A Ureido-Thioisobutyric Acid (GW9578) Is a Subtype-Selective PPARα Agonist with Potent Lipid-Lowering Activity

Brown, Peter J.; Winegar, Deborah A.; Plunket, Kelli D.; Moore, Linda B.; Lewis, Michael C.; Wilson, Joan G.; Sundseth, Scott S.; Koble, Cecilia S.; Wu, Zhengdong; Chapman, James; Lehmann, Jürgen; Kliewer, Steven A.; Willson, Timothy M.

doi:10.1021/jm9903601

Cited by 119 publications

(68 citation statements)

References 23 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…These discrepancies should be attributed to the different selectivity of the fibrates studied in both studies. Bezafibrate, similar to fatty acids (33) and in contrast to other fibrates, such as ciprofibrate and fenofibrate, activates PPAR␣, PPAR␤, and PPAR␥ with comparable EC 50 values (34). Therefore, although it is not the subject of the present study, it is likely that bezafibrate may influence body weight and glucose homeostasis through the activation of PPAR␤ and/or PPAR␥ subtypes in adipocytes.…”

Section: Discussionmentioning

confidence: 84%

Bezafibrate Reduces mRNA Levels of Adipocyte Markers and Increases Fatty Acid Oxidation in Primary Culture of Adipocytes

et al. 2001

View full text Add to dashboard Cite

The molecular mechanisms by which peroxisome proliferator-activated receptor (PPAR) activation by fibrates reduces fat deposition and improves insulin sensitivity are not completely understood. We report that exposure of a rat primary culture of adipocytes for 24 h to the PPAR activator bezafibrate increased the mRNA levels of crucial genes involved in peroxisomal and mitochondrial ␤-oxidation. The mRNA levels of the peroxisomal ␤-oxidation rate-limiting enzyme acyl-CoA oxidase and of the muscle-type carnitine palmitoyl transferase I (M-CPT-I), which determines the flux of mitochondrial ␤-oxidation, increased by 1.6-fold (P < 0.02) and 4.5-fold (P ‫؍‬ 0.001), respectively. These changes were accompanied by an increase in the transcript levels of the uncoupling protein-2 (UCP-2; 1.5-fold induction; P < 0.05) and UCP-3 (3.7-fold induction; P < 0.001), mitochondrial proteins that reduce ATP yield and may facilitate the oxidation of fatty acids. Furthermore, bezafibrate increased the mRNA levels of the fatty acid translocase (2-fold induction; P < 0.01), suggesting a higher fatty acid uptake into adipocytes. In agreement with these changes, bezafibrate caused a 1.9-fold induction (P < 0.02) in 9,10-[ 3 H]palmitate oxidation. Moreover, bezafibrate reduced the mRNA expression of several adipocyte markers, including PPAR␥ (30% reduction; P ‫؍‬ 0.05), tumor necrosis factor-␣ (33% reduction; P < 0.05), and the ob gene (26% reduction). In contrast, adipocyte fatty acid binding protein mRNA levels increased (1.5-fold induction; P < 0.01), pointing to a mobilization of fatty acids to mitochondria and peroxisomes. The reduction of the adipocyte markers caused by bezafibrate was accompanied by an increase in the mRNA levels of the preadipocyte marker Pref-1 (1.6-fold induction; P < 0.01). Some of the changes observed in the primary culture of rat adipocytes also were studied in the epididymal white adipose tissue of bezafibrate-treated rats for 7 days. In vivo, M-CPT-I mRNA levels increased (4.5-fold induction; P ‫؍‬ 0.001) in epididymal white adipose tissue of bezafibrate-treated rats. Similarly, fatty acid translocase (2.6-fold induction; P ‫؍‬ 0.002) and Pref-1 (5.6-fold induction) mRNA levels increased, although differences in the latter were not significant because of huge individual variations. These results indicate that exposure of adipocytes to bezafibrate, independent of its hepatic effects, increases the degradation of fatty acids, reducing their availability to synthesize triglycerides. As a result, some degree of dedifferentiation of adipocytes to preadipocyte-like cells is achieved. These changes may be involved in the reduction in fat depots and in the improvement of insulin sensitivity observed after bezafibrate treatment.

