Enhancement of activities relative to fatty acid oxidation in the liver of rats depleted of L-carnitine by D-carnitine and a gamma-butyrobetaine hydroxylase inhibitor.

This study was designed to examine whether the depletion of L-carnitine may induce compensatory mechanisms allowing higher fatty acid oxidative activities in liver, particularly with regard to mitochondrial carnitine palmitoyltransferase I activity and peroxisomal fatty acid oxidation. Wistar rats received D-carnitine for 2 days and 3-(2,2,2,-trimethylhydrazinium)propionate (mildronate), a noncompetitive inhibitor of gamma-butyrobetaine hydroxylase, for 10 days. They were starved for 20 hr before being sacrificed. A dramatic reduction in carnitine concentration was observed in heart, skeletal muscles and kidneys, and to a lesser extent, in liver. Triacylglycerol content was found to be significantly more elevated on a gram liver and whole liver basis as well as per mL of blood (but to a lesser extent), while similar concentrations of ketone bodies were found in the blood of D-carnitine/mildronate-treated and control rats. In liver mitochondria, the specific activities of acyl-CoA synthetase and carnitine palmitoyltransferase I were enhanced by the treatment, while peroxisomal fatty acid oxidation was higher per gram of tissue. It is suggested that there may be an enhancement of cellular acyl-CoA concentration, a signal leading to increased liver fatty acid oxidation in acute carnitine deficiency.

Effect of dietary n-3 and n-6 polyunsaturated fatty acids on lipid-metabolizing enzymes in obese rat liver.

This study was designed to examine whether n-3 and n-6 polyunsaturated fatty acids at a very low dietary level (about 0.2%) would alter liver activities in respect to fatty acid oxidation. Obese Zucker rats were used because of their low level of fatty acid oxidation, which would make increases easier to detect. Zucker rats were fed diets containing different oil mixtures (5%, w/w) with the same ratio of n-6/n-3 fatty acids supplied either as fish oil or arachidonic acid concentrate. Decreased hepatic triacylglycerol levels were observed only with the diet containing fish oil. In mitochondrial outer membranes, which support carnitine palmitoyltransferase I activity, cholesterol content was similar for all diets, while the percentage of 22:6n-3 and 20:4n-6 in phospholipids was enhanced about by 6 and 3% with the diets containing fish oil and arachidonic acid, respectively. With the fish oil diet, the only difference found in activities related to fatty acid oxidation was the lower sensitivity of carnitine palmitoyltransferase I to malonyl-CoA inhibition. With the diet containing arachidonic acid, peroxisomal fatty acid oxidation and carnitine palmitoyltransferase I activity were markedly depressed. Compared with the control diet, the diets enriched in fish oil and in arachidonic acid gave rise to a higher specific activity of aryl-ester hydrolase in microsomal fractions. We suggest that slight changes in composition of n-3 or n-6 polyunsaturated fatty acids in mitochondrial outer membranes may alter carnitine palmitoyltransferase I activity.

Short term treatment by fenofibrate enhances oxidative activities towards long-chain fatty acids in the liver of lean Zucker rats.

Lean Zucker rats were dosed orally for 1 week with fenofibrate (100 mg/kg/day). Liver weights of treated rats, expressed as per cent of body weight, were increased, while protein, DNA and triacylglycerol contents were not changed to any great extent per gram of liver, but increased when expressed per whole liver. Compared with the control animals, activities of fatty acid oxidase, of the peroxisomal fatty acid-oxidizing system and of catalase were markedly enhanced by fenofibrate, both per gram of liver and per total liver, while urate oxidase activity was slightly depressed when expressed per gram of liver. The activity of cytochrome c oxidase used as a mitochondrial marker was only higher when expressed per total liver. Besides, fenofibrate treatment induced a pronounced increase in the mitochondrial activities of carnitine palmitoyl- and acetyltransferases, of palmitoyl-CoA dehydrogenase and of carnitine-dependent oleate oxidation. Fenofibrate also enhanced significantly the carnitine content in liver and hepatic mitochondria. Malonyl-CoA content per gram of liver was found to be twice as high as in control rats, while the sensitivity of carnitine acyltransferase I to malonyl-CoA inhibition was hardly altered. The drug enhanced the percentage of palmitic acid in lipids of liver, but not in adipose tissues. The present data show that fenofibrate induced greater oxidative activities towards fatty acids, even in the lean animal. This stimulation could be related to the energy used for building new cells. In turn, at the same time of treatment, an enhanced fatty acid synthesis would provide specific fatty acids for the formation of new membranes. This latter effect will eventually disappear and the maintenance of a higher fatty acid oxidation may explain part of the overall hypolipaemic effect of fenofibrate.

[In vivo incorporation of labeled palmitic and oleic acids into skeletal muscle lipids of normal and thyroidectomized rats during swimming]. / Incorporation in vivo des acides palmitique et oléique marqués dans les lipides du muscle squelettique chez le rat normal et thyreoprive au cours d'une épreuve de nage.

The purpose of this work was to study the incorporation of [1-14C] palmitic and and [9,10(-3)H] oleic acids, after intravenous administration in the lipids of rat hind leg muscles. The animals were fasting or fed, at rest or swimming during 10 min before test, euthyroid or thyroidectomised. All these animals have been taking the same daily swimming training, during 15 days before the injection of labelled molecules. They were killed 10 min (+/-1)later. The lipidic muscle composition, the incorporation rate of labelled fatty acids in these lipids and the radioactivity distribution among the different lipids in the various cases have been determined. Moreover the plasmatic non-esterified acid radioactivity has been measured. These various values are affected by nutritional, hormonal state, and by physical activity of the animals. Particularly, it seems that supplementary energy spent during swimming test will be covered by the oxidation of different nutriments, according to the nutritional and hormonal state of animals.