Modulation of NF-кB/NLRP3 signaling by sitagliptin attenuates cholestatic hepatic fibrosis

Cholestatic hepatic fibrosis which ultimately may lead to cirrhosis and hepatic failure, is a serious condition that results from prolonged cholestasis. Sitagliptin (SG), a dipeptidyl peptidase IV inhibitor, has shown beneficial effects in multiple hepatic disorders. However, the effect of SG on cholestatic hepatic fibrosis remains unexplored. Thus, this investigation elucidated the protective effect of SG against cholestatic hepatic fibrosis induced by multiple doses of alpha-naphthyl isothiocyanate (ANIT). Male Sprague-Dawley rats were assigned into five groups as follows: control, SG20, ANIT, SG10 + ANIT, and SG20 + ANIT groups. SG dose dependently antagonized the development of cholestatic hepatic fibrosis as it ameliorated the levels of serum alanine transaminase (ALT), alkaline phosphatase (ALP), and total bilirubin. Biochemical results were further supported by histopathological examination and transmission electron microscopy. SG decreased collagen deposition and expression of transforming growth factor-β1 (TGF-β1). Additionally, SG alleviated ANIT-induced inflammation via significant suppression of the expression of nuclear factor kappa B (NF-κB), nucleotide-binding domain, leucine-rich-containing family, pyrin domain-containing-3 (NLRP3) inflammasome, interleukin-1β (IL-1β), and caspase-1. SG reduced oxidative stress as indicated by elevation of glutathione and catalase and reduction of malondialdehyde content in hepatic tissues. These findings suggest that SG could mitigate ANIT-mediated cholestatic hepatic fibrosis via its anti-inflammatory, anti-fibrotic, and antioxidant impact through suppression of NF-κB and NLRP3-caspase-1-IL-1β axis.