Carnitine (earlier known as vitamin Bt) is a quaternary amine, beta-hydroxy-gamma-trimethylaminobutyrate. It is a very hygroscopic compound and is found in biological samples both as the free carnitine and as the ester of a wide variety of acyl compounds. Of the two types of carnitine, L-and D-carnitine, only L-carnitine is biologically active. This has been shown in a number of species (Grandjean et al., 1993).Carnitine is synthesized in the liver and kidneys. The synthesis depends on two precursors, L-lysine and methionine, as well as ascorbic acid, nicotinamide, vitamin B6 and iron (Borum, 1991). Deficiency in any cofactor will cause L-carnitine deficiency. In rats, total acid-soluble carnitine and free carnitine in plasma and tissues were reduced in a vitamin B6 deficiency, but increased when vitamin B6 was provided in a repletion diet (Cho and LeKlem, 1990; Ha et al., 1994). It has been suggested that early features of scurvy (fatigue and weakness) may be attributed to carnitine deficiency. Vitamin C is a cofactor for two alpha-ketoglutarate-requiring dioxygenase reactions (epsilon-N-trimethyllysine hydroxylase and gamma-butyrobetaine hydroxylase) in the pathway of carnitine biosynthesis. Carnitine concentrations are variably low in some tissues of vitamin C-deficient guinea pigs (Rebouche, 1991). Choline has also been shown to affect carnitine homeostasis in humans and guinea pigs (Daily and Sachan, 1995). Choline supplementation resulted in decreased urinary excretion of carnitine in young adult women. Choline resulted in the conservation of carnitine in guinea pigs. In adult women Hongu and Sachan (2003) concluded that the choline-induced decrease in serum and urinary carnitine is buffered by carnitine preloading, and these supplements shift tissue partitioning of carnitine that favors fat mobilization, incomplete oxidation of fatty acids and disposal of their carbons in urine.
Carnitine appears to be absorbed across the gut by an active process dependent on Na+ as well as by a passive diffusion that may be important for the absorption of large doses of the factor. The uptake of carnitine from the intestinal lumen into the mucosa is rapid, and about one-half of the carnitine taken up is acetylated in that tissue. Absorption of carnitine in dietary supplements (0.5 to 4 g per day) is 15% to 25% (Rebouche, 2006). Tissues such as cardiac muscle and skeletal muscle require carnitine for normal fuel metabolism but cannot synthesize carnitine and are totally dependent on the transport of carnitine from other tissues. Free carnitine is excreted in urine, with the principal excretory product being trimethylamine oxide (Mitchell, 1978). Carnitine is highly conserved by the human kidney, which reabsorbs more than 90% of filtered carnitine, thus, playing an important role in the regulation of carnitine concentration in blood. For the dog, 95% to 98% of the carnitine body pool is in skeletal muscle and the heart (Rebouche and Engel, 1983). With rats, Flores et al. (1996) recently reported that the small intestine is a considerable and previously unrecognized proportion of the carnitine pool of suckling animals.
Carnitine is required for transport of long-chain fatty acids into the matrix compartment of mitochondria from cytoplasm for subsequent oxidation by the fatty acid oxidase complex for energy production. The oxidation of long-chain fatty acids in animal tissues is dependent on carnitine because it allows long-chain acyl-CoA esters to cross the mitochondrial membrane, which is otherwise impermeable to CoA compounds. Carnitine facilitates the beta-oxidation of long-chain fatty acids in the mitochondria by transporting the substrate into the mitochondria. Carnitine acyltransferase is the enzyme responsible for this shuttle mechanism. It exists in two forms, carnitine acyltransferase I and carnitine acyltransferase II. After the long-chain fatty acid is activated to acyl-CoA, it is converted to acylcarnitine by the enzyme carnitine acyltransferase I and crosses to the matrix side of the inner mitochondrial membrane. Carnitine acyltransferase II then releases carnitine and the acyl-CoA into the mitochondrial matrix. Acyl-CoA is then catabolized via beta-oxidation (Borum, 1991). Thus, utilization of long-chain fatty acids as a fuel source depends on adequate concentrations of carnitine. The role of carnitine in the transport of long-chain fatty acids across the inner mitochondrial membrane is known, but liver medium-chain fatty acid (MCFA) metabolism has been considered carnitine independent owing to their passive diffusion through the inner mitochondrial membrane and intramitochondrial activation (Bremer, 1990). However, evidence suggests that MCFA metabolism may be affected by supplemental carnitine (Van Kempen and Odle, 1993; 1995). Recently, dietary carnitine was shown to enhance the lymphatic absorption of fat and alpha-tocopherol in ovariectomized rats (Zou et al., 2005).
