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. 2025 Mar 11:2025:5423221.
doi: 10.1155/ppar/5423221. eCollection 2025.

Single and Multiple Doses of Seladelpar Decrease Diurnal Markers of Bile Acid Synthesis in Mice

Affiliations

Single and Multiple Doses of Seladelpar Decrease Diurnal Markers of Bile Acid Synthesis in Mice

Edward E Cable et al. PPAR Res. .

Abstract

Peroxisome proliferator-activated receptors (PPARs) modulate bile metabolism and are important therapeutic options in cholestatic diseases. This study was aimed at understanding the effects of single and multiple doses of seladelpar, a PPARδ (peroxisome proliferator-activated receptor delta) agonist, on plasma C4 (a freely diffusible metabolite accepted as a proxy for de novo bile acid biosynthesis), Fibroblast Growth Factor 21 (Fgf21), and gene expression changes in the liver of male and female mice. C57BL/6 mice were treated with seladelpar 10 mg/kg/day or vehicle through oral gavage before lights out on Day 1 (single dose) or from Day 1 to Day 7 (multiple doses). Liver samples were obtained at 0, 1, 2, 4, 8, 12, 16, and 24 h postdosing, and plasma C4 and Fgf21 levels were measured. In vehicle-treated mice, C4 levels were higher in the dark cycle compared to the light cycle, with higher levels in females than in males. Plasma Fgf21 did not vary substantially over the dark-light cycle or show a sex-specific expression pattern. Seladelpar treatment significantly reduced plasma C4 and increased Fgf21 levels in both sexes, which coincided with a decrease in cholesterol 7α-hydroxylase mRNA and an increase in Fgf21 mRNA in the livers. Untargeted RNA sequencing revealed a strong correlation between the genes differentially expressed after single- and multiple-dose seladelpar treatment. PPAR-responsive genes, including pyruvate dehydrogenase kinase 4, acyl-CoA thioesterase 2, and angiopoietin-like 4, were upregulated. No changes in nuclear receptors, clock genes, and sex-specific genes were observed. Overall, these results are consistent with a model where seladelpar treatment reduces bile acid synthesis by upregulating Fgf21 and modulating other PPAR-responsive genes.

Keywords: PPAR; PPAR delta; bile metabolism; circadian rhythm; seladelpar.

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Conflict of interest statement

Edward E. Cable, Jeffrey W. Stebbins, Jeff D. Johnson, Yun-Jung Choi, Jiangao Song, and Charles A. McWherter are employees of CymaBay Therapeutics Inc. Sole Gatto and Matthew Onorato are employees of Monoceros Biosystems LLC.

Figures

Figure 1
Figure 1
Study design. C57BL/6 mice were maintained on a reverse 12-h dark and 12-h lights-on cycle. Seladelpar 10 mg/kg/day or vehicle (5 mL/kg of water) was administered to mice before lights off (9 AM) via oral gavage once on Day 1 (single dose) or once daily from Day 1 to Day 7 (multiple doses). On Day 1 and Day 7, mice were sacrificed at 0, 1, 2, 4, 8, 12, 16, and 24 h postdose. Each seladelpar and control group had 10 mice (5 M and 5 F) for each time point on Day 1 and Day 7. D0h0, 0 h untreated; F, female; h, hours; M, male.
Figure 2
Figure 2
Plasma C4 and Fgf21 levels in control and seladelpar-treated mice. Plasma C4 and Fgf21 levels in (a, d) control (gray circles for female mice and gray squares for male mice), single, or multiple doses of seladelpar-treated (b, e) female (blue circles) and (c, f) male (blue squares) mice. Open symbols denote a single dose of seladelpar treatment or vehicle administration on Day 1 (1x). Multiple doses of seladelpar or vehicle administration from Day 1 to Day 7 (7x) are denoted using closed symbols. Data were expressed as mean ± SEM. h, hours; SEM, standard error of the mean; Tx, treated; Veh, vehicle.
Figure 3
Figure 3
Seladelpar-induced changes in Cyp7a1 and Fgf21. Cyp7a1, Fgf21, Cyp27a1, and Cyp8b1 expression in (a, c, e, g) control (gray circles for female mice and gray squares for male mice) and (b, d, f, h) single- or multiple-dose seladelpar-treated female or male mice (blue circles for females and blue squares for males). Open symbols denote a single dose of seladelpar treatment or vehicle administration on Day 1 (1x). Multiple doses of seladelpar or vehicle administration from Day 1 to Day 7 (7x) are denoted using closed symbols. h, hours; TPM, transcripts per million.
Figure 4
Figure 4
Global RNA-seq changes in the liver of mice following seladelpar treatment. (a) The heat map shows globally upregulated/downregulated genes in female and male mice following single- and multiple-dose seladelpar treatment (lights-on/off). (b) Scatterplots showing the correlation between DEGs from single and multiple doses of seladelpar treatment (left, light-off 2–8 h) and between females and males (right, 2–4 h). (c) A volcano plot comparing DEGs (2–4 h) in control and multiple-dose seladelpar-treated female or male mice. DE, differentially expressed; DEGs, differentially expressed genes; h, hours.
Figure 5
Figure 5
Seladelpar treatment–induced expression of PPAR-modulated genes. Pdk4, Angptl4, Acot2, Lpl, Krt23, and GM15441 expression in (a, c, e, g, i, k) control (gray circles for females and gray squares for males) and (b, d, f, h, j, l) single- or multiple-dose seladelpar-treated female or male mice (blue circles for females and blue squares for males). Open symbols denote a single dose of seladelpar treatment or vehicle administration on Day 1 (1x). Multiple doses of seladelpar or vehicle administration from Day 1 to Day 7 (7x) are denoted using closed symbols. The y-axis indicates TPM. TPM, transcripts per million.
Figure 6
Figure 6
Seladelpar treatment does not affect clock genes. Bmal, Clock, Rev-erbα, Rev-erbβ, Dbp, Per1 and 2, and Cry1 expression in (a, c, e, g, i, k, m, o) control (gray circles for females and gray squares for males) and (b, d, f, h, j, l, n, p) single- or multiple-dose seladelpar-treated female or male mice (blue circles for females and blue squares for males). Open symbols denote a single dose of seladelpar treatment or vehicle administration on Day 1 (1x). Multiple doses of seladelpar or vehicle administration from Day 1 to Day 7 (7x) are denoted using closed symbols. The y-axis indicates TPM. h, hours; TPM, transcripts per million.

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