Cigarette smoking differentially regulates inflammatory responses in a mouse model of nonalcoholic steatohepatitis depending on exposure time point.

Cigarette smoke (CS) is a risk factor for the development of nonalcoholic fatty liver disease. However, the role of mainstream CS (MSCS) in the pathogenesis of nonalcoholic steatohepatitis (NASH) remains unclear. During the first (early exposure) or last (late exposure) three weeks of methionine-choline deficient with high fat diet feeding (6 weeks), each diet group was exposed to MSCS (300 or 600 µg/L). Hepatic or serum biochemical analysis showed that MSCS differentially modulated hepatic injury in NASH milieu, depending on exposure time points. Consistently, NASH-related hepatocellular apoptosis and fibrosis were increased in the early exposure group, but decreased in the late exposure group, except for steatosis. Ex vivo experiments showed that CS extract differentially regulated inflammatory responses in co-cultured hepatocytes and macrophages isolated from steatohepatitic livers after 10 days or 3 weeks of diet feeding. Furthermore, CS differentially up- and down-regulated the expression levels of M1/M2 polarization markers and peroxisome proliferator-activated receptor-gamma (PPARγ) in livers (29% and 38%, respectively) or co-cultured macrophages (2 and 2.5 fold, respectively). Collectively, our findings indicate that opposite effects of MSCS on NASH progression are mediated by differential modulation of PPARγ and its-associated M1/M2 polarization in hepatic macrophages, depending on exposure time points.