Adverse effect of fenofibrate on branched-chain α-ketoacid dehydrogenase complex in rat's liver

Knapik-Czajka, Małgorzata; Goździalska, Anna; Jaśkiewicz, Jerzy

doi:10.1016/j.tox.2009.10.002

Cited by 8 publications

(5 citation statements)

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“…Similarly, fenofibrate has also been reported to lower the hyperinsulinaemia and hyperglycaemia in HFD-induced (C57BL/6) mice (8) . Furthermore, fenofibrate could stimulate the branched-chain amino acid (leucine, isoleucine, and valine) catabolism of rats, resulting in attenuating leucinestimulated protein synthesis in a low protein (LP) diet (9) . This result suggested that fenofibrate may play an important role in amino acid metabolism and affect the animal growth.…”

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confidence: 99%

The metabolic regulation of fenofibrate is dependent on dietary protein content in male juveniles of Nile tilapia (Oreochromis niloticus)

et al. 2019

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The fenofibrate functions in mammals could be affected by many factors such as dietary nutrient levels and physiological status. However, this phenomenon has not been well studied in fish. The goal of our study was to investigate the effect of dietary protein contents on metabolic regulation of fenofibrate in Nile tilapia. An 8-week experiment was conducted to feed fish with four diets at two protein levels (28 and 38 %) with or without the supplementation of fenofibrate (200 mg/kg body weight per d). After the trial, the body morphometric parameters, plasma biochemical parameters and quantitative PCR data were examined. These results showed that fenofibrate significantly reduced the feeding intake and weight gain rate, increased the oxidative stress (increased plasma methane dicarboxylic aldehyde) and liver : body ratio (increased hepatosomatic index) in the low protein (LP)-fed fish. In contrast, fenofibrate exhibited a lipid-lowering (reduced hepatic lipid) effect and up-regulated the expressions of the genes related to lipid catabolism, transport and anabolic metabolism in the high protein (HP)-fed fish. The present study suggested that lipid-lowering effect of fenofibrate would be strengthened in the fish fed with the HP diet containing high energy, but in the fish fed with the LP diet containing low energy, the fenofibrate treatment would cause adverse effects for metabolism. Taking together, our study showed that the metabolic regulation of fenofibrate in Nile tilapia was dependent not only on feed energy content but also on dietary nutrient composition, such as dietary protein and/or lipid levels.

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confidence: 99%

The metabolic regulation of fenofibrate is dependent on dietary protein content in male juveniles of Nile tilapia (Oreochromis niloticus)

et al. 2019

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“…Results of the present and previous studies have indicated that clinically relevant doses of fibrates increase 2-OGDH and BCKDH activities in rats fed low-protein diet. Stimulation of liver BCKDH by fibrates was mainly due to increased dephosphorylation (and thus activation of the complex) and was not associated with changes in mRNA levels for BCKDH catalytic and regulatory enzymes (Knapik-Czajka et al, 2009;Knapik-Czajka, 2013). It has well been known that unlike BCKDH the activity of 2-OGDH is not regulated by reversible phosphorylation.…”

Section: Discussionmentioning

confidence: 93%

“…Stimulation of liver BCKDH activity has been observed not only for high but also for low, more clinically relevant doses of fibrates. Fibrates may also alter mRNA levels for BCKDH components, though this effect depends on the dose administered (Knapik-Czajka and Jaskiewicz, 2003;Knapik-Czajka et al, 2009;Knapik-Czajka, 2013;Kobayashi et al, 2002). To our best knowledge the effect of fibrates on liver 2-OGDH complex has not been studied yet.…”

Section: Introductionmentioning

confidence: 99%

Effect of low doses of bezafibrate and fenofibrate on liver 2-oxo-glutarate dehydrogenase complex in low-protein diet fed rats

Knapik-Czajka

2015

Bangladesh J Pharmacol

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Multienzyme 2-oxoglutarate complex (2-OGDH) together with branched chain -ketoacid dehydrogenase (BCKDH) and pyruvate dehydrogenase belong to the family of mitochondrial 2-oxoacid dehydrogenases. Hypolipidemic drugs, bezafibrate and fenofibrate, up-regulate liver BCKDH. The present study has been undertaken to determine the effect of low doses of bezafibrate and fenofibrate on liver 2-OGDH. Fibrates were administrated to rats fed low-protein diet at 5, 10 or 20 mg/kg. In rats treated with increasing doses of bezafibrate 2-OGDH activity increased by 7, 35 and 42%, while in rats administered with fenofibrate by 8, 18, and 56% (p<0.05 for bezafibrate 10 and 20, and fenofibrate 20 mg/kg). Changes in 2-OGDH activity did not correspond with changes in mRNA levels of the complex enzymes. Moreover, mRNA levels of PPAR remained unaltered. It is conceivable that stimulation of 2-OGDH activity by low doses of fibrates is the result of post-transcriptional events and may have a significant effect on liver metabolism. Article Info

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“…Fenofibrate repairs liver injury by decreasing acylcarnitine levels and activating fatty acid β-oxidation genes that cause intracellular oxidative stress (e.g., Cpt1b, Cpt2, Mcad, and Hadha) [ 49 ]. However, the adverse effect of fenofibrate of decreasing amino acids by stimulating their catabolism has also been observed [ 49 , 50 ].…”

Section: Resultsmentioning

confidence: 99%

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

Chu

Paul

et al. 2022

Cancers

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Our previous study demonstrated that peroxisome proliferator-activated receptor (PPAR) agonists downregulated cereblon (CRBN) expression and reduced the anti-myeloma activity of lenalidomide in vitro and in vivo. We aimed to determine whether DNA methylation and protein degradation contribute to the effects of PPAR agonists. CRBN promoter methylation status was detected using methylation-specific polymerase chain reaction. The CRBN protein degradation rate was measured using a cycloheximide chase assay. Metabolomic analysis was performed in multiple myeloma (MM) cells treated with PPAR agonists and/or lenalidomide. Our retrospective study determined the effect of co-administration of PPAR agonists with immunomodulatory drugs on the outcomes of patients with MM. CpG islands of the CRBN promoter region became highly methylated upon treatment with PPAR agonists, whereas treatment with PPAR antagonists resulted in unmethylation. The CRBN protein was rapidly degraded after treatment with PPAR agonists. Lenalidomide and fenofibrate showed opposite effects on acylcarnitines and amino acids. Co-administration of immunomodulatory drugs and PPAR agonists was associated with inferior treatment responses and poor survival. Our study provides the first evidence that PPAR agonists reduce CRBN expression through various mechanisms including inducing methylation of CRBN promoter CpG island, enhancing CRBN protein degradation, and affecting metabolomics of MM cells.

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Adverse effect of fenofibrate on branched-chain α-ketoacid dehydrogenase complex in rat's liver

Cited by 8 publications

References 38 publications

The metabolic regulation of fenofibrate is dependent on dietary protein content in male juveniles of Nile tilapia (Oreochromis niloticus)

The metabolic regulation of fenofibrate is dependent on dietary protein content in male juveniles of Nile tilapia (Oreochromis niloticus)

Effect of low doses of bezafibrate and fenofibrate on liver 2-oxo-glutarate dehydrogenase complex in low-protein diet fed rats

Mechanistic Studies and a Retrospective Cohort Study: The Interaction between PPAR Agonists and Immunomodulatory Agents in Multiple Myeloma

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