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

Hirose, Akihiko; Yamazaki, Tohru; Sakamoto, Takeshi; Sunaga, Katsuyoshi; Tsuda, Tadashi; Mitsumoto, Atsushi; Kudo, Naomi; Kawashima, Yasunaru

doi:10.1254/jphs.11020fp

Cited by 3 publications

(4 citation statements)

References 41 publications

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“…Moreover, in accordance with previous findings (34,35), fibrates markedly elevated the expression of both Elovl6 and SCD1 participating in oleic acid synthesis from palmitic acid and stearic acid, results that suggest increased formation of oleic acid not only from palmitic acid synthesized de novo but also from palmitic acid and stearic acid taken up from the circulation. The latter had been demonstrated by our previous study that the in vivo conversion of [ 14 C] stearic acid to [ 14 C] oleic acid in the liver is stimulated by the treatment of rats with clofibric acid (36,37). Therefore, despite slight down-regulation of DGAT2 expression by fibrates, it is most likely that a massive amount of oleic acid is formed and available for the formation of TAG in the liver of rats treated with fibrates because oleic acid is known to be incorporated into TAG more preferentially than other fatty acids (38 -40).…”

Section: Discussionmentioning

confidence: 90%

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Karahashi¹,

Hoshina²,

Yamazaki³

et al. 2013

J Pharmacol Sci

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Abstract. Hepatic triacylglycerol (TAG) homeostasis is maintained by carefully regulated balance between its synthesis and disposal. Impairment in this balance causes steatosis. The aims of this study were i) to uncover whether fibrates control TAG concentration through the action of adipose triglyceride lipase (ATGL) and ii) to compare the potency of the effects on ATGL expression and TAG concentration among fenofibrate, bezafibrate, and clofibric acid in the liver of rats. Treatments of rats with the three fibrates induced ATGL and concomitantly decreased hepatic TAG concentration. The upregulation of ATGL was likely mediated through the activation of peroxisome proliferator-activated receptor a. Fibrates also expanded capacity of fatty acid b-oxidation. Importantly, three fibric acids (fenofibric, bezafibric, and clofibric acids) that are active metabolites formed in the liver exhibited almost the same potency to elevate ATGL expression in vivo, despite the fact that there were considerable differences in this regard among fenofibrate, bezafibrate, and clofibric acid when compared on the basis of their dosage. These results suggest that ATGL represents a potential therapeutic target for ameliorating hepatic steatosis and that fibric acids are promising agents to ameliorate and/or protect against hepatic steatosis.

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Section: Discussionmentioning

confidence: 90%

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Karahashi¹,

Hoshina²,

Yamazaki³

et al. 2013

J Pharmacol Sci

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“…11) In addition, our recent studies demonstrated that fibrates induce the expression of mRNAs encoding SCD1 and SCD2 in the liver 25) and that clofibric acid increases the formation of 18 : 1n-9 and the incorporation of the newly formed 18 : 1n-9 into sn-2 position of PC in endoplasmic reticulum in the liver. 26) Thus, it seems likely that fibrates significantly elevated the proportion of 18 : 1n-9 of PC in the liver as the results of both the induction of LPCAT and the increase in supply of 18 : 1n-9. With regard to proportions of 18 : 2n-6, 20 : 3n-6 and 20 : 4n-6 in PC, it is considered that those proportions are regulated by the activity and substrate specificity of LPCAT and the amounts of available acyl-CoAs as substrates.…”

Section: Discussionmentioning

confidence: 99%

Induction of 1-Acylglycerophosphocholine Acyltransferase Genes by Fibrates in the Liver of Rats

