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.
Highlights
To produce transforming growth factor (TGF)-βto secrete collagen from activated hepatic stellate cells (HSC), leading to fibrosis[5]
We examined whether PFD prevents the development of non-alcoholic steatohepatitis (NASH) in MC4R-KO mice during a western diet (WD)
PFD has ameliorated pharmacologically- and surgically-induced rodent models of liver injury and fibrosis[16,17,18,19], whether PFD can be effective in a rodent model that closely reflects the liver condition of human NASH has not been addressed so far
Summary
PFD prevents WD-fed MC4R-KO mice from liver fibrosis without affecting hepatic steatosis. TUNEL staining demonstrated that PFD markedly inhibits the GalN/TNF-α-induced hepatocyte apoptosis (Fig. 5c). The GalN/TNF-α-induced expression of fibrogenic genes such as Col1a1, Acta[2], Tgfb[1], and Timp[1] in WT mice were significantly blunted by PFD (Fig. 5d). These observations suggest that PFD inhibits the TNF-α-induced hepatocyte apoptosis and upregulation of fibrogenic genes in the liver of WT mice. Western blotting and caspase activity assay showed that PFD dose-dependently inhibits the GalN/TNF-α-induced caspases-8 and -3 activation in primary hepatocytes without affecting TNF-R1 expression (Fig. 6b and c). PFD did not change the lipopolysaccharides (LPS)-induced Tnfa, Ccl[2], Tgfb[1], and Timp[1] expression in macrophage cell line RAW264.7 cells (Supplementary Fig. S6b)
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
