The role of fenofibrate in clinical practice

Zambón, Alberto; Cusi, Kenneth

doi:10.3132/dvdr.2007.053

Cited by 41 publications

(35 citation statements)

References 52 publications

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“…For example, metformin and α-lipoic acid prevent hepatic steatosis by inhibiting SREBP-1c production [29,40]. Fenofibrate has beneficial effects on metabolic syndrome by downregulating multiple target genes involved in the pathogenesis of hepatic steatosis [41][42][43]. Recent studies show that fenofibrate induces CREBH production to a level comparable with that observed under fasting conditions [44].…”

Section: Discussionmentioning

confidence: 94%

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min

Jeong

et al. 2012

Diabetologia

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Aims/hypothesis Fenofibrate is a drug used to treat hyperlipidaemia that works by inhibiting hepatic triacylglycerol synthesis. Sterol regulatory element binding protein-1c (SREBP-1c) is a major regulator of the expression of genes involved in hepatic triacylglycerol synthesis. In addition, endoplasmic reticulum (ER)-bound transcription factor families are involved in the control of various metabolic pathways. Here, we show a novel function for an ER-bound transcription factor, cAMP response element binding protein H (CREBH), in fenofibrate-mediated inhibition of hepatic lipogenesis. Methods The effects of fenofibrate and adenovirus-mediated Crebh (also known as Creb313) overexpression (Ad-Crebh) on hepatic SREBP-1c production and lipogenesis in vitro and in vivo were investigated. We also examined whether downregulation of endogenous hepatic Crebh by small interfering (si)RNA restores the fenofibrate effect on hepatic lipogenesis and SREBP-1c production. Finally, we examined the mechanism by which CREBH inhibits hepatic SREBP-1c production. Results Fasting and fenofibrate treatment induced CREBH production and decreased SREBP-1c levels. Indeed, AdCrebh inhibited insulin-and liver X receptor agonist TO901317-induced Srebp-1c (also known as Srebf1) mRNA expression in cultured hepatocytes. Moreover, increased production of CREBH in the liver of mice following tail-vein injection of Ad-Crebh inhibited high-fat diet-induced hepatic steatosis through inhibition of Srebp-1c expression. The inhibition of endogenous Crebh expression by siRNA restored fenofibrate-induced suppression of Srebp-1c expression and hepatic lipid accumulation both in vitro and in vivo. Conclusions/interpretation These results show that fenofibrate decreases hepatic lipid synthesis through induction of CREBH. This study suggests CREBH as a novel negative regulator of SREBP-1c production and hepatic lipogenesis.

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Section: Discussionmentioning

confidence: 94%

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Min

Jeong

et al. 2012

Diabetologia

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“…The half-life of fenofibrate has been reported to be 20 h in individuals with normal renal functions, and the level of fenofibrate required to achieve IC 50 for MCL is within the therapeutic range that is used to treat hyperlipidemia. [43][44][45][46] In light of the excellent safety, tolerability and affordability of fenofibrate, there is merit in investigating the possibility of extending the clinical use of fenofibrate, either as a sole agent or in combination with conventional chemotherapy, in the treatment of MCL.…”

Section: Minomentioning

confidence: 99%

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

2010

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Mantle cell lymphoma (MCL) is a type of aggressive B-cell non-Hodgkin's lymphoma characterized by frequent resistance to conventional chemotherapy. In this study we provided evidence that fenofibrate, which is widely known as an agonist for peroxisome proliferator-activated receptor-a (PPARa), can induce effective apoptosis in treating MCL cells. Addition of fenofibrate to MCL cell lines significantly decreased the number of viable cells by 50% at approximately 20 lM at 72 h. This decrease in cell growth was due to apoptosis, as evidenced by the cleavage of caspase 3 and poly(ADP-ribose) polymerase. The fenofibrate-mediated effects were not significantly affected by GW6471, a specific PPARa antagonist. Using an apoptosis pathway-specific oligonucleotide array, we found that fenofibrate significantly downregulated several pro-survival genes, including tumor necrosis factor-a (TNFa). Importantly, addition of recombinant TNF-a conferred partial protection against fenofibrate-induced apoptosis. Fenofibrate also decreased the nuclear translocation of nuclear factor (NF)-jB-p65 and significantly inhibited the DNA binding of NF-jB in a dose-dependent manner. To conclude, fenofibrate shows efficacy against MCL, and the mechanism can be attributed to its inhibitory effects on the TNF-a/NF-jB signaling axis. In view of the documented safety of fenofibrate in humans, it may provide a valuable therapeutic option for MCL patients.

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“…Fenofibrate, a PPARα agonist, can specifically bind to PPARα and activate expression of numerous genes participating in fatty acid oxidation, control of triglycerides and cholesterol metabolism (9,10). Fenofibrate, therefore, was very effective to the nonalcoholic fatty liver diseases by modulating lipid metabolic enzymes such as fatty acid transport protein, fatty acid binding protein, long chain acyl-CoA dehydrogenase and acyl-CoA oxidase (11).…”

Section: Introductionmentioning

confidence: 99%

Comparative analysis of fat and muscle proteins in fenofibratefed type II diabetic OLETF rats: the fenofibrate-dependent expression of PEBP or C11orf59 protein

Hahm

Ahn²,

Noh³

et al. 2010

BMB Reports

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Fenofibrate, an agonist of PPARα, plays an important role in activating many proteins catalyzing lipid metabolism, and it also has a considerable effect on improvement of insulin sensitivity in the diabetic condition. To investigate fenofibratedependent expression of peripheral tissue proteins in diabetes, we analyzed whole muscle or fat proteins of fenofibrate-fed OLETF rats, an animal model of type II diabetes, using 2-dimensional gel electrophoresis. We found that many proteins were specifically expressed in a fenofibrate-dependent manner in these diabetic rats. In particular, a functionally unknown C11orf59 protein was differentially expressed in the muscle tissues (about 5-fold increase) in fenofibrate-fed OLETF rats as compared to control rats. Additionally, the signal proteins phosphatidylethanolamine binding protein and IkB interacting protein were differentially regulated in the fenofibrate-treated adipose tissues. We suggest here that these proteins might be involved in controlling lipid or carbohydrate metabolism in diabetes via PPARα activation. [BMB reports 2010; 43(5): 337-343]

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The role of fenofibrate in clinical practice

Cited by 41 publications

References 52 publications

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

cAMP response element binding protein H mediates fenofibrate-induced suppression of hepatic lipogenesis

Fenofibrate induces effective apoptosis in mantle cell lymphoma by inhibiting the TNFα/NF-κB signaling axis

Comparative analysis of fat and muscle proteins in fenofibratefed type II diabetic OLETF rats: the fenofibrate-dependent expression of PEBP or C11orf59 protein

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