KMID : 1038820200230040346
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Pediatric Gastroenterology, Hepatology & Nutrition 2020 Volume.23 No. 4 p.346 ~ p.355
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Peroxisome Proliferator-Activated Receptor Gamma Agonist Attenuates Liver Fibrosis by Several Fibrogenic Pathways in an Animal Model of Cholestatic Fibrosis
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Alatas Fatima Safira
Matsuura Toshiharu Pudjiadi Antonius Hocky Wijaya Stephanie Taguchi Tomoaki
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Abstract
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Purpose: Peroxisome proliferator-activated receptor gamma (PPAR-¥ã) has a key role in hepatic fibrogenesis by virtue of its effect on the hepatic stellate cells (HSCs). Although many studies have shown that PPAR-¥ã agonists inhibit liver fibrosis, the mechanism remains largely unclear, especially regarding the cross-talk between PPAR-¥ã and other potent fibrogenic factors.
Methods: This experimental study involved 25 male Wistar rats. Twenty rats were subjected to bile duct ligation (BDL) to induce liver fibrosis, further divided into an untreated group (BDL; n=10) and a group treated with the PPAR-¥ã agonist thiazolidinedione (TZD), at 14 days post-operation (BDL+TZD; n=10). The remaining 5 rats had a sham operation (sham; n=5). The effect of PPAR-¥ã agonist on liver fibrosis was evaluated by histopathology, protein immunohistochemistry, and mRNA expression quantitative polymerase chain reaction.
Results: Histology and immunostaining showed markedly reduced collagen deposition, bile duct proliferation, and HSCs in the BDL+TZD group compared to those in the BDL group (p<0.001). Similarly, significantly lower mRNA expression of collagen ¥á-1(I), matrix metalloproteinase-2, platelet-derived growth factor (PDGF)-B chain, and connective tissue growth factor (CTGF) were evident in the BDL+TZD group compared to those in the BDL group (p=0.0002, p<0.035, p<0.0001, and p=0.0123 respectively). Moreover, expression of the transforming growth factor beta1 (TGF-¥â1) was also downregulated in the BDL+TZD group (p=0.0087).
Conclusion: The PPAR-¥ã agonist inhibits HSC activation in vivo and attenuates liver fibrosis through several fibrogenic pathways. Potent fibrogenic factors such as PDGF, CTGF, and TGF-¥â1 were downregulated by the PPAR-¥ã agonist. Targeting PPAR-¥ã activity may be a potential strategy to control liver fibrosis.
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KEYWORD
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Peroxisome proliferator-activator receptor gamma, Liver cirrhosis, Hepatic stellate cell, Connective tissue growth factor, Platelet-derived growth factor, Transforming growth factor beta1
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