associated with arterial hypertension.”

“Secondary carnitine deficiency can be caused by increased losses, pharmacological therapy, a number of inherited metabolic disorders [38], poor diet or malabsorption of carnitine, from increased renal tubular loss of free carnitine (Fanconi syndrome), haemodialysis, peritoneal dialysis, or the increased excretion of a…”

“It has been further suggested that carnitine deficiency might negatively impact cardiac function which might in turn, further contribute to the outcome of patients suffering sepsis [97-99].”

“Several mutations have been described [21,22,25,26,29,31-33].”

“Plasma concentration of free carnitine is in dynamic balance with acylcarnitines with the acyl to fee carnitine ration of ≤ 0.4 being considered normal [ 11 ].”

“However the dietary impact is controversial [166].”

“There has even been suggestion that maintenance of normal carnitine levels might inhibit muscle wasting, hepatic lipogenesis, hypertriglycerdemia and decreased fatty acid oxidation that are seen in sepsis [ 95 ].”

“Ascorbic acid, ferrous iron, pyroxidine and niacin are also necessary cofactors [1] and deficiencies of any of these can lead to carnitine deficiency.”

“Patients with secondary carnitine deficiency accumulate organic acids which causes enhanced urinary excretion of carnitine in the form of acyl-carnitines [36,37].”

“It has been shown that cells of the osteoblastic lineage generate 40-80% of their energy demands through fatty acid oxidation [153].”

“L-Carnitine supplementation an lead to improvements in several complications seen in uremic patients, including cardiac complications, impaired exercise and functional capacities, muscle symptoms, increased symptomatic intradialytic hypotension, and erythropoietin-resistant anemia through normalizing the reduced carni…”

“Carnitine transporter mutations in Crohn's disease consists of missense mutation(s) in the gene coding plasma membrane transporter OCTN1 (SLC22A4) and/ or mutation(s) in the promoter of the gene encoding OCTN2 (SLC22A5) [14,35].”

“Due to defective renal absorption (free) carnitine is excreted in the urine of patients with primary deficiency and can result in tissue carnitine levels dropping to below 10% of normal [14,22,24-26].”

“Several mutations have been described [21,22,25,26,29,31-33].”

“There is a strong correlation between hepatic encephalopathy and abnormal ammonia handling, and ALC has been shown to induce ureagenesis leading to decreased blood and brain ammonia levels [ 60 ].”

“Administration of a combination of mitochondrial targeting nutrients, including carnitine, suggested carnitine may be effective in improving immune function in type 2 diabetes through enhancement of mitochondrial function, decreased oxidative damage, and delayed cell death in the immune organs and blood [81].”

“Siemes H, Nau H, Schultze K, Wittfoht W, Drews E, Penzien J, Seidel U: Valproate (VPA) metabolites in various clinical conditions of probable VPA-associated hepatotoxicity.”

“Xue and colleagues suggest that the beneficial effects of L-carnitine in cardiovascular disease are due to the resumption of normal oxidative metabolism and restoration of myocardial energy reserves [ 128 ,129].”

“Experiments with fasted and calorie-restricted rats showed increased mRNA concentrations of acyl-CoA and CPT-1 in the liver, heart and kidneys compared to control animals due to upregulation of PPARα [111].”

“Carnitine levels decrease with age [151].”

“Malnutrition, fasting and vegetarianism Reduced plasma carnitine levels have been noted in malnourished children [ 106 ] and adults [107].”

“GCDH can be controlled nutritionally and supplementation includes L-carnitine to avoid secondary carnitine depletion [84-87].”

“Secondary carnitine deficiency can be caused by increased losses, pharmacological therapy, a number of inherited metabolic disorders [38], poor diet or malabsorption of carnitine, from increased renal tubular loss of free carnitine (Fanconi syndrome), haemodialysis, peritoneal dialysis, or the increased excretion of a…”

“As the disease progresses however it becomes increasingly nonresponsive to therapeutic interventions [92,93].”

