The mechanism for the increased supply of phosphatidylcholine for the proliferation of biological membranes by clofibric acid, a peroxisome proliferator

Kawashima, Yasunaru; Mizuguchi, Hiroki; Musoh, Keiichi; Kono, Hiroshi

doi:10.1016/0005-2760(94)90205-4

Cited by 24 publications

(23 citation statements)

References 42 publications

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“…The most characteristic alterations caused by PFCAs in fatty acid profile were an increase in the total content of fatty acids, originating from the increases in the contents and proportions of 16 : 1 and 18 : 1, and the content of 16 : 0 in TG. It should be noted here that clofibrate, a typical peroxisome proliferator, decreases the hepatic content of TG, 35) in contrast to PFCAs. The content and proportion of 20 : 3 were considerably increased by PFCAs in hepatic PL, to a lesser extent than those of 16 : 1 and 18 : 1 in TG.…”

Section: Pfca-mediated Alterations In Fatty Acid Profile In Hepatic Lmentioning

confidence: 67%

Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

Kudo

Yamazaki

Sakamoto

et al. 2011

Biological & Pharmaceutical Bulletin

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A growing body of evidence supporting the key role of fatty acid species in maintaining systemic metabolic homeostasis has been accumulated in recent years. Many studies showed that free fatty acids and a particular molecular species of phosphatidylcholine (PC), palmitoyl-oleoyl-PC, extend molecular effects to cellular homeostasis as lipid signaling molecules through nuclear receptors.1-3) Palmitic acid (16 : 0) and stearic acid (18 : 0) are known to cause endoplasmic reticulum stress, leading to inductions of insulin resistance, and apoptosis of liver cells and pancreatic b-cells. 4-8)Moreover, oleic acid (18 : 1) in a large amount was shown to induce hepatic endoplasmic reticulum stress, resulting in inhibition of very low-density-lipoprotein secretion. 9) 18 : 1 is a major component of triacylglycerol (TG), the accumulation of which causes fatty liver, obesity and muscle insulin resistance. [10][11][12] Recently, palmitoleic acid (16 : 1) was demonstrated to strongly stimulate muscle insulin action and suppress hepatosteatosis.13) Thus, the nature of the fatty acid species is now considered crucial for maintaining homeostasis in organs. Accordingly, it is plausible that xenobiotics affect systemic metabolic homeostasis through changing the fatty acid profile of organs, especially the liver, because the changes that occur in the liver extend to the fatty acid composition of extrahepatic tissues.14) In this context, it is clearly important to accumulate information with respect to the effects of xenobiotics on the fatty acid profile for hepatic lipids.Perfluorinated fatty acids (PFCAs) are straight-chain fatty acid analogues of which all aliphatic hydrogens are substituted with fluorine. Because of their surfactant properties and their chemical and thermal stability, PFCAs are primarily used as industrial materials.15) Since perfluorooctanoic acid (PFOA) accumulates in the environment and in the serum of not only occupationally exposed workers, but also the general population, [16][17][18][19] most research has been focused on the study of the toxicological effects of PFOA, so toxicological information pertaining to PFCAs is limited largely to PFOA. However, PFCAs having shorter perfluoroalkyl chains are candidates of substitutes for PFOA, and PFCAs having longer perfluoroalkyl chains exist in the environment as pollutants. Therefore, more information on the toxicological aspects of PFCAs having shorter or longer perfluoroalkyl chains must be accumulated.The primary target organ of PFCAs is considered to be the liver. 19,20) PFOA was shown to be accumulated in the liver of rats and mice and to cause hepatomegaly, 21) induction of enzymes including peroxisomal acyl-CoA oxidase (AOX) in particular [22][23][24] and accumulation of TG. 24) Our previous studies showed that, although a striking difference exists in the effects of PFCAs on the liver when they are estimated by the induction of AOX as a parameter, the induction of AOX by PFCAs depends on only the number of PFCA molecules, but not the difference in their...

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Section: Pfca-mediated Alterations In Fatty Acid Profile In Hepatic Lmentioning

confidence: 67%

Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

Kudo

Yamazaki

Sakamoto

et al. 2011

Biological & Pharmaceutical Bulletin

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“…Transcription of peroxisomal (3-oxidation genes and liver cytochrome P450 genes is induced up to 20-fold by peroxisome proliferators (2)(3)(4), while the transcription of lipogenic genes such as S14 and fatty acid synthase is repressed (5). Also, the transcription of genes involved in phospholipid biosynthesis is induced, probably as a result of the increase in the size of peroxisomal, mitochondrial, and plasma membranes (6). These transcriptional effects are presumed to be mediated by peroxisome proliferator-activated receptors (PPARs) (7).…”

mentioning

confidence: 92%

“…Oleic and palmitoleic acids are the major unsaturated fatty acids in fat depots and membrane phospholipids. The peroxisome proliferator-mediated increase in SCD1 activity corresponds to an increase in the levels of oleic acid incorporated into phospholipids relative to stearic acid (15). The ratio of stearic to oleic acid is one of the factors influencing cell membrane fluidity and cell-cell interactions (16).…”

mentioning

confidence: 99%

Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.