Another role of carnitine may be to protect cells against toxic accumulation of acyl-CoA compounds of either endogenous or exogenous origin by trapping such acyl groups as carnitine esters, which may then be transported to the liver for catabolism or to the kidney for excretion in the urine. Carnitine also has functions in other physiological processes critical to survival, such as lipolysis, thermogenesis, ketogenesis and possibly regulation of certain aspects of nitrogen metabolism (Borum, 1985). Carnitine was found to be beneficial in detoxification of aflatoxins (Yatim and Sachan, 2001). For rats there was a modification of aflatoxin binding to proteins and DNA by carnitine, which reduced the carcinogenic and hepatotoxic potential of aflatoxins.
In mammals, gamma-butyrobetaine, the immediate precursor of carnitine, can be synthesized from the essential amino acids lysine and methionine in most tissues. The four-carbon chain comes from lysine; the methyl groups come from methionine. The ultimate conversion of gamma-butyrobetaine to carnitine occurs in the liver (Olson and Rebouche, 1987).
Higher animals, including mammals, can synthesize carnitine. However, recent studies have indicated that the biosynthesis of carnitine may be limited or inadequate in certain animals. Both the NRC (2006) and AAFCO (2007) offer no requirement recommendations for carnitine in dog and cat diets. There is no evidence that dogs in a normal domestic environment require carnitine supplementation, nor is there any indication that carnitine is required in the diet of cats (NRC, 2006).
Carnitine has been observed to be beneficial in the treatment of dilated cardiomyopathy in certain families of dogs (Keene et al., 1986; 1988; Sanderson, 2006), but ineffective in others (Costa and Labuc, 1994). A carnitine level of 50 mg per kg (22.7 mg per lb) of body weight has been used as a preventive therapy. Working dogs have been shown to have a need for supplemental carnitine (Grandjean et al., 1993).In the dog, maintenance requirements of endogenous L-carnitine appear sufficient, while in other physiological states (e.g., exercise, exposure to cold and reproduction) or deficiencies (e.g., myopathies and muscle damage), where mobilization of fatty acids is desirable, L-carnitine supplementation has been suggested at a level of 50 mg per kg (22.7 mg per lb) of body weight (Pelletier, 1992). On the basis of physiology tests (e.g., cardiac frequency, free fatty acids and lactic acid) after exercising Alaskan husky dogs, Grandjean et al. (1993) concluded that supplemental carnitine was beneficial.
Carnitine requirements for cats have not been reported.
In general, foods of plant origin are low in carnitine, whereas animal-derived foods are rich in carnitine (Mitchell, 1978). Red meats and dairy products are particularly rich sources. The carnitine concentration increases in the order of fish, poultry, pork, beef and lamb. In general, the redder the meat, the higher the concentration of carnitine. Typical concentrations of carnitine could be 600 µg per kg (272.7 µg per lb) for beef, 45 to 90 µg per kg (20.5 to 40.9 µg per lb) for chicken and 75 µg per kg (34.1 µg per lb) for lamb (Mitchell, 1978). Carnitine is located principally in skeletal muscle, which has about 40 times the concentration of carnitine than in blood. On the contrary, grains such as barley, corn and wheat have undetectable or negligible concentrations. Most plant foods that are low in carnitine are also likely to be low in lysine and methionine, the precursors of carnitine.