“A selective CPT-1 stimulator produced long lasting hypophagia (reduced food intake) and persistent weight loss [75].”

“Reduced plasma carnitine levels have been noted in malnourished children [106] and adults [107].”

“The nucleotide sequences of cDNA and genomic DNA encoding human CPTI have been characterized [45,46].”

“Use of carnitine in artificial tears has demonstrated rapid and consistent improvements in signs and symptoms in patients with dry eye [159] suggesting an intrinsic homeostatic role for carnitine in the eye [160].”

“Several studies have reported that supplementing rats with both L-carnitine and alpha-lipoic acid halts age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in heart, skeletal muscle and brain, concomitant with improvement in mitochondrial enzyme and…”

“Recently, Pescosolido and colleagues [161] evaluated the presence of carnitine in tears of dry eye patients and suggested that the damage incurred on the ocular surface of dry eye patients may, in part, be due to a lack of carnitine in the tear film of these patients relative to the ocular surface cells and suggested…”

“Hyperthyroid patients exhibit higher urinary carnitine concentrations compared with controls while hypothyroid patients exhibit concomitantly lower levels [88].”

“Several mutations have been described [21,22,25,26,29,31-33].”

“A study of plasma and urinary levels of free carnitine and short-chain acyl-carnitines in surgical patients showed that the septic state was associated with increased urinary excretion of free carnitine and lower plasma levels of short-chain acyl-carnitines [101].”

“L-carnitine reduces early mortality but not overall risk of death or heart failure at 6 months [127].”

“One suggested mechanism of carnitine action is its reduction of serum ammonia levels leading to improved psychometric measures [63-65].”

“Several studies have reported that supplementing rats with both L-carnitine and alpha-lipoic acid halts age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in heart, skeletal muscle and brain, concomitant with improvement in mitochondrial enzyme and…”

“Its transport within cells of various tissues is limited by their respective uptake capacities [10].”

“One suggested mechanism of carnitine action is its reduction of serum ammonia levels leading to improved psychometric measures [63-65].”

“Patients with Duchenne dystrophy and Becker dystrophy showed lower carnitine levels in muscle biopsies than controls [131] though these levels were higher than in patients suffering primary carnitine deficiency as a result of severe muscle damage [1].”

“Carnitine levels are reduced in patients suffering Gram-negative sepsis and urinary loss of carnitine is proportional to the degree of injury [96].”

“During sustained low to moderate exercise, fatty acid oxidation increases to become the predominant energy source to muscles [17].”

“As opposed to PCD, SCD occurs due to, or in association with, other disorders such as liver or kidney disease, defects in fatty acid metabolism, or administration of pharmacological agents such as pivampicillin or valproic acid (discussed below) [27,41,42].”

“Using an aging ovariectomized rat model they found supplementation of L-carnitine can influence bone density and slow the rate of bone turnover by slowing bone loss and improving bone microstructural properties through decreasing bone turnover [154].”

“Roomets et al. examined the expression of CPT-1 isoforms in photoreceptor cells and retinal pigment epithelial cells that are known to be affected morphologically and functionally in complete MTP deficiency and deficiency of long-chain 3-hydroxyacyl-CoA hydratase (LCHAD) [ 167 ].”

“[100] have suggested that inhibition of myocardial CPT I activity may be a common feature of systemic inflammation, or of inflammation localized to the heart.”

“Oxidized fat was shown to upregulate PPARα and OCNT2 and lead to reduced rate of weight gain compared to controls, indicating an impairment of the feed conversion ratio [112].”

“There have been varying reports of urinary freecarnitine excretion with PEM as either increasing [108] or decreasing [109].”

“In relation to burns and wound healing; one study involving 14 patients with severe burns over eight days showed dramatically increased levels of excreted carnitine [ 102 ].”

“There appears to be an anomalous storage of mitochondrial ATP synthase subunit c that is neither the result of mutation nor enhanced expression of the protein but rather a slower degradation of the mitochondrial ATP synthase in comparison with normal cells [116].”

