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The pharmacodynamic and differential gene expression analysis of PPAR ?/? agonist GFT505 in CDAHFD-induced NASH model.

ABSTRACT: Peroxisome proliferator-activated receptor ?/? (PPAR ?/?), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR ?/? agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR ?/? agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model was used to test the pharmacodynamics and transcriptome regulation of GFT505 in this study. The results showed that GFT505 ameliorated hepatic steatosis, inflammation and fibrosis in CDAHFD mice model. RNA-sequencing yielded 3995 up-regulated and 3576 down-regulated genes with GFT505 treatment. And the most significant differentialy expressed genes involved in glucolipid metabolism (Ppar?, Acox1, Cpt1b, Fabp4, Ehhadh, Fabp3), inflammation (Ccl6, Ccl9, Cxcl14) and fibrosis (Timp1, Lamc3, Timp2, Col3a1, Col1a2, Col1a1, Hapln4, Timp3, Pik3r5, Pdgf?, Pdgf?, Tgf?1, Tgf?2) were confirmed by RT-qPCR. The down-regulated genes were enriched in cytokine-cytokine receptor interaction pathway and ECM-receptor interaction pathway, while the up-regulated genes were enriched in PPAR signaling pathway and fatty acid degradation pathway. This study provides clues and basis for further understanding on the mechanism of PPAR ?/? agonist on NASH.

SUBMITTER: Liu L

PROVIDER: S-EPMC7743980 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model.

Liu Linfu L Liu Chuang C Zhao Manyu M Zhang Qianru Q Lu Ying Y Liu Ping P Yang Hua H Yang Jinliang J Chen Xiaoxin X Yao Yuqin Y

PloS one 20201216 12

Peroxisome proliferator-activated receptor α/δ (PPAR α/δ), regulating glucolipid metabolism and immune inflammation, has been identified as an effective therapeutic target in non-alcoholic steatohepatitis (NASH). Dual PPAR α/δ agonist, such as GFT505 (also known as elafibranor), demonstrated potential therapeutic effect for NASH in clinical trials. To profile the regulatory network of PPAR α/δ agonist in NASH, the choline-deficient, L-amino acid-defined, high-fat diet (CDAHFD) induced NASH model ...[more]

PMID: 33326461

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Project description:BackgroundThe Wnt/β-catenin pathway regulates liver growth, repair, and regeneration. Chronic ethanol (EtOH) exposure blunts normal liver regenerative responses, in part by inhibiting insulin/IGF signaling, and correspondingly, previous studies showed that EtOH-impaired liver regeneration could be restored by insulin sensitizer (proliferator-activated receptor [PPAR]-δ agonist) treatment. As Wnt/β-catenin functions overlap and cross talk with insulin/IGF pathways, we investigated the effects of EtOH exposure and PPAR-δ agonist treatment on Wnt pathway gene expression in relation to liver regeneration.MethodsAdult male Long Evans rats were fed with isocaloric liquid diets containing 0 or 37% EtOH for 8 weeks and also treated with vehicle or a PPAR-δ agonist during the last 3 weeks of the feeding regimen. The rats were then subjected to 70% partial hepatectomy (PH) and livers harvested at various post-PH time points were used to quantitate expression of 19 Wnt pathway genes using Quantigene 2.0 Multiplex Assay.ResultsEtOH broadly inhibited expression of Wnt/β-catenin signaling-related genes, including down-regulation of Wnt1, Fzd3, Lef1, and Bcl9 throughout the post-PH time course (0 to 72 hours), and suppression of Wnt7a, Ccnd1, Fgf4, Wif1, Sfrp2, and Sfrp5 at 18- and 24-hour post-PH time points. PPAR-δ agonist treatments rescued the EtOH-induced suppression of Wnt1, Wnt7a, Fzd3, Lef1, Bcl9, Ccnd1, and Sfrp2 gene expression in liver, corresponding with the improvements in DNA synthesis and restoration of hepatic architecture.ConclusionsChronic high-dose EtOH exposures inhibit Wnt signaling, which likely contributes to the impairments in liver regeneration. Therapeutic effects of PPAR-δ agonists extend beyond restoration of insulin/IGF signaling mechanisms and are mediated in part by enhancement of Wnt pathway signaling. Future studies will determine the degree to which targeted restoration of Wnt signaling is sufficient to improve liver regeneration and remodeling in the context of chronic EtOH exposure.

Dataset Information

The pharmacodynamic and differential gene expression analysis of PPAR ?/? agonist GFT505 in CDAHFD-induced NASH model.

Publications

The pharmacodynamic and differential gene expression analysis of PPAR α/δ agonist GFT505 in CDAHFD-induced NASH model.

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