Milk is essential for the nursing mammal’s supply of carnitine. Although carnitine is synthesized in growing young and adult animals, previous studies in humans provide evidence that exogenous carnitine is necessary to maintain normal fat metabolism during infancy. Studies by Davis (1989) indicated that up to 50% of tissue carnitine in suckling rats is derived from the mother’s milk. Studies with neonatal rabbits (Penn and Schmidt-Sommerfeld, 1988) and rats (Flores et al., 1996) demonstrated that body tissues of carnitine are generally diminished in newborns deprived of milk during early life. Coffey et al. (1991) showed that diminished dietary intake is associated with decreased levels of carnitine in the liver, but not in the heart or muscle, of neonatal piglets receiving low levels of dietary carnitine compared with piglets receiving carnitine supplementation. These observations indicate the importance of milk. The demand for carnitine during the suckling period may exceed the capacity for its synthesis.
In carnitine deficiency, fatty acid oxidation is reduced, and fatty acids are diverted into triglyceride synthesis, particularly in the liver. Mitochondrial failure develops in carnitine deficiency when there is insufficient tissue carnitine available to buffer toxic acyl-coenzyme (CoA) metabolites. Toxic amounts of acyl-CoA impair the citrate cycle, gluconeogenesis, the urea cycle and fatty acid oxidation. Carnitine replacement treatment is safe and induces excretion of toxic acyl groups in the urine (Stumpf et al., 1985). If carnitine deficiency involves the liver, the supply of ketones and the utilization of long-chain fatty acids during starvation are cut off; all tissues become glucose dependent. When liver carnitine is depleted, starvation tends to cause nonketotic, insulinopenic hypoglycemia. Because liver hepatocytes depend on fatty acids for their energy requirements during fasting, carnitine depletion may also cause clinical liver dysfunction, shown by hyperammonemia, encephalopathy and hyperbilirubinemia (Feller and Rudman, 1988). Skeletal muscles are generally involved, with weakness, lipid myopathy and myoglobinuria often aggravated or precipitated by fasting or exercise. The heart, like skeletal muscle, is dependent on fatty acids for energy during fasting, and heart failure and arrhythmias are frequent manifestations of systemic carnitine deficiency. The heart derives approximately 60% of its ATP supply from beta-oxidation of fatty acids. Carnitine concentrations in the heart are normally very high in many species (Rebouche and Paulson, 1986).
Carnitine deficiency is differentiated into three categories: excessive loss of free carnitine, excessive loss of acylcarnitine as a result of accumulation of acyl-CoA in tissues, and a combined type. The first condition is reported in humans as Fanconi syndrome and renal carnitine transport deficiency (primary carnitine deficiency), and the latter two types are found in various inborn errors of fatty acid metabolism (DiDonato et al., 1992).
Assessment of the carnitine status of a particular animal or human is difficult because plasma carnitine concentrations and urinary carnitine excretion are not good indicators of tissue carnitine status (Borum, 1991). Individuals with low carnitine concentrations in plasma may have normal carnitine concentrations in muscle or liver, and those with normal plasma carnitine concentrations may have low carnitine concentrations in muscle or liver.