show abstract

Section: Discussionmentioning

confidence: 84%

Bezafibrate Reduces mRNA Levels of Adipocyte Markers and Increases Fatty Acid Oxidation in Primary Culture of Adipocytes

et al. 2001

View full text Add to dashboard Cite

show abstract

“…This ligand has (almost) no PPAR␣-agonizing activity. 29,30 BRL49653 (10 mol/L) was unable to suppress cholesterol 7␣-hydroxylase (105Ϯ21%, nϭ4) and sterol 27-hydroxylase (97Ϯ25%, nϭ4) mRNA levels. This indicates that the suppressive effect of fibrates on both enzymes requires PPAR␣ and not PPAR␥ activation.…”

Section: Fibrates and Wy14643 Suppress Cholesterol 7␣-hydroxylase Anmentioning

confidence: 98%

“…29, 30 Therefore, we tested the effect of a high-affinity ligand for PPAR␥, the thiazolidinedione, BRL49653. This ligand has (almost) no PPAR␣-agonizing activity.…”

Section: Fibrates and Wy14643 Suppress Cholesterol 7␣-hydroxylase Anmentioning

confidence: 99%

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

Post¹,

Duez²,

Gervois³

et al. 2001

ATVB

189

124

View full text Add to dashboard Cite

Abstract-Fibrates are hypolipidemic drugs that affect the expression of genes involved in lipid metabolism by activating peroxisome proliferator-activated receptors (PPARs). Fibrate treatment causes adverse changes in biliary lipid composition and decreases bile acid excretion, leading to an increased incidence of cholesterol gallstones. In this study, we investigated the effect of fibrates on bile acid synthesis. Ciprofibrate and the PPAR␣ agonist Wy14,643 decreased bile acid synthesis in cultured rat hepatocytes and suppressed cholesterol 7␣-hydroxylase and sterol 27-hydroxylase activities, paralleled by a similar reduction of the respective mRNAs. Treatment of rats with 0.05% (wt/wt) ciprofibrate decreased cholesterol 7␣-hydroxylase enzyme activity and mRNA. The functional involvement of PPAR␣ in the suppression of both enzymes was proven with the use of PPAR␣-null mice. In wild-type mice, ciprofibrate reduced cholesterol 7␣-hydroxylase and sterol 27-hydroxylase enzyme activities and mRNA. The decrease in mRNA of both enzymes is regulated transcriptionally and posttranscriptionally, respectively, resulting in a decline in the output of fecal bile acids (Ϫ45%) and a 3-fold increase in fecal cholesterol secretion. These effects were completely abolished in PPAR␣-null mice. A decreased bile acid production by PPAR␣-mediated downregulation of cholesterol 7␣-hydroxylase and sterol 27-hydroxylase may contribute to the increased risk of gallstone formation after fibrate treatment.

show abstract

“…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

View full text Add to dashboard Cite

A Ureido-Thioisobutyric Acid (GW9578) Is a Subtype-Selective PPARα Agonist with Potent Lipid-Lowering Activity

Cited by 119 publications

References 23 publications

Bezafibrate Reduces mRNA Levels of Adipocyte Markers and Increases Fatty Acid Oxidation in Primary Culture of Adipocytes

Bezafibrate Reduces mRNA Levels of Adipocyte Markers and Increases Fatty Acid Oxidation in Primary Culture of Adipocytes

Fibrates Suppress Bile Acid Synthesis via Peroxisome Proliferator–Activated Receptor-α–Mediated Downregulation of Cholesterol 7α-Hydroxylase and Sterol 27-Hydroxylase Expression

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

Contact Info

Product

Resources

About