Fibrate and Statin Synergistically Increase the Transcriptional Activities of PPARα/RXRα and Decrease the Transactivation of NFκB

Inoue, Ituro; Itoh, Fumiaki; Aoyagi, Shigemi; Tazawa, Shigeki; Kusama, Hiroshi; Akahane, Masuo; Mastunaga, Toshiyuki; Hayashi, Kenji; Awata, Takuya; Komoda, Tugikazu; Katayama, Sigehiro

doi:10.1006/bbrc.2001.6141

Cited by 115 publications

(72 citation statements)

References 19 publications

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“…4). Such an effect, which has already been pointed out by others (2,48), is consistent with the existence of a cross-talk between the PPAR␣ and statin signaling pathways. This observation Results were normalized to GAPDH (Fao cells) and to 28 S (for mice).…”

Section: Statin-mediated Induction Of L-fabp Gene Expression Is Disrusupporting

confidence: 89%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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Statins are drugs widely used in humans to treat hypercholesterolemia. Statins act by inhibiting cholesterol synthesis resulting in the activation of the transcription factor sterol-responsive element-binding protein-2 that controls the expression of genes involved in cholesterol homeostasis. Statin therapy also decreases plasma triglyceride and non-esterified fatty acid levels, but the mechanism behind this effect remains more elusive. Liver fatty acid-binding protein (L-FABP) plays a role in the influx of long-chain fatty acids into hepatocytes. Here we show that L-FABP is a target for statins. In rat hepatocytes, simvastatin treatment induced L-FABP mRNA levels in a dose-dependent manner. Moreover, L-FABP promoter activity was induced by statin treatment. Progressive 5 -deletion analysis revealed that the peroxisome proliferator-activated receptor (PPAR)-responsive element located at position ؊67/؊55 was responsible for the statin-mediated transactivation of the rat L-FABP promoter. Moreover, treatment with simvastatin and the PPAR␣ agonist Wy14,649 resulted in a synergistic induction of L-FABP expression (mRNA and protein) in rat Fao hepatoma cells. This effect was also observed in vivo in wild-type mice but not in PPAR␣-null animals demonstrating the direct implication of PPAR␣ in L-FABP regulation by statin treatment. Statin treatment resulted in a rise in PPAR␣ mRNA levels both in vitro and in vivo and activated the mouse PPAR␣ promoter in a reporter assay. Altogether, these data demonstrate that L-FABP expression is up-regulated by statins through a mechanism involving PPAR␣. Moreover, PPAR␣ might be a statin target gene. These effects might contribute to the triglyceride/non-esterified fatty acid-lowering properties of statins.Statins are competitive inhibitors of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme in cholesterol biosynthesis. The resulting lower intracellular cholesterol concentration after statin treatment leads to a proteolytic activation of the transcription factor sterol responsive element-binding protein-2 (SREBP-2), 1 which up-regulates several genes controlling cholesterol homeostasis, including the LDL receptor (LDLr) (1). Induction of LDLr in the liver enhances clearance of circulating LDL resulting in decreased plasma LDL-cholesterol levels. Statins also increase, at least in part via a PPAR␣-dependent mechanism (2), the level of high density lipoproteins (3, 4). As a consequence, statins improve the blood cholesterol profile and markedly reduce cardiovascular mortality and morbidity in dyslipidemic patients (5-7). Statins also influence plasma TG and NEFA levels in rats and humans (4, 8 -11) through mechanisms not yet fully elucidated. Sustained hepatic clearance of TG-rich very low density lipoproteins by the LDLr (12), statin-dependent up-regulation of the lipoprotein lipase (LPL) gene, and down-regulation of the LPL inhibitor apolipoprotein C-III (13) may all contribute to the TG-lowering effect of statins. By contrast, it is not known if statins control th...

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Section: Statin-mediated Induction Of L-fabp Gene Expression Is Disrusupporting

confidence: 89%

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Landrier

Thomas

Grober

et al. 2004

Journal of Biological Chemistry

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“…The result indicated a mechanism by which induction of LPL expression by pitavastatin might not be due to PPAR γ activation. Inoue et al (32) reported that cerivastatin, fluvastatin, pitavastatin were not ligands for PPAR α, δ, and γ in an in vitro assay. PPAR α, which regulates LPL expression, is considered to exist in the liver, kidney, vascular endothelial cells and vascular and smooth muscle cells.…”

Section: Discussionmentioning

confidence: 99%

Pitavastatin Enhanced Lipoprotein Lipase Expression in 3T3-L1 Preadipocytes

Saiki

Murano

Watanabe

et al. 2005

JAT

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“…For example, PPARα activation enhances hepatic expression of mRNA encoding sterol 12α-hydroxylase (CYP8B1), an enzyme involved in bile acid synthesis from cholesterol [12], and multidrug resistance 2 (Mdr2), a phospholipid transporter for bile formation [13]. On the other hand, it is known that bezafibrate can also activate other PPAR subtypes [β (δ) and γ] [14][15][16]. Thus, it remains unclear whether the effect of bezafibrate on cholesterol reduction is singularly due to its effect on PPARα.…”

Section: Introductionmentioning

confidence: 99%

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

Nakajima

Tanaka

Sugiyama

et al. 2008

Biochemical Pharmacology

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Fibrate and Statin Synergistically Increase the Transcriptional Activities of PPARα/RXRα and Decrease the Transactivation of NFκB

Cited by 115 publications

References 19 publications

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Statin Induction of Liver Fatty Acid-Binding Protein (L-FABP) Gene Expression Is Peroxisome Proliferator-activated Receptor-α-dependent

Pitavastatin Enhanced Lipoprotein Lipase Expression in 3T3-L1 Preadipocytes

Cholesterol-lowering effect of bezafibrate is independent of peroxisome proliferator-activated receptor activation in mice

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