Miller

Ntambi

1996

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

231

152

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Peroxisome proliferators induce stearoyl-CoA desaturase activity (EC 1.14.99.5) in liver [Kawashima, Y., Hanioka, N., Matsumura, M. & Kozuka, H. (1983) Biochim. Biophys. Acta 752, 259-264]. We analyzed the changes in stearoyl-CoA desaturase 1 (SCD1) mRNA to further define the molecular mechanism for the induction of stearoyl-CoA desaturase by peroxisome proliferators. SCD1 mRNA was analyzed from the livers of BALB/c mice that had been fed diets supplemented with clofibrate or gemfibrozil. Clofibrate was found to induce liver SCD1 mRNA levels 3-fold within 6 hr to a maximum of 22-fold in 30 hr. Gemfibrozil administration resulted in a similar induction pattern. This induction is primarily due to an increase in transcription of the SCD1 gene, as shown by nuclear run-on transcription assays and DNA deletion analysis of transfected SCD1-chloramphenicol acetyltransferase fusion genes. The cis-linked response element for peroxisome proliferator-activated receptor (PPAR) was localized to an AGGTCA consensus sequence between base pairs -664 to -642 of the SCD1 promoter. Clofibrate-mediated induction of SCD1 mRNA was shown to be independent of polyunsaturated fatty acids, with peroxisome proliferators and arachidonic acid having opposite effects on SCD1 mRNA levels. Additionally, the activation of SCD1 mRNA by clofibrate was inhibited 77% by cycloheximide administration. Levels of liver beta-actin and albumin mRNAs were unchanged by these dietary manipulations. Our data show that hepatic SCD1 gene expression is regulated by PPARs and suggest that peroxisome proliferators and poly-unsaturated fatty acids act through distinct mechanisms.

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“…As a result, the absolute amounts of 18:1 formed from 18:0 in whole endoplasmic reticulum in the liver of clofibric acid-treated rats are assumed to be 9.3-to 12.8-fold higher than that of control rats at 30 min after administering [ 18:1 formed in endoplasmic reticulum is considered to be incorporated into esterified lipids such as glycerolipids and cholesterol ester, which are utilized as components of biological membranes and of VLDL. Our previous study showed that the treatment of rats with clofibric acid increased absolute contents of PC and PE and mass proportions of 18:1 in PC and PE in the liver (12). Moreover, the mass proportion of 18:1 at the C-2 position, but not the C-1 position, was strikingly increased by clofibric acid (13).…”

Section: Discussionmentioning

confidence: 97%

“…On the other hand, however, a previous study showed that clofibric acid has a different type of effect on fatty acid metabolism in the liver; namely, the administration of clofibric acid to rats increased the mass proportion of 18:1 in hepatic lipids (9). To elucidate the physiological significance of this observation, a series of studies was performed and demonstrated that the administration of clofibric acid to rats induced stearoyl-CoA desaturase (SCD) (9, 10), 1-acylglycerophosphocholine acyltransferase (LPCAT) (11) and CTP:phosphocholine cytidylyltransferase (12), resulting in striking increases in the mass proportion and content of 18:1 at the C-2 position of PC (13) and of a particular molecular species of PC, palmitoyl-oleoyl-PC (14,15), in the liver. Subsequent studies revealed that the induction of SCD by clofibric acid is due to the elevation of the expression of SCD1, one of the isoforms of SCD, through the activation of PPARα, and to the suppression of the degradation of SCD (16).…”

Section: Introductionmentioning

confidence: 99%

Clofibric Acid Increases the Formation of Oleic Acid in Endoplasmic Reticulum of the Liver of Rats

Hirose¹,

Yamazaki²,

Sakamoto³

et al. 2011

J Pharmacol Sci

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Abstract. The effects of 2-(4-chlorophenoxy)-2-methylpropionic acid (clofibric acid) on the formation of oleic acid (18:1) from stearic acid (18:0) and utilization of the 18:1 formed for phosphatidylcholine (PC) formation in endoplasmic reticulum in the liver of rats were studied in vivo. [14 C]18:0 was intravenously injected into control Wistar male rats and rats that had been fed on a diet containing 0.5% (w/w) clofibric acid for 7 days; and the distribution of radiolabeled fatty acids among subcellular organelles, microsomes, peroxisomes, and mitochondria, was estimated on the basis of correction utilizing the yields from homogenates of marker enzymes for these organelles.The radioactivity was mostly localized in microsomes and the radiolabeled fatty acids present in microsomes were significantly increased by the treatment of rats with clofibric acid. The formation of radiolabeled 18:1 in microsomes markedly increased and incorporations of the formed [ 14 C]18:1 into PC and phosphatidylethanolamine in microsomes were augmented in response to clofibric acid. The [ 14 C]18:1 incorporated into PC was mostly located at the C-2 position, but not the C-1 position, of PC, and the radioactivity in 18:1 at the C-2 position of PC was strikingly increased by clofibric acid. These results obtained from the in vivo experiments directly link the findings that clofibric acid treatment induces microsomal stearoyl-CoA desaturase and 1-acylglycerophosphocholine acyltransferase in the liver and the findings that the treatment with the drug elevated absolute mass and mass proportion of 18:1 at the C-2 position, but not the C-1 position, of PC in the liver together.

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The mechanism for the increased supply of phosphatidylcholine for the proliferation of biological membranes by clofibric acid, a peroxisome proliferator

Cited by 24 publications

References 42 publications

Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

Effects of Perfluorinated Fatty Acids with Different Carbon Chain Length on Fatty Acid Profiles of Hepatic Lipids in Mice

Peroxisome proliferators induce mouse liver stearoyl-CoA desaturase 1 gene expression.

Clofibric Acid Increases the Formation of Oleic Acid in Endoplasmic Reticulum of the Liver of Rats

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