Branched Chain Amino Acid Oxidation in Cultured Rat Skeletal Muscle Cells

Pardridge, William M.; Casanello-Ertl, Delia; Duducgian-Vartavarian, Luiza

doi:10.1172/jci109839

Cited by 18 publications

(6 citation statements)

References 26 publications

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“…Clofibric acid was shown in previous studies to inhibit branched-chain amino acid oxidation by rat skeletal-muscle cells [4,5] and muscle homogenates [3], an effect likely to be due to direct inhibition of BCODC, as demonstrated with the purified enzyme [6,11]. This inhibitory effect was apparent also with isolated hepatocytes in the present study, but occurred at higher clofibric acid concentrations than those required to activate BCODC by inhibition of its kinase.…”

Section: Discussionsupporting

confidence: 75%

“…Clofibric acid (p-chlorophenoxymethylpropionic acid), a wellknown antihyperlipidaemic drug [1], has been observed to lower tissue levels of branched-chain amino acids [2] and both to inhibit [3][4][5] and to stimulate [2,6] flux through the branchedchain 2-oxo acid dehydrogenase complex (BCODC), the enzyme recognized as rate-limiting in the oxidation of branched-chain amino acids [7]. Clofibric acid therapy also induces a muscular weakness syndrome called myotonia [8][9][10], and this condition may be linked to altered branched-chain amino acid metabolism [2,4,11]. This work was initiated after the report by Ono et al [12] of induction of BCODC by clofibric acid in the liver of the rat.…”

Section: Introductionmentioning

confidence: 99%

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Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex

Zhao

Jaśkiewicz

Harris

1992

Biochemical Journal

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Feeding clofibric acid to rats caused little or no change in total activity of the liver branched-chain 2-oxo acid dehydrogenase complex (BCODC). No change in mass of liver BCODC was detected by immunoblot analysis in response to dietary clofibric acid. No changes in abundance of mRNAs for the BCODC E1 alpha, E1 beta and E2 subunits were detected by Northern-blot analysis. Likewise, dietary clofibric acid had no effect on the activity state of liver BCODC (percentage of enzyme in the dephosphorylated, active, form) of rats fed on a chow diet. However, dietary clofibric acid greatly increased the activity state of liver BCODC of rats fed on a diet deficient in protein. No stable change in liver BCODC kinase activity was found in response to clofibric acid in either chow-fed or low-protein-fed rats. Clofibric acid had a biphasic effect on flux through BCODC in hepatocytes prepared from low-protein-fed rats. Stimulation of BCODC flux at low concentrations was due to clofibric acid inhibition of BCODC kinase, which in turn allowed activation of BCODC by BCODC phosphatase. Inhibition of BCODC flux at high concentrations was due to direct inhibition of BCODC by clofibric acid. The results suggest that the effects of clofibric acid in vivo on branched-chain amino acid metabolism can be explained by the inhibitory effects of this drug on BCODC kinase.

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Section: Discussionsupporting

confidence: 75%

Section: Introductionmentioning

confidence: 99%

Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex

Zhao

Jaśkiewicz

Harris

1992

Biochemical Journal

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Section: Hepatic Lipid and Reactive Oxygen Species (Ros)mentioning

confidence: 99%

“…Peroxisomal FAO consumes NAD ϩ and generates NADH, which will then be transported to the cytosol via redox shuttles, and increases redox potential in the cytosol because, unlike mitochondria, a NAD ϩ regenerating system is absent in peroxisomes (15)(16)(17). Enhanced peroxisomal FAO results in increased NADH generation in peroxisomes, which further increases the cytosolic NADH/NAD ϩ ratio, thereby inhibiting the activity of SIRT1 and its downstream targets and negatively regulating mitochondrial FAO and cellular ROS metabolism.…”

