Effect of clofibrate treatment on carnitine acyltransferases in different subcellular fractions of rat liver

Kähönen, Matti T.

doi:10.1016/0304-4165(76)90199-9

Cited by 69 publications

(15 citation statements)

References 25 publications

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“…Markwell et al [24] have estimated that peroxisomes contain 14% and mitochondria 52% of the total carnitine acetyltransferase activity in hepatic tissue from rat; whereas the corresponding values reported by Kahonen [25] were 50% and 36%. Nonetheless, Moody and Reddy [26] reported that the increase in peroxisome numbers and size in rats treated with nafenopin, clofibrate or methylclofenapate correlates well with the increase in carnitine acetyltransferase activity.…”

Section: Choice Of the Enzyme Measuredmentioning

confidence: 88%

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Lundgren

Meijer

DePierre

1987

European Journal of Biochemistry

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We have found here that there are clear structural requirements for peroxisome proliferation (monitored as increases in carnitine acetyltransferase activity, cyanide‐insensitive palmitoyl‐CoA oxidation, catalase and increases in the protein designated PPA 80) in mouse liver. From the investigation of ten structural analogues of 2‐ethylhexanoic acid, it could be concluded that the most effective proliferators all have an ethyl group as the substituent on carbon 2 of the main chain, which consists of six carbons. The further observation from this group of compounds that a charged group is required for effective proliferation leads us to speculate that such a group is involved in the molecular mechanism as well. Many, but not all, of the effective peroxisome proliferators in a second group of compounds contain a phenoxy group, often with a substituted α carbon. Interestingly, the 2,4‐dichlorophenoxyacetic and 2,4,5‐trichlorophenoxyacetic acids are both effective peroxisome proliferators, but the closely related p‐chlorophenoxyacetic acid is inactive in this respect, indicating that the chlorine atom at position 2 must be essential to the process in these cases. The results presented here also indicate that the structural requirements for proliferation of mitochondria are similar to those for proliferation of peroxisomes. Certainly, the most effective peroxisome proliferators also cause large increases in ‘mitochondrial’ protein and cytochrome oxidase activity, i.e. there is an obvious qualitative correlation.

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Section: Choice Of the Enzyme Measuredmentioning

confidence: 88%

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Lundgren

Meijer

DePierre

1987

European Journal of Biochemistry

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“…The fact that conditions that enhance ketone body production (12,32) can affect acetylcarnitine levels indicates that carnitine in some tissues may affect ketone body production or utilization. It is also well documented that clofibrate, a drug that can decrease circulating cholesterol and triglyceride levels in humans, increases the amount of carnitine acetyl-and octanyltransferases in rat liver (16,17,19). Although it is unlikely that one can, at present, provide an entirely adequate explanation for the.above results, multiple roles for carnitine seem to be indicated.…”

Section: Discussionmentioning

confidence: 59%

“…The enzyme could be involved in shuttling the C4 and C5 acyl residues of the acyl-CoAs derived from branched-chain amino acid metabolism across intracellular permeability barriers. In this regard it is intriguing that liver peroxisomes contain carnitine octanyltransferase activity (6,8,16) and transaminase activity for leucine (23). Is it possible that acyl-CoAs formed in peroxisomes have to be transported to mitochondria for complete catabolism?…”

Section: Discussionmentioning

confidence: 99%

“…Other roles for carnitine are indicated by (i) the multiorganelle location of medium-chain and short-chain carnitine acyltransferases in liver (5-7), (ii) the high activity of carnitine octanoyltransferase in many tissues (8-10), (iii) the occurrence of short-chain acylcarnitines, especially in muscle, some of which apparently are not acetylcarnitine (11-15), and (iv) the clofibrate-induced increase in short-chain and medium-chain carnitine acyltransferase activity (16)(17)(18)(19)). …”

Section: Introductionmentioning

confidence: 99%

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Isolation and identification of aliphatic short-chain acylcarnitines from beef heart: possible role for carnitine in branched-chain amino acid metabolism.

Bieber¹

1977

Proc. Natl. Acad. Sci. U.S.A.

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Aliphatic acylcarnitines isolated from a water-soluble fraction of beef heart have been characterized by gas chromatography and mass spectrometry. The following acyl residues derived from the acylcarnitine fraction were unequivocally identified: acetyl, pro ionyl, isobutyryl, butyryl, a-methylbutyryl, valeryl, isovalery, tiglyl, and caproyl. flmethylcrotonyl and methacrylyl were tentatively identified. This occurrence of considerable quantities of branched-chain acylcarnitines indicates a role for carnitine in branched-chain amino acid metabolism.Although it is well established that carnitine participates in shuttling long-chain acyl residues across the inner membrane of mitochondria (1-4), some data indicate additional functions for carnitine. Other roles for carnitine are indicated by (i) the multiorganelle location of medium-chain and short-chain carnitine acyltransferases in liver (5-7), (ii) the high activity of carnitine octanoyltransferase in many tissues (8-10), (iii) the occurrence of short-chain acylcarnitines, especially in muscle, some of which apparently are not acetylcarnitine (11-15), and (iv) the clofibrate-induced increase in short-chain and medium-chain carnitine acyltransferase activity (16)(17)(18)(19)).An approach to elucidating broader roles for carnitine would be to identify and quantitate the products of the short chain and medium chain carnitine acyltransferases in specific tissues. These products should be water-soluble and would be found in the water-soluble acylcarnitine fraction. Herein we show that aliphatic branched-chain acylcarnitines constitute a major portion of the water-soluble carnitine fraction isolated from beef heart. METHODS Isolation of Acylcarnitines. Fresh beef heart was obtained from the slaughterhouse and immediately chilled. The fat was removed and the acylcarnitine fractions were isolated therefrom. Water-soluble aliphatic acylcarnitines were isolated and the acyl moieties were separated as described elsewhere (20).Identification of Acyl Residues. The short-chain fatty acids derived from the acylcarnitine fraction were subjected to gas chromatography as described (20) for tentative identification. Positive identification was made by subjecting the individual fatty acid peaks obtained from gas chromatography to mass spectral analyses and comparing with standard free fatty acids. These analyses were performed by the mass spectrometry facilities at Michigan State University, under the supervision of C. C. Sweeley. RESULTSThe water-soluble acylcarnitine fraction was isolated from several rat tissues and from sheep muscle and beef heart. As anticipated, considerable amounts of acetylcarnitine and lesser quantities of propionylcarnitine were found. However, all of the tissues investigated contain several other acylcarnitines. A gas chromatographic profile of the volatile fatty acids obtained from a hydrolysate of the water-soluble acylcarnitines of beef heart is shown in Fig. 1. The prevalence of fatty acids with retention times of C4 and C5 volatile fatty acids...