“carnitine which is available for acylation [72].”

“In one example of a physiological response to osmotic pressure, in early mammary gland milk production osmoregulatory pathways are exploited using asymmetric kinetics to increase the carnitine concentration in milk for suckling neonates who have reduced carnitine stores, even though this results in decreased maternal…”

“They further suggest that accumulation of 3-hydroxylated intermediates of long-chain fatty acids may contribute to the pathogenesis of retinopathy in MTP deficiencies [ 164 ].”

“Acetyl-L-carnitine is neuroprotective when administered at supraphysiological concentration [114].”

“Origlia and colleagues further demonstrated L-PC-associated reduction in lipid hydroperoxide content and morphological abnormalities associated with chronic CyA administration [57].”

“However acetylL-carnitine was not found to benefit young men suffering Down's Syndrome [117].”

“[163]) might be related to osmotic stress rather than pathological modification of the eye lens and that chronic aberration of osmotic pressure causes net loss of carnitine which can lead to triggering of cataracts.”

“Although the mechanisms by which carnitine provides neurological protection are unknown, a systematic review of the literature confirmed that L-acyl-carnitine is promising as a safe and effective treatment for HE [58].”

“Several studies have reported that supplementing rats with both L-carnitine and alpha-lipoic acid halts age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in heart, skeletal muscle and brain, concomitant with improvement in mitochondrial enzyme and…”

“Several studies have reported that supplementing rats with both L-carnitine and alpha-lipoic acid halts age-related increases in reactive oxygen species (ROS), lipid peroxidation, protein carbonylation, and DNA strand breaks in heart, skeletal muscle and brain, concomitant with improvement in mitochondrial enzyme and…”

“GCDH can be controlled nutritionally and supplementation includes L-carnitine to avoid secondary carnitine depletion [84-87].”

“Patano and colleagues suggest that this decrease in energy availability might compromise osteoblast activity and bone remodeling in an age-related manner [152].”

“Thus a vegetarian lifestyle has an impact on fat metabolism causing a remarkable stimulation of carnitine uptake [113].”

“Handelman however cautions that evidence for effectiveness of carnitine supplements in dialysis suffers from trials limited in subject number and open labeled, and suggests more rigorous testing is needed [55].”

“Cardiomyopathy has also be observed [30].”

“Argani and colleagues showed a decrease in plasma levels of triglyceride (TG) and very low-density lipoprotein, and increases in total high-density lipoprotein cholesterol (HDL-C and HDL2-C) and albumin, in hemodialysis patients upon administration of 500 mg/day carnitine taken orally for 2 months [44].”

“McCarty and Rubin suggest supplementation of micronutrients including carnitine to aid wound healing in diabetics [103].”

“One case study found a novel mutation in CPT II (del1737C), an autosomal recessive disease with a distinct phenotype [49].”

“This is supported by other studies that showed a protective effect of L-carnitine against ammonia-evoked encephalopathy in cirrhotic patients, with ALC administration improving neurological symptoms and plasmatic parameters in cirrhotic patients with hepatic coma [60-67].”

“In both experimental models and human diabetic subjects, there is an initial metabolic phase that is responsive to metabolic corrections [90,91].”

“[122] demonstrated that carnitine worsened the recovery of contractile function in transient ischemia.”

“However, a relationship between disease and mutation of the human CPTI gene has not been reported [47].”

“It has been further suggested that carnitine deficiency might negatively impact cardiac function which might in turn, further contribute to the outcome of patients suffering sepsis [97-99].”

“It has been further suggested that carnitine deficiency might negatively impact cardiac function which might in turn, further contribute to the outcome of patients suffering sepsis [97-99].”

“Animal products like meat, fish, poultry, and milk (whey fraction) are highest in carnitine, whereas plants contain little carnitine (42).”

“Indeed, carnitine has proven efficacious for treatment of cardiovascular disease (Flanagan et al., 2010).”