Effect of clofibrate on the CoA thioester profile in rat liver

Ball, Michael; Gumaa, K.A.; McLean, Patricia

doi:10.1016/0006-291x(79)91822-9

Cited by 33 publications

(11 citation statements)

References 19 publications

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“…It is known that hypolipidemic drugs raise the concentration of both free and total CoA in rat liver (40)(41)(42). Thus, evaluation of the free CoApool offers an additional possibility to characterize the effects of perfluorinated carboxylic acids on hepatic lipid metabolism and peroxisome proliferation.…”

Section: Peroxisomal Polypeptides Sds-polyacrylamidementioning

confidence: 98%

Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver

et al. 1989

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Rats were treated for 5 to 14 days with perfluoroacetate, perfluorobutyrate and perfluorooctanoate. Alterations in hepatic morphology with special reference to the peroxisomal compartment were investigated by light and electron microscopy following cytochemical staining of catalase activity with the alkaline 3,3'-diaminobenzidine medium. All three compounds induced hepatomegaly and peroxisome proliferation. Perfluorobutyrate and perfluorooctanoate were found to be more active than perfluoroacetate. Perfluorooctanoate-induced peroxisome proliferation was more prevalent in centrilobular than in periportal hepatocytes. Peroxisomes in centrilobular liver cells frequently were of round shape, exhibited diameters of up to 1.5 microns and were predominantly located within smooth endoplasmic reticulum-glycogen areas. In periportal cells, however, clusters of polymorphous peroxisomes ranging from 250 to 1,100 nm in diameter were observed at the periphery of smooth endoplasmic reticulum-glycogen regions. Peroxisome proliferation was accompanied by a change of peroxisomal and mitochondrial enzyme activities, in particular an increase in peroxisomal palmitoyl-CoA oxidation. Significant alterations in the concentration of peroxisomal matrix and membrane polypeptides were also noted. Within the first 2 days, perfluorooctanoate treatment exerted a strong hypolipidemic activity and both compounds perfluorooctanoate and perfluorobutyrate raised the level of hepatic free acid-soluble CoA nearly 10-fold as compared with control livers. The results suggest perfluorinated carboxylic acids to be model substances suitable to correlate biochemical and morphological parameters with the zonal heterogeneity of the peroxisomal compartment in rat liver. Due to the manifold hepatic effects, contact of humans with perfluorinated carboxylic acids or their metabolic precursors may represent a severe health risk.

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Section: Peroxisomal Polypeptides Sds-polyacrylamidementioning

confidence: 98%

Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver

et al. 1989

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“…Analogues of clofibrate (fibrates) which are hypolipidaemic in man and rodents induce a variety of hepatic changes when administered to rats in vivo, including proliferation of peroxisomes [1][2][3], induction of several peroxisomal enzymes [4][5][6], and increased concentrations of CoA [7] and carnitine [8]. Various mechanisms have been proposed to explain their multiplicity of effects, including: (i) binding of the fibrate to a cytosolic '.receptor' protein [9]; (ii) conversion into the CoA ester, which in turn binds to a recognition site [10,11]; (iii) reaction of the CoA ester with carnitine, glycerol 3phosphate, amino acids or other conjugates [12].…”

Section: Introductionmentioning

confidence: 99%

Interactions of inhibitors of carnitine palmitoyltransferase I and fibrates in cultured hepatocytes

Gerondaes

Alberti

Agius

1988

Biochemical Journal

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Culture of rat hepatocytes with etomoxir, an inhibitor of carnitine palmitoyltransferase I (CPT I), for 48 h, resulted in increased carnitine acetyltransferase (CAT) activity (74%), a marked decrease in CPT activity (82%) measured in detergent extracts, and increased activities of glucose-6-phosphate dehydrogenase (227%) and fructose-1,6-bisphosphatase (65%). Changes in CAT and CPT activities were not observed after 4 h culture with etomoxir. When hepatocytes were cultured with etomoxir and benzafibrate (a hypolipidaemic analogue of clofibrate) for 48 h, etomoxir prevented the 5-fold increase in CAT activity caused by bezafibrate, whereas bezafibrate suppressed the increase in glucose-6-phosphate dehydrogenase and fructose-bisphosphatase caused by etomoxir. However, bezafibrate did not prevent the suppression of CPT activity by etomoxir. Etomoxir inhibited palmitate beta-oxidation and ketogenesis after short-term (0-4 h) and long-term (48 h) exposure, but it caused accumulation of triacylglycerol in hepatocytes only after short-term exposure (0-4 h). These effects of etomoxir on fatty acid metabolism and suppression of CPT (after 48 h) were similar in periportal and perivenous hepatocytes, but the increases in CAT and glucose-6-phosphate dehydrogenase activities were higher in periportal than in perivenous cells. The effects of CPT I inhibitors on CAT activity and long-term suppression of CPT activity are probably mediated by independent mechanisms.

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“…Similarly, no bezafibroylcarnitine formation was observed with the respective carnitine transferase preparations derived from livers of bezafibrate-treated rats. Hence the involvement of the carnitine acyltransferase activity in the induction of peroxisomal proliferation could implicate the possible sequestration of mitochondrial CoA (Ball et al, 1979;Berge et al, 1983) or some possible novel function of the transferase protein.…”

Section: Resultsmentioning

confidence: 99%

Prevention of peroxisomal proliferation by carnitine palmitoyltransferase inhibitors in cultured rat hepatocytes and in vivo

Hertz¹,

Bar‐Tana²

1987

Biochemical Journal

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1. The induction of peroxisomal beta-oxidation activities by bezafibrate in cultured rat hepatocytes and in the rat in vivo was prevented by inhibitors of carnitine acyltransferase, e.g. 2-bromopalmitate, 2-[5-(4-chlorophenyl)pentyl]oxirane-2-carboxylate or 2-tetradecylglycidic acid. 2. The prevention of peroxisomal proliferation by carnitine palmitoyltransferase inhibitors could not be accounted for by inhibition of mitochondrial beta-oxidation, since 2-bromo-octanoate, acting as an inhibitor of beta-oxidation, did not prevent the induction of peroxisomal activities in cultured rat hepatocytes. 3. The putative role of the acylcarnitine derivative of bezafibrate was analysed by studying the formation of bezafibroylcarnitine with bezafibroyl-CoA as substrate. However, no bezafibroylcarnitine formation was demonstrated in the presence of rat liver preparations capable of catalysing transfer to carnitine of medium- or long-chain fatty acids. 4. The prevention of peroxisomal proliferation by carnitine acyltransferase inhibitors may help in dissecting the causal relationship between the multiple effects mediated by peroxisomal proliferators.

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Effect of clofibrate on the CoA thioester profile in rat liver

Cited by 33 publications

References 19 publications

Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver

Biochemical effects and zonal heterogeneity of peroxisome proliferation induced by perfluorocarboxylic acids in rat liver

Interactions of inhibitors of carnitine palmitoyltransferase I and fibrates in cultured hepatocytes

Prevention of peroxisomal proliferation by carnitine palmitoyltransferase inhibitors in cultured rat hepatocytes and in vivo

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