title: Fatty acid metabolism in liver of rats treated with hypolipidemic sulphur-substituted fatty acid analogues.
abstract: The purpose of this study was to investigate early biochemical changes and possible mechanisms via which alkyl(C12)thioacetic acid (CMTTD, blocked for beta-oxidation), alkyl(C12)thiopropionic acid (CETTD, undergo one cycle of beta-oxidation) and a 3-thiadicarboxylic acid (BCMTD, blocked for both omega- (and beta-oxidation) influence the peroxisomal beta-oxidation in liver of rats. Treatment of rats with CMTTD caused a stimulation of the palmitoyl-CoA synthetase activity accompanied with increased concentration of hepatic acid-insoluble CoA. This effect was already established during 12-24 h of feeding. From 2 days of feeding, the cellular level of acid-insoluble CoA began to decrease, whereas free CoASH content increased. Stimulation of [1-14C]palmitoyl-CoA oxidation in the presence of KCN, palmitoyl-CoA-dependent dehydrogenase (termed peroxisomal beta-oxidation) and palmitoyl-CoA hydrolase activities were revealed after 36-48 h of CMTTD-feeding. Administration of BCMTD affected the enzymatic activities and altered the distribution of CoA between acid-insoluble and free forms comparable to what was observed in CMTTD-treated rats. It is evident that treatment of peroxisome proliferators (BCMTD and CMTTD), the level of acyl-CoA esters and the enzyme activity involved in their formation precede the increase in peroxisomal and palmitoyl-CoA hydrolase activities. In CMTTD-fed animals the activity of cyanide-insensitive fatty acid oxidation remained unchanged when the mitochondrial beta-oxidation and carnitine palmitoyltransferase operated at maximum rates. The sequence and redistribution of CoA and enzyme changes were interpreted as support for the hypothesis that substrate supply is an important factor in the regulation of peroxisomal fatty acid metabolism, i.e., the fatty acyl-CoA species appear to be catabolized by peroxisomes at high rates only when uptake into mitochondria is saturated. Administration of CETTD led to an inhibition of mitochondrial fatty acid oxidation accompanied with a rise in the concentration of acyl-CoA esters in the liver. Consequently, fatty liver developed. The peroxisomal beta-oxidation was marginally affected. Whether inhibition of mitochondrial beta-oxidation may be involved in regulation of peroxisomal fatty acid metabolism and in development of fatty liver should be considered.
authors.affiliation: Laboratory of Clinical Biochemistry, University of Bergen, Norway.
authors.forename: D
authors.initials: D
authors.lastname: Asiedu
authors.forename: A
authors.initials: A
authors.lastname: Aarsland
authors.forename: J
authors.initials: J
authors.lastname: Skorve
authors.forename: A M
authors.initials: AM
authors.lastname: Svardal
authors.forename: R K
authors.initials: RK
authors.lastname: Berge
mesh_terms: D000818:Animals; D002334:Carnitine O-Palmitoyltransferase / Q000378:metabolism; D002458:Cell Fractionation; D003065:Coenzyme A / Q000378:metabolism; D003066:Coenzyme A Ligases / Q000378:metabolism; D003486:Cyanides / Q000494:pharmacology; D003998:Dicarboxylic Acids / Q000378:metabolism*; D005227:Fatty Acids / Q000378:metabolism*; D008099:Liver / Q000032:analysis / Q000033:anatomy & histology / Q000378:metabolism*; D008297:Male; D008830:Microbodies / Q000378:metabolism; D009929:Organ Size; D010084:Oxidation-Reduction; D010170:Palmitoyl-CoA Hydrolase / Q000378:metabolism; D011422:Propionates / Q000378:metabolism*; D011506:Proteins / Q000032:analysis; D051381:Rats; D011919:Rats, Inbred Strains; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013440:Sulfides / Q000378:metabolism*; D013455:Sulfur; D013997:Time Factors; D014280:Triglycerides / Q000032:analysis / Q000378:metabolism; D000098859:Long-Chain-Fatty-Acid-CoA Ligase
chemical_list: D003486:Cyanides; D003998:Dicarboxylic Acids; D005227:Fatty Acids; D011422:Propionates; D011506:Proteins; D012097:Repressor Proteins; D029701:Saccharomyces cerevisiae Proteins; D013440:Sulfides; D014280:Triglycerides; C062077:1-(carboxyethylthio)tetradecane; C062079:1,10-bis(carboxymethylthiodecane); D013455:Sulfur; C062078:1-(carboxymethylthio)tetradecane; D002334:Carnitine O-Palmitoyltransferase; D010170:Palmitoyl-CoA Hydrolase; D003066:Coenzyme A Ligases; C090799:FAA2 protein, S cerevisiae; D000098859:Long-Chain-Fatty-Acid-CoA Ligase; D003065:Coenzyme A