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“…Palmitoyl-CoA-dependent NAD' reduction was measured by the method of Lazarow and de Duve [16]. Carnitine acetyltransferase was assayed by measuring the rate of release of CoA [30]. D-amino acid oxidase activity with D-alanine as substrate was estimated as described previously [31].…”

Section: Other Enzymes and Protein Assaymentioning

confidence: 99%

Intraparticulate localization and some properties of a clofibrate-induced peroxisomal aldehyde dehydrogenase from rat liver

Antonenkov¹,

Pirozhkov²,

Панченко³

1985

Eur J Biochem

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A study was made of the effect of chronic administration of the hypolipidemic drug clofibrate on the activity and intracellular localization of rat liver aldehyde dehydrogenase. The enzyme was assayed using several aliphatic and aromatic aldehydes. Clofibrate treatment caused a 1.5 to 2.3-fold increase in the liver specific aldehyde dehydrogenase activity. The induced enzyme has a high K , for acetaldehyde and was found to be located in peroxisomes and microsomes. Clofibrate did not alter the enzyme activity in the cytoplasmic fraction.The total peroxisomal aldehyde dehydrogenase activity increased 3 to 4-fold under the action of clofibrate. Disruption of the purified peroxisomes by the hypotonic treatment or in the alkaline conditions resulted in the release of catalase from the broken organelles, while aldehyde dehydrogenase as well as nucleoid-bound urate oxidase and the peroxisomal membrane marker NADH : cytochrome c reductase remained in the peroxisomal 'ghosts'. At the same time, treatment by Triton X-100 led to solubilization of the membrane-bound NADH : cytochrome c reductase and aldehyde dehydrogenase from intact peroxisomes and their 'ghosts'. These results indicate that aldehyde dehydrogenase is located in the peroxisomal membrane.The peroxisomal aldehyde dehydrogenase is active with different aliphatic and aromatic aldehydes, except for formaldehyde and glyceraldehyde. The enzyme K, values lie in the millimolar range for acetaldehyde, propionaldehyde, benzaldehyde and phenylacetaldehyde and in the micromolar range for nonanal. Both NAD and NADP serve as coenzymes for the enzyme. Aldehyde dehydrogenase was inhibited by disulfiram, Nethylmaleimide and 5,5'-dithiobis(2-nitrobenzoic)acid. According to its basic kinetic properties peroxisomal aldehyde dehydrogenase seems to be similar to a clofibrate-induced microsomal enzyme. The functional role of both enzymes in the liver cells is discussed.There are two isoenzymes of aldehyde dehydrogenase in rat liver which differ in their subcellular distribution, kinetic and molecular properties. Isoenzyme with a low K, for acetaldehyde was found in the mitochondria1 matrix [I, 21. Another species of aldehyde dehydrogenase has a high K,,, for acetaldehyde. The latter isoenzyme is tightly membranebound and distributed among mitochondria and microsomes [l, 3, 41. Except for these organelles, the activity of aldehyde dehydrogenase was detected in peroxisomes [5, 61. However, its intraparticulate location and properties were not described.Some xenobiotics and chemical carcinogens are able to induce at least two new isoenzymes of aldehyde dehydrogenase which are localized in supernatant fraction and not detectable in normal liver [7-lo]. In rat hepatomas the specific cytosolic isoenzymes which preferentially oxidize aromatic aldehydes using NADP as coenzyme are found [lo -121. All these isoenzymes consistently differ in a number of kinetic and molecular properties from aldehyde dehydrogenase of normal liver.It is known that clofibrate and other hypolipidemic agents with...

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Effect of clofibrate treatment on carnitine acyltransferases in different subcellular fractions of rat liver

Cited by 69 publications

References 25 publications

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Examination of the structural requirements for proliferation of peroxisomes and mitochondria in mouse liver by hypolipidemic agents, with special emphasis on structural analogues of 2‐ethylhexanoic acid

Isolation and identification of aliphatic short-chain acylcarnitines from beef heart: possible role for carnitine in branched-chain amino acid metabolism.

Intraparticulate localization and some properties of a clofibrate-induced peroxisomal aldehyde dehydrogenase from rat liver

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