In dogs suffering from dilated cardiomyopathy (DCM), myocardial concentrations of L-carnitine are sometimes very low. Carnitine deficiency associated with DCM has been documented in doberman pinschers (Keene et al., 1989) and in a family of boxers (Keene et al., 1986). More recently, Keene (1992) reported DCM in a wide range of dog breeds and found that myocardial free L-carnitine deficiency occurred in 50% to 90% of dogs with DCM. In these dogs, the myocardial concentrations of carnitine were very low and substantial clinical improvement after intravenous or oral therapy with L-carnitine was observed. The potential explanation is that these dogs suffer from a membrane transport defect that prevents adequate quantities of carnitine from moving into the heart from the plasma (Keene, 1991; Keeneet al., 1991). McEntee et al. (1995) reported DCM in a female Labrador retriever, whose diet was exclusively from vegetables and cereals because of a presumed allergy to animal proteins. The dog had a poor appetite, coughing, abdominal distention, exercise intolerance and a body odor. After four days of carnitine supplementation there was a spectacular improvement in appetite, increased tolerance to exercise and reduction of the peculiar body odor. The peculiar body odor has been described in children with carnitine deficiency (Waber et al., 1982).Grandjean et al.(1993) demonstrated the need of supplemental carnitine for working husky dogs. After exercise, carnitine-supplemented dogs showed better utilization of lipids, free fatty acid blood levels were lower, blood glucose was more stable, and accumulation of lactate residues was less.
Systemic and myopathic forms of L-carnitine deficiency are well-known etiologies of DCM in human medicine. Recent evidence suggests that congestive heart failure caused by rapid ventricular pacing in dogs is also associated with myocardial carnitine deficiency (Keene, 1994).
Carnitine is synthesized exclusively in the liver, therefore liver disease will likely influence carnitine metabolism (Neumann et al., 2007). An experiment was deisgned to compare plasma L-carnitine concentrations in dogs with different liver diseases of differing severity with the plasma L-carnitine concentrations of healthy dogs (Neumann et al., 2007). Liver disease in dogs was accompanied by elevated plasma L-carnitine concentration with the severity of hepatitis appearing to influence L-carnitine concentration.
Some breeds of dogs have an autosomal recessive defect in the carnitine synthetic pathway, which leads to a deficiency (Katz and Siakotos, 1995). These dogs have ceroid lipofuscinoses and dilated cardiomyopathy. Supplementation with carnitine in some cases leads to a reduction in clinical signs of the disease (NRC, 2006).
No carnitine deficiencies in cats have been reported.
Only the physiological L-carnitine should be used for fortification of diets. Oral doses of 100 to 150 mg per kg (45.5 to 68.2 mg per lb) have been used as supplementation doses. The liver and kidney of mammals are able to synthesize carnitine from lysine and methionine; however, endogenous biosynthesis alone is not sufficient to keep carnitine concentrations at adequate levels (Duran et al., 1990). Nevertheless, pets receiving food with high amounts of animal products (e.g., meat and milk) should need no additional supplemental carnitine. Likewise, nursing puppies and kittens will be receiving sufficient carnitine, since milk is rich in the vitamin. The greatest concern for the need to supplement carnitine would be for dogs with DCM (sometimes of genetic origin) and for dogs that work rigorously and receive diets lacking in sufficient animal protein. In the working dog, L-carnitine increases aerobic capacity due to glycogen sparing effect, delaying onset of fatigue and hypoglycemia and decreasing production of lactic acid (Pelletier, 1992). After exercise, L-carnitine speeds up recovery.
Some newer more promising therapies for dogs with DCM are carnitine and taurine (Sanderson, 2006). Deficiencies of these nutrients have been shown to cause DCM in dogs, and some breeds of dogs have shown dramatic improvement in myocardial function after supplementation with one or both nutrients. Although most dogs diagnosed with DCM do not have a documented taurine or carnitine deficiency, they may still benefit from supplementation.
In cats, fat accumulates in the liver during fasting, leading to a fatty liver syndrome or feline hepatic lipidosis (FHL). Blanchard et al. (2002) completed a study to determine whether a carnitine supplement could protect fasting cats from ketosis and, therefore, whether a carnitine supplement would improve carnitine and lipid metabolism in FHL. The results demonstrated the protective effect of a dietary L-carnitine level in cats with a high risk of obesity.
No data have been reported for carnitine toxicity studies in dogs and cats. Oral dosages of 100 mg per kg (45.5 mg per lb) have been given to infants and 1 to 3 g daily to adult humans with little problem. Some patients experienced diarrhea, but not if they started with smaller dosages and then increased gradually (Borum, 1991).
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