Dataset Information

Fatty acid metabolism in hepatocytes cultured with hypolipidaemic drugs. Role of carnitine.

ABSTRACT: The direct effects of clofibrate analogues on carnitine acyltransferase activities and fatty acid metabolism were studied in cultured hepatocytes. Rat hepatocytes cultured with bezafibrate or ciprofibrate (0.1-10 micrograms/ml) for 48 h had increased activities of carnitine acetyltransferase (CAT; 4-6-fold) and carnitine palmitoyltransferase (CPT; 12-34%). The increase in CAT was higher in hepatocytes from the periportal zone (440%) of rat liver compared with cells from the perivenous zone (266%). In human hepatocytes, in contrast with rat, the fibrates did not cause a marked increase in CAT activity. The effects of fibrates on palmitate metabolism were dependent on the carnitine status. In the presence of exogenous carnitine (1 mM), rat hepatocytes cultured with bezafibrate had higher rates of total palmitate metabolism (29-34%) without increased partitioning of palmitate towards beta-oxidation, relative to control cultures. At low endogenous carnitine concentrations, cells cultured with bezafibrate had a greater increase in palmitate metabolism, esterification and cellular accumulation of triacylglycerol compared with the corresponding increases in the presence of carnitine. The changes in palmitate metabolism at either high or low carnitine concentrations were small in comparison with the changes in CAT activity. It is concluded that the increase in hepatic carnitine that occurs in vivo after fibrate feeding probably plays the major role in the changes in partitioning of fatty acid between beta-oxidation and esterification.

SUBMITTER: Gerondaes P

PROVIDER: S-EPMC1149270 | biostudies-other | 1988 Jul

REPOSITORIES: biostudies-other

ACCESS DATA

Similar Datasets

Project description:Carnitine is essential for the transfer of long-chain fatty acids across the inner mitochondrial membrane for subsequent β-oxidation. It can be synthesized by the body or assumed with the diet from meat and dairy products. Defects in carnitine biosynthesis do not routinely result in low plasma carnitine levels. Carnitine is accumulated by the cells and retained by kidneys using OCTN2, a high affinity organic cation transporter specific for carnitine. Defects in the OCTN2 carnitine transporter results in autosomal recessive primary carnitine deficiency characterized by decreased intracellular carnitine accumulation, increased losses of carnitine in the urine, and low serum carnitine levels. Patients can present early in life with hypoketotic hypoglycemia and hepatic encephalopathy, or later in life with skeletal and cardiac myopathy or sudden death from cardiac arrhythmia, usually triggered by fasting or catabolic state. This disease responds to oral carnitine that, in pharmacological doses, enters cells using the amino acid transporter B(0,+). Primary carnitine deficiency can be suspected from the clinical presentation or identified by low levels of free carnitine (C0) in the newborn screening. Some adult patients have been diagnosed following the birth of an unaffected child with very low carnitine levels in the newborn screening. The diagnosis is confirmed by measuring low carnitine uptake in the patients' fibroblasts or by DNA sequencing of the SLC22A5 gene encoding the OCTN2 carnitine transporter. Some mutations are specific for certain ethnic backgrounds, but the majority are private and identified only in individual families. Although the genotype usually does not correlate with metabolic or cardiac involvement in primary carnitine deficiency, patients presenting as adults tend to have at least one missense mutation retaining residual activity. This article is part of a Special Issue entitled: Mitochondrial Channels edited by Pierre Sonveaux, Pierre Maechler and Jean-Claude Martinou.

Project description:Biomethylation is the major pathway for the metabolism of inorganic arsenic (iAs) in many mammalian species, including the human. However, significant interspecies differences have been reported in the rate of in vivo metabolism of iAs and in yields of iAs metabolites found in urine. Liver is considered the primary site for the methylation of iAs and arsenic (+3 oxidation state) methyltransferase (As3mt) is the key enzyme in this pathway. Thus, the As3mt-catalyzed methylation of iAs in the liver determines in part the rate and the pattern of iAs metabolism in various species. We examined kinetics and concentration-response patterns for iAs methylation by cultured primary hepatocytes derived from human, rat, mice, dog, rabbit, and rhesus monkey. Hepatocytes were exposed to [(73)As]arsenite (iAs(III); 0.3, 0.9, 3.0, 9.0 or 30 nmol As/mg protein) for 24 h and radiolabeled metabolites were analyzed in cells and culture media. Hepatocytes from all six species methylated iAs(III) to methylarsenic (MAs) and dimethylarsenic (DMAs). Notably, dog, rat and monkey hepatocytes were considerably more efficient methylators of iAs(III) than mouse, rabbit or human hepatocytes. The low efficiency of mouse, rabbit and human hepatocytes to methylate iAs(III) was associated with inhibition of DMAs production by moderate concentrations of iAs(III) and with retention of iAs and MAs in cells. No significant correlations were found between the rate of iAs methylation and the thioredoxin reductase activity or glutathione concentration, two factors that modulate the activity of recombinant As3mt. No associations between the rates of iAs methylation and As3mt protein structures were found for the six species examined. Immunoblot analyses indicate that the superior arsenic methylation capacities of dog, rat and monkey hepatocytes examined in this study may be associated with a higher As3mt expression. However, factors other than As3mt expression may also contribute to the interspecies differences in the hepatocyte capacity to methylate iAs.

Dataset Information

Fatty acid metabolism in hepatocytes cultured with hypolipidaemic drugs. Role of carnitine.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets