Disruption of lipid metabolism in the liver of the pregnant rat fed folate-deficient and methyl donor-deficient diets
Christopher J. McNeilSusan M. HayGarry J. RucklidgeMartin ReidGary DuncanChris MaloneyWilliam D. Rees
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Abstract:
The importance of folic acid and the methionine cycle in fetal development is well recognised even though the mechanism has not been established. Since the cycle is active in the maternal liver, poor folate status may modify hepatic metabolism. Pregnant rats were fed diets deficient in folic acid (-F) or in three key methyl donors, folic acid, choline and methionine (-FLMLC) and the maternal liver was analysed on day 21 of gestation. Two-dimensional gel electrophoresis of soluble proteins identified differentially abundant proteins, which could be allocated into nine functional groups. Five involved in metabolic processes, namely, folate/methionine cycle, tyrosine metabolism, protein metabolism, energy metabolism and lipid metabolism, and three in cellular processes, namely, endoplasmic reticulum function, bile production and antioxidant defence. The mRNA for sterol regulatory element-binding protein-1c and acetyl-CoA carboxylase-1 (fatty acid synthesis) were decreased by both -F and -FLMLC diets. The mRNA for PPARalpha and PPARgamma and carnitine palmitoyl transferase (fatty acid oxidation) were increased in the animals fed the -FLMLC diets. Changes in the abundance of proteins associated with intracellular lipid transport suggest that folate deficiency interferes with lipid export. Reduced fatty acid synthesis appeared to prevent steatosis in animals fed the -F diet. Even with increased oxidation, TAG concentrations were approximately three-fold higher in animals fed the -FLMLC diet and were associated with an increase in the relative abundance of proteins associated with oxidative stress. Fetal development may be indirectly affected by these changes in hepatic lipid metabolism.Keywords:
Fatty acid synthesis
Methionine synthase
Fatty Acid Metabolism
Choline
The relationship between the concentration of carnitine and the oxidation of oleate was examined in homogenates prepared from skeletal muscle, liver, kidney, and heart of the rat, and from canine and human skeletal muscle. The carnitine content of these tissues in situ spanned a wide range, from about 0.1 μmol per gram in rat liver to about 3.0 μmol per gram in human muscle. The concentration of carnitine required for half-maximal rates of fatty acid oxidation in vitro also varied greatly (10 to 15 μM for rat liver to 200 to 400 μM for human muscle), and in rough proportion to the normal carnitine content of the tissues. For any given tissue, the carnitine content seems to be set at a level necessary for optimal rates of fatty acid oxidation. The data provide a plausible explanation for the fact that muscle fatty acid metabolism is severely impaired in the syndrome of human carnitine deficiency, since measured carnitine levels are in the range expected to limit substantially the capacity for fatty acid oxidation.
Fatty Acid Metabolism
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Carbohydrate Metabolism
Fatty Acid Metabolism
Coenzyme A
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CARNITINE (β-hydroxy-γ-trimethylaminobutyric acid) is an essential cofactor for the oxidation of fatty acids by mitochondria. It serves to carry long-chain fatty acids in the form of their acyl-carnitine esters across the barrier of the inner mitochondrial membrane before β-oxidation. Since 1973,1 a total of 46 patients have been described with evidence of impaired fatty acid oxidation associated with reduced levels of carnitine.2 These patients have been divided into a group with a "systemic carnitine deficiency," which presents in infancy or early childhood with recurrent episodes of coma and hypoglycemia, and a group with a "muscle carnitine deficiency," which presents later . . .
Coenzyme A
Carnitine O-palmitoyltransferase
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Fatty Acid Metabolism
Long chain
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Carnitine O-palmitoyltransferase
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Carnitine, a short-chain nitrogen containing carboxylic acid, is found in meat and dairy foods. Carnitine aids in a shuttle process that makes long-chain, fatty-acid coenzyme A derivatives available for B-oxidation. Normal healthy adults have adequate carnitine stores and do not require dietary carnitine. However, neonates, chronically and critically ill patients with decreased muscle and liver carnitine store seem to benefit from carnitine supplementation to enhance their tolerance of metabolic stress.