Yamazaki

Wakabayashi

Ikeda

et al. 2012

Biological & Pharmaceutical Bulletin

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The effect of fibrates (clofibric acid, bezafibrate and fenofibrate) on the gene expression and activity of 1-acylglycerophosphocholine acyltransferase (LPCAT) was investigated. The administration of 0.1% (w/w) clofibric acid, bezafibrate or fenofibrate in diet for 14 d to rats induced LPCAT activity in hepatic microsomes in the following order: fenofibrate>bezafibrate>clofibric acid. The LPCAT induced by fenofibrate preferred to arachidonoyl-CoA and linoleoyl-CoA to a greater extent than did LPCAT in control microsomes. The treatment with the fibrates resulted in upregulation of the relative expression of mRNAs encoding LPCAT3 and LPCAT4 in the following order: fenofibrate>bezafibrate>clofibric acid. The administration of fibrates did not change the expression of genes encoding either LPCAT1 or LPCAT2. The treatment with fibrates elevated relative levels of both mRNAs encoding Δ6 desaturase (Fads2) and Δ5 desaturase (Fads1) in the order of fenofibrate>bezafibrate>clofibric acid, and the extent of the increase in the level of Δ6 desaturase mRNA was greater than that of Δ5 desaturase. Fatty acid profile in hepatic phosphatidylcholine (PC) was significantly changed by the treatments with fibrates. These results suggest (i) that fibrates induce LPCAT activity in hepatic microsomes by elevating the expression of genes encoding LPCAT3 and LPCAT4, (ii) that the changes in fatty acid profile of hepatic PC are, in part, due to the elevated expression of two isoforms, LPCAT3 and LPCAT4, and (iii) that the ability of fibrates to induce these changes are in the order of fenofibrate>bezafibrate>clofibric acid.Key words 1-acylglycerophosphocholine acyltransferase; clofibric acid; bezafibrate; fenofibrate; rat liver 2-(4-Chlorophenoxy)-2-methylpropionic acid (clofibric acid), a hypolipidemic drug, is well known to enhance fatty acid degradation through inducing the proliferation of peroxisomes and fatty acid β-oxidation in the liver.1) In addition to lipid degradation, clofibric acid (or clofibrate) affects lipid biosynthesis of animals through the enzymes such as stearoyl-CoA desaturase (SCD), 2,3) palmitoyl-CoA elongase, 4,5) acyl-CoA synthetase, 5) glycerophosphate acyltransferase, 6) 1-acylglycerophosphate acyltransferase, 5) CoA-dependent transacylase 7) and 1-acylglycerophosphocholine acyltransferase (LPCAT). 8,9) Of these enzymes, LPCAT is of particular interest in relation to the acyl composition of membrane phospholipid. Namely, the primary physiological role of LPCAT is considered to be generation of phosphatidylcholine (PC) having an unsaturated fatty acid at the sn-2 position. 10) A previous study showed that the treatment of rats with clofibric acid caused a marked alteration in acyl composition of PC 5) and, consequently, in the composition of molecular species of PC in the liver.11) The clofibric acid-caused changes in acyl composition of hepatic PC were demonstrated to be the result of the inductions of SCD and LPCAT in the liver. 5,12,13) Although studies focusing on the effect of clofibric acid on the induct...

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“…Previous studies demonstrated that the treatment of rodents with fibrates markedly induced SCD activity, thereby increasing 18:1n-9 content in the liver [13][14][15][16][17]. However, the regulation of SCD in extrahepatic tissues, in particular the small intestine, has not been thoroughly investigated, and little is known about whether fibrates affect the MUFA profile in intestinal mucosa.…”

Section: Discussionmentioning

confidence: 99%

“…To elucidate the physiological significance of this observation, a series of studies were performed and demonstrated that the administration of clofibric acid to rats induced SCD in the liver [13,14] and that the induction of SCD by clofibric acid is due to elevation of the expression of SCD1 through the activation of PPARα [15,16] and to the suppression of the degradation of SCD [16]. Thus, accelerated formation of oleic acid (18:1n-9) by inducing SCD in the liver of rats is considered to be one of the pharmacological effects of clofibric acid [17]. In a recent study, fibrates were shown to elevate the gene expression of SCD1 and SCD2 in the liver of rats [18].…”

Section: Introductionmentioning

confidence: 99%

Inducing Effect of Clofibric Acid on Stearoyl‐CoA Desaturase in Intestinal Mucosa of Rats

Yamazaki

Kadokura

Mutoh

et al. 2014

Lipids

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Fibrates have been reported to elevate the hepatic proportion of oleic acid (18:1n-9) through inducing stearoyl-CoA desaturase (SCD). Despite abundant studies on the regulation of SCD in the liver, little is known about this issue in the small intestine. The present study aimed to investigate the effect of clofibric acid on the fatty acid profile, particularly monounsaturated fatty acids (MUFA), and the SCD expression in intestinal mucosa. Treatment of rats with a diet containing 0.5% (w/w) clofibric acid for 7 days changed the MUFA profile of total lipids in intestinal mucosa; the proportion of 18:1n-9 was significantly increased, whereas those of palmitoleic (16:1n-7) and cis-vaccenic (18:1n-7) acids were not changed. Upon the treatment with clofibric acid, SCD was induced and the gene expression of SCD1, SCD2, and fatty acid elongase (Elovl) 6 was up-regulated, but that of Elovl5 was unaffected. Fat-free diet feeding for 28 days increased the proportions of 16:1n-7 and 18:1n-7, but did not effectively change that of 18:1n-9, in intestinal mucosa. Fat-free diet feeding up-regulated the gene expression of SCD1, but not that of SCD2, Elovl6, or Elovl5. These results indicate that intestinal mucosa significantly changes its MUFA profile in response to challenges by clofibric acid and a fat-free diet and suggest that up-regulation of the gene expression of SCD along with Elovl6 is indispensable to elevate the proportion of 18:1n-9 in intestinal mucosa.

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

Cited by 3 publications

References 41 publications

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Fibrates Reduce Triacylglycerol Content by Upregulating Adipose Triglyceride Lipase in the Liver of Rats

Induction of 1-Acylglycerophosphocholine Acyltransferase Genes by Fibrates in the Liver of Rats

Inducing Effect of Clofibric Acid on Stearoyl‐CoA Desaturase in Intestinal Mucosa of Rats

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