Leucine Oxidation and Protein Turnover in Clofibrate-induced Muscle Protein Degradation in Rats

Paul, Harbhajan S.; Adibi, Siamak A.

doi:10.1172/jci109791

Cited by 53 publications

(31 citation statements)

References 46 publications

(48 reference statements)

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“…To our knowledge there is only one previous study that reports effects of a PPAR␣ agonist on plasma amino acid levels in rodents (28). A high dose of clofibrate (300 mg⅐kg Ϫ1 ⅐day Ϫ1 ) was given to rats fed a standard chow diet for 2 wk.…”

Section: Discussionmentioning

confidence: 99%

“…Along these lines, clofibrate is known to be a direct inhibitor of branched-chain ␣-keto acid dehydrogenase kinase at pharmacologically relevant concentrations, whereas WY 14,643 is not (18). Indeed, elevated branched-chain amino acid oxidation has been proposed to be responsible for the state of muscle wasting seen in clofibrate-treated animals due to impaired protein synthesis resulting from a lack of branchedchain amino acids (28). Regarding the generality of the current findings, we have recently observed a very similar amino acid response to a structurally unrelated PPAR␣ agonist in chowfed mice (Oakes ND, unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat

Sheikh

Camejo²,

Lanne³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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nists have been characterized largely in terms of their effects on lipids and glucose metabolism, whereas little has been reported about effects on amino acid metabolism. We studied responses to the PPAR␣ agonist WY 14,643 (30 mol⅐ kg Ϫ1 ⅐ day Ϫ1 for 4 wk) in rats fed a saturated fat diet. Plasma and urine were analyzed with proton NMR. Plasma amino acids were measured using HPLC, and hepatic gene expression was assessed with DNA arrays. The high-fat diet elevated plasma levels of insulin and triglycerides (TG), and WY 14,643 treatment ameliorated this insulin resistance and dyslipidemia, lowering plasma insulin and TG levels. In addition, treatment decreased body weight gain, without altering cumulative food intake, and increased liver mass. WY 14,643 increased plasma levels of 12 of 22 amino acids, including glucogenic and some ketogenic amino acids, whereas arginine was significantly decreased. There was no alteration in branched-chain amino acid levels. Compared with the fat-fed control animals, WY 14,643-treated animals had raised plasma urea and ammonia levels as well as raised urine levels of N-methylnicotinamide and dimethylglycine. WY 14,643 induced changes in a number of key genes involved in amino acid metabolism in addition to expected effects on hepatic genes involved in lipid catabolism and ketone body formation. In conclusion, the present results suggest that, in rodents, effects of pharmacological PPAR␣ activation extend beyond control of lipid metabolism to include important effects on whole body amino acid mobilization and hepatic amino acid metabolism.peroxisome proliferator-activated receptor-␣ PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-␣ (PPAR␣) agonists are used clinically to treat dyslipidemia and to reduce the risk of cardiovascular complications (7). The beneficial effects of these agents appear to be most significant in patients with insulin resistance and diabetes (32). It is clear that a major and primary action of PPAR␣ activation is the transcriptional regulation of genes involved in lipid metabolism (36). However, the effects of PPAR␣ activation may not be limited to lipid metabolism, given the established interactions between the major substrate classes (19), e.g., the glucose-fatty acid cycle (29) and the glucose-alanine cycle (10). In terms of glucose metabolism, an important physiological role of PPAR␣ is suggested by the hypoglycemia in response to prolonged fasting developed by mice lacking PPAR␣ (17). Furthermore, treatment of fat-fed rats with the selective PPAR␣ agonist WY 14,643 resulted in increases in whole body and skeletal muscle insulin-stimulated glucose utilization, with the enhancement in muscle insulin sensitivity related to the degree of reduction in local lipid accumulation (39). Surprisingly little has been reported concerning effects of PPAR␣ activation on amino acid metabolism, although work based largely on analysis of mRNA in mouse liver (23) suggests an important influence on the handling of this substrate class.The aim of the present study was to provide...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat

Sheikh

Camejo²,

Lanne³

et al. 2007

American Journal of Physiology-Endocrinology and Metabolism

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show abstract

“…This could be caused by decreased input of TML from protein degradation, which is known to be the rate-limiting step of the carnitine biosynthetic pathway (49). In support of this, clofibrate indeed is known to induce protein breakdown in skeletal muscle (50). Further research is needed to fully resolve the role of PPAR␣ in carnitine metabolism.…”

Section: Discussionmentioning

confidence: 99%

A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

Gloerich

Vlies

Jansen

et al. 2005

Journal of Lipid Research

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Branched-chain fatty acids (such as phytanic and pristanic acid) are ligands for the nuclear hormone receptor peroxisome proliferator-activated receptor ␣ (PPAR ␣ ) in vitro . To investigate the effects of these physiological compounds in vivo, wild-type and PPAR ␣ -deficient (PPAR ␣ ؊ / ؊ ) mice were fed a phytol-enriched diet. This resulted in increased plasma and liver levels of the phytol metabolites phytanic and pristanic acid. In wild-type mice, plasma fatty acid levels decreased after phytol feeding, whereas in PPAR ␣ ؊ / ؊ mice, the already elevated fatty acid levels increased. In addition, PPAR ␣ ؊ / ؊ mice were found to be carnitine deficient in both plasma and liver. Dietary phytol increased liver free carnitine in wild-type animals but not in PPAR ␣ ؊ / ؊ mice. Investigation of carnitine biosynthesis revealed that PPAR ␣ is likely involved in the regulation of carnitine homeostasis. Furthermore, phytol feeding resulted in a PPAR ␣ -dependent induction of various peroxisomal and mitochondrial ␤ -oxidation enzymes. In addition, a PPAR ␣ -independent induction of catalase, phytanoyl-CoA hydroxylase, carnitine octanoyltransferase, peroxisomal 3-ketoacyl-CoA thiolase, and straight-chain acyl-CoA oxidase was observed. In conclusion, branched-chain fatty acids are physiologically relevant ligands of PPAR ␣ in mice. These findings are especially relevant for disorders in which branched-chain fatty acids accumulate, such as Refsum disease and peroxisome biogenesis disorders.

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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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Leucine Oxidation and Protein Turnover in Clofibrate-induced Muscle Protein Degradation in Rats

Cited by 53 publications

References 46 publications

Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat

Beyond lipids, pharmacological PPARα activation has important effects on amino acid metabolism as studied in the rat

A phytol-enriched diet induces changes in fatty acid metabolism in mice both via PPARα-dependent and -independent pathways

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

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