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A bstract : Mitochondrial oxidation of long‐chain fatty acids provides an important source of energy for the heart as well as for skeletal muscle during prolonged aerobic work and for hepatic ketogenesis during long‐term fasting. The carnitine shuttle is responsible for transferring long‐chain fatty acids across the barrier of the inner mitochondrial membrane to gain access to the enzymes of β‐oxidation. The shuttle consists of three enzymes (carnitine palmitoyltransferase 1, carnitine acylcarnitine translocase, carnitine palmitoyl‐transferase 2) and a small, soluble molecule, carnitine, to transport fatty acids as their long‐chain fatty acylcarnitine esters. Carnitine is provided in the diet (animal protein) and also synthesized at low rates from trimethyl‐lysine residues generated during protein catabolism. Carnitine turnover rates (300‐500 μmol/day) are <1% of body stores; 98% of carnitine stores are intracellular (total carnitine levels are 40‐50 μM in plasma vs. 2‐3 mM in tissue). Carnitine is removed by urinary excretion after reabsorption of 98% of the filtered load; the renal carnitine threshold determines plasma concentrations and total body carnitine stores. Because of its key role in fatty acid oxidation, there has long been interest in the possibility that carnitine might be of benefit in genetic or acquired disorders of energy production to improve fatty acid oxidation, to remove accumulated toxic fatty acyl‐CoA metabolites, or to restore the balance between free and acyl‐CoA. Two disorders have been described in children where the supply of carnitine becomes limiting for fatty acid oxidation: (1) A recessive defect of the muscle/kidney sodium‐dependent, plasma membrane carnitine symporter, which presents in infancy with cardiomyopathy or hypoketotic hypoglycemia; treatment with oral carnitine is required for survival. (2) Chronic administration of pivalate‐conjugated antibiotics in which excretion of pivaloyl‐carnitine can lead to carnitine depletion; tissue levels may become low enough to limit fatty acid oxidation, although no cases of illness due to carnitine deficiency have been described. There is speculation that carnitine supplements might be beneficial in other settings (such as genetic acyl‐CoA oxidation defects—“secondary carnitine deficiency”, chronic ischemia, hyperalimentation, nutritional carnitine deficiency), but efficacy has not been documented. The formation of abnormal acylcarnitines has been helpful in expanded newborn screening programs using tandem mass‐spectrometry of blood spot acylcarnitine profiles to detect genetic fatty acid oxidation defects in neonates. Carnitine‐deficient diets (vegetarian) do not have much effect on carnitine pools in adults. A modest 50% reduction in carnitine levels is associated with hyperalimentation in newborn infants, but is of doubtful significance. The above considerations indicate that carnitine does not become rate‐limiting unless extremely low; testing the benefits of nutritional supplements may require invasive endurance studies of fasting ketogenesis or muscle and cardiovascular work.
Ketogenesis
Carnitine O-palmitoyltransferase
Fatty Acid Metabolism
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Carnitine O-palmitoyltransferase
Carnitine palmitoyltransferase I
Anaerobic glycolysis
Carbohydrate Metabolism
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Diastereomer
Fatty Acid Metabolism
Carnitine palmitoyltransferase I
Carnitine O-palmitoyltransferase
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Background/Aim Fatty liver is closely associated with lifestyle‐related illness and liver diseases. However, the effective therapy for fatty liver has not been established yet. Carnitine is an essential factor to transport fatty acid into mitochondria. This study examined the effectiveness of carnitine on fatty acid catabolism in fatty liver culture cell model. Methods In human Fa2N4 and mouse AML12 cells, fatty liver induced by synthetic LXR‐ligand ( To901317 ) exposure was treated with 0–10 mM carnitine for 3 days. The levels of triglyceride (TG) and fatty acid metabolism‐related genes were evaluated. Further, normal cell was loaded to 200 μM parmitic acid with 1 mM carnitine for up to 20h, and β‐oxidation metabolites in medium was measured. Results In both cells, TG level was significantly and dose‐dependently decreased by carnitine treatment. The enhanced mRNA levels of SREBP‐1, ACC, FAS, and SCD were significantly decreased by carnitine. After 20h of fatty acid load, ketone body excretion from cell was significantly increased with carnitine compared to that without carnitine. The mRNA levels of PPARα, CPT‐1α, PGC‐1α, and OCTN2 were significantly increased after 20h compared to these at 0 time. Conclusion In the cell model, fatty liver was improved by carnitine treatment through β‐oxidation activation. Therefore, carnitine administration would be a possible therapy for metabolic syndrome with fatty liver.
Catabolism
Fatty Acid Metabolism
Steatosis
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