Inhibition of long-chain ACYL-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes
Identifieur interne : 003733 ( Main/Merge ); précédent : 003732; suivant : 003734Inhibition of long-chain ACYL-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes
Auteurs : RBID : ISTEX:D631B1060BC88FFA6A51AC15B363B5A2977FAD21English descriptors
- KwdEn :
- 4-THA : 2-hydroxy-3-propyl-4-[6-(tetrazol-5yl)hexyloxy]acetophenone, ACS : acyl-CoA synthetase, And HEPES : N-2-hydroxyethylpiperazine-N′-2-enthanesulfonic acid, BSA : bovine serum albumin, CPT : carnitine palmitoyltransferase, CoA : coenzyme A, PFDA : perfluorodecanoic acid, PFOA : perfluorooctanoic acid, POCA : 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate.
Abstract
Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P<0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seen in vivo is yet to be determined.
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DOI: 10.1016/0006-2952(91)90716-I
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ISTEX:D631B1060BC88FFA6A51AC15B363B5A2977FAD21Le document en format XML
<record><TEI><teiHeader><fileDesc><titleStmt><title xml:lang="en">Inhibition of long-chain ACYL-CoA synthetase by the peroxisome proliferator perfluorodecanoic acid in rat hepatocytes</title>
<author><name sortKey="Vanden Heuvel, John P" uniqKey="Vanden Heuvel J">John P. Vanden Heuvel</name>
<affiliation wicri:level="2"><mods:affiliation>Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706, U.S.A.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706</wicri:regionArea>
<placeName><region type="state">Wisconsin</region>
</placeName>
</affiliation>
</author>
<author><name sortKey="Kuslikis, Benedict I" uniqKey="Kuslikis B">Benedict I. Kuslikis</name>
<affiliation wicri:level="2"><mods:affiliation>School of Pharmacy, University of Wisconsin, Madison, WI 53706, U.S.A.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Pharmacy, University of Wisconsin, Madison, WI 53706</wicri:regionArea>
<placeName><region type="state">Wisconsin</region>
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<affiliation wicri:level="2"><mods:affiliation>Current address: Blodgett Regional Poison Center, Blodgett Memorial Medical Center, 1840 Wealthy S.E., Grand Rapids, MI 49506.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Michigan</region>
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<wicri:cityArea>Current address: Blodgett Regional Poison Center, Blodgett Memorial Medical Center, 1840 Wealthy S.E., Grand Rapids</wicri:cityArea>
</affiliation>
</author>
<author><name sortKey="Shrago, Earl" uniqKey="Shrago E">Earl Shrago</name>
<affiliation wicri:level="2"><mods:affiliation>Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706, U.S.A.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Department of Nutritional Sciences, University of Wisconsin, Madison, WI 53706</wicri:regionArea>
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<author><name sortKey="Peterson, Richard E" uniqKey="Peterson R">Richard E. Peterson</name>
<affiliation wicri:level="2"><mods:affiliation>To whom correspondence should be sent: Dr. Richard E. Peterson, University of Wisconsin, School of Pharmacy, 425 North Charter St., Madison, WI 53706.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<placeName><region type="state">Wisconsin</region>
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<wicri:cityArea>To whom correspondence should be sent: Dr. Richard E. Peterson, University of Wisconsin, School of Pharmacy, 425 North Charter St., Madison</wicri:cityArea>
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<affiliation wicri:level="2"><mods:affiliation>Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706, U.S.A.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>Environmental Toxicology Center, University of Wisconsin, Madison, WI 53706</wicri:regionArea>
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<affiliation wicri:level="2"><mods:affiliation>School of Pharmacy, University of Wisconsin, Madison, WI 53706, U.S.A.</mods:affiliation>
<country xml:lang="fr">États-Unis</country>
<wicri:regionArea>School of Pharmacy, University of Wisconsin, Madison, WI 53706</wicri:regionArea>
<placeName><region type="state">Wisconsin</region>
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<date when="1991">1991</date>
<idno type="doi">10.1016/0006-2952(91)90716-I</idno>
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<profileDesc><textClass><keywords scheme="KwdEn" xml:lang="en"><term>4-THA : 2-hydroxy-3-propyl-4-[6-(tetrazol-5yl)hexyloxy]acetophenone</term>
<term>ACS : acyl-CoA synthetase</term>
<term>And HEPES : N-2-hydroxyethylpiperazine-N′-2-enthanesulfonic acid</term>
<term>BSA : bovine serum albumin</term>
<term>CPT : carnitine palmitoyltransferase</term>
<term>CoA : coenzyme A</term>
<term>PFDA : perfluorodecanoic acid</term>
<term>PFOA : perfluorooctanoic acid</term>
<term>POCA : 2[5(4-chlorophenyl)pentyl]oxirane-2-carboxylate</term>
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<front><div type="abstract" xml:lang="eng">Perfluorodecanoic acid (PFDA) is a potent peroxisome proliferator and is known to affect hepatic lipid metabolism in rats. The effects of PFDA on fatty acid utilization were examined in isolated rat hepatocyte suspensions and in rat liver mitochondria and microsomes. PFDA inhibited the oxidation of palmitic acid but not octanoic or pyruvic acids when hepatocytes were incubated with 1 mM PFDA. At this PFDA concentration the esterification of palmitic acid into triacylglycerols was also reduced. The activity of long-chain acyl-CoA synthetase (ACS), an enzyme essential for both oxidation and esterification of fatty acids, was reduced in hepatocytes incubated with 1 mM PFDA. Carnitine palmitoyltransferase (CPT), an important enzyme for the oxidation of long-chain fatty acids, was not altered in hepatocytes incubated with this PFDA concentration. In rat liver mitochondria, palmitate oxidation and ACS activity were reduced significantly (P<0.01) at a PFDA concentration that had no effect on CPT activity. The inhibition of ACS by PFDA was similar in liver mitochondria and microsome preparations. In mitochondria incubated with PFDA, the inhibition of ACS appears to be noncompetitive for the substrates palmitic acid and CoA. However, the ACS inhibition by PFDA appeared to be competitive for the ATP binding site of the enzyme. Several chain length perfluorinated fatty acids were examined for their ability to inhibit mitochondrial ACS. Short-chain perfluorinated fatty acids (perfluoroproprionic and -butyric acid) did not inhibit ACS activity. However, medium-chain perfluorinated acids (perfluorooctanoic, -ananoic and -decanoic acid) were found to be potent inhibitors of ACS in isolated mitochondria. Whether ACS inhibition is causally related to PFDA-induced peroxisome proliferation and altered lipid metabolism seen in vivo is yet to be determined. </div>
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