Antifibrotic effect of pirfenidone in a mouse model of human nonalcoholic steatohepatitis

Abstract

Non-alcoholic steatohepatitis (NASH) is characterized by steatosis with lobular inflammation and hepatocyte injury. Pirfenidone (PFD) is an orally bioavailable pyridone derivative that has been clinically used for the treatment of idiopathic pulmonary fibrosis. However, it remains unknown whether PFD improves liver fibrosis in a mouse model with human NASH-like phenotypes. In this study, we employed melanocortin 4 receptor-deficient (MC4R-KO) mice as a mouse model with human NASH-like phenotypes to elucidate the effect and action mechanisms of PFD on the development of NASH. PFD markedly attenuated liver fibrosis in western diet (WD)-fed MC4R-KO mice without affecting metabolic profiles or steatosis. PFD prevented liver injury and fibrosis associated with decreased apoptosis of liver cells in WD-fed MC4R-KO mice. Pretreatment of PFD inhibited the tumor necrosis factor-α (TNF-α)-induced liver injury and fibrogenic responses associated with decreased apoptosis of liver cells in wild-type mice. PFD also prevented TNF-α-induced hepatocyte apoptosis in vitro with reduced activation of caspase-8 and -3. This study provides evidence for the antifibrotic effect of PFD in a mouse model of human NASH. The data of this study highlight hepatocyte apoptosis as a potential therapeutic target, and suggest that PFD can be repositioned as an antifibrotic drug for human NASH.

Antifibrotic Agent Pirfenidone Suppresses Proliferation of Human Pancreatic Cancer Cells by Inducing G0/G1 Cell Cycle Arrest

“…Specifically, PFD was shown to be effective in various in vivo models including a rat model of myocardial infarction [5,6], a mouse model of pulmonary fibrosis [7], a mouse model of nonalcoholic steatohepatitis [8], and a rats model of renal fibrosis [9]. In agreement with in vivo model data, in vitro antiproliferative effects of PFD were also confirmed with human leiomyoma cells [10], human Tenon fibroblasts [11], and rat cardiac fibroblasts [12].…”

Systematic Development and Optimization of Inhalable Pirfenidone Liposomes for Non-Small Cell Lung Cancer Treatment

“…In a recent study reported by Zou et al, pirfenidone was found to promote apoptosis in hepatocellular carcinoma cells, which was confirmed by Western blot analysis [53]. In another study by Komiya et al, it was reported that PFD could be repurposed for human non-alcoholic steatohepatitis [72].…”

Pirfenidone Is an Agonistic Ligand for PPARα and Improves NASH by Activation of SIRT1/LKB1/pAMPK

“…Second, Komiya et al measured these metabolic sensors only at the mRNA level. (15) It has been described previously that most molecules involved in hepatic lipolytic processes can be regulated at different gene-expression levels, not only the transcriptional one. (26) Therefore, we examined the hepatic tissue key enzymes and upstream effectors in lipid metabolism at the protein level, using western blot and immunofluorescence.…”

“…Third, another explanation for this discrepancy is that Komiya et al used MC4R-KO mice, rodents with no membrane-bound receptor of the melanocortin receptor family associated with autosomal dominant obesity. (15) Such a mice model would strictly resemble a genetic morbid disease that causes obesity since the neonatal stages. (27) They did not observe differences by regular PFD treatment in mRNA levels of molecules implicated in lipid metabolism, probably due to the fact that genetic predisposition to obesity is present since birth in these animals and could be masking differences in fat metabolism.…”