Section: Hepatic Lipid and Reactive Oxygen Species (Ros)mentioning

confidence: 99%

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Zeng

Deng

Wang

et al. 2017

Journal of Biological Chemistry

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Edited by Dennis R. VoelkerA chronic high fat diet results in hepatic mitochondrial dysfunction and induction of peroxisomal fatty acid oxidation (FAO); whether specific inhibition of peroxisomal FAO benefits mitochondrial FAO and reactive oxygen species (ROS) metabolism remains unclear. In this study a specific inhibitor for the rate-limiting enzyme involved in peroxisomal FAO, acyl-CoA oxidase-1 (ACOX1) was developed and used for the investigation of peroxisomal FAO inhibition upon mitochondrial FAO and ROS metabolism. Specific inhibition of ACOX1 by 10,12-tricosadiynoic acid increased hepatic mitochondrial FAO via activation of the SIRT1-AMPK (adenosine 5-monophosphateactivated protein kinase) pathway and proliferator activator receptor ␣ and reduced hydrogen peroxide accumulation in high fat diet-fed rats, which significantly decreased hepatic lipid and ROS contents, reduced body weight gain, and decreased serum triglyceride and insulin levels. Inhibition of ACOX1 is a novel and effective approach for the treatment of high fat dietor obesity-induced metabolic diseases by improving mitochondrial lipid and ROS metabolism. Hepatic lipid and reactive oxygen species (ROS)2 accumulation due to hyperlipidemia and obesity are critical factors associated with the prevalence of metabolic and cardiovascular diseases (1, 2). Decreased mitochondrial fatty acid oxidation (FAO) and increased lipogenesis are major contributors to lipid accumulation in liver and other tissues (3). Excessive hepatic ROS generation and decreased cellular antioxidative activity lead to oxidative stress and hepatic oxidative injury (2, 4). Agents that are able to promote mitochondrial fatty acid oxidation or have antilipogenic and antioxidative effects will improve lipid and ROS metabolism and attenuate hepatic steatosis and oxidative injury.Peroxisomes are subcellular respiratory organelles that are critical for the metabolism of long chain and branched-chain fatty acids (5). Peroxisomes are sensitive to external signals and are easy to proliferate under conditions of high fat diet (HFD) (6, 7), diabetes (8), or hypolipidemic drug treatment (9); peroxisomal FAO is induced, oxidation capacity is increased by 2-10-fold, and peroxisomal FAO is regulated by the peroxisome proliferator activator receptor ␣ isoform (PPAR␣) (5).Acyl-CoA oxidase-1 (ACOX1, EC 1.3.3.6) is a flavoenzyme that catalyzes the initial and rate-determining reaction of the classical peroxisomal FAO using straight-chain fatty acyl-CoAs as the substrates, which donates electrons to molecular oxygen generating hydrogen peroxide; this byproduct is further decomposed by catalase, as shown in Fig. 1. The classical peroxisomal FAO has been known for nearly 40 years (9), but it is still not clear about the exact role of peroxisomal FAO in cellular fatty acid metabolism and especially its effect on mitochondrial fatty acid oxidation. Several lines of evidence have shown that chronic induction of peroxisomal FAO may cause oxidative stress and is potentially detrimental to mitochondrial fa...

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“…Since the BCOD kinase gene is subject to tissue-specific regulation by glucocorticoids and nutritional stimuli, a similar mechanism may exist for regulating kinase gene expression in the liver. For example, clofibrate (p-chlorophenoxymethylpropionic acid), a well-known anti-hyperlipidaemic drug, was reported to increase hepatic BCOD-complex activity [43][44][45], which may be linked to the development of a muscular weakness syndrome after long-term treatment with the drug [46][47][48]. In a recent study [45], administration of clofibrate to chow-fed rats reduced the hepatic kinase mRNA and protein levels to 60 % and 30 % respectively of controls, which appeared to be responsible for the increased activity of the BCOD complex.…”

Section: Discussionmentioning

confidence: 99%

Down-regulation of rat mitochondrial branched-chain 2-oxoacid dehydrogenase kinase gene expression by glucocorticoids

Huang

Chuang²

1999

Biochemical Journal

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The mammalian mitochondrial branched-chain 2-oxoacid dehydrogenase (BCOD) complex is regulated by a reversible phosphorylation (inactivation)\dephosphorylation (activation) cycle. In the present study, the effects of glucocorticoids on the level of BCOD kinase mRNA were investigated in rat hepatoma cell lines (H4IIE and FTO-2B), as well as in the rat. In H4IIE cells, dexamethasone was found to significantly reduce steadystate concentrations of BCOD kinase mRNA after a 48 h culture, and this was correlated with a 2-fold increase in the dephosphorylated form of the BCOD complex. The half-life of the kinase mRNA in H4IIE cells was not affected by dexamethasone treatment. Therefore, the decrease in the steady-state kinase mRNA level resulting from dexamethasone treatment was not caused by changes in mRNA stability, which raised the possibility of regulation at the level of gene transcription. To identify the negative glucocorticoid-responsive element in the kinase pro-

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Branched Chain Amino Acid Oxidation in Cultured Rat Skeletal Muscle Cells

Abstract: A B S T R A C T Leucinie metabolism in

Cited by 18 publications

References 26 publications

Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex

Effects of clofibric acid on the activity and activity state of the hepatic branched-chain 2-oxo acid dehydrogenase complex

Specific Inhibition of Acyl-CoA Oxidase-1 by an Acetylenic Acid Improves Hepatic Lipid and Reactive Oxygen Species (ROS) Metabolism in Rats Fed a High Fat Diet

Down-regulation of rat mitochondrial branched-chain 2-oxoacid dehydrogenase kinase gene expression by glucocorticoids

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