TLR4‑dependent signaling pathway modulation: A novel mechanism by which pioglitazone protects against nutritional fibrotic steatohepatitis in mice.

Activation of the innate immune system is involved in the development of chronic liver diseases, including nonalcoholic steatohepatitis. Toll‑like receptor 4 (TLR4) is one of the sensors of the innate immune system. The aim of the present study was to elucidate the role of the TLR4‑dependent signaling pathway, and examine the effect of pioglitazone on hepatic fibrosis, through modulation of the TLR4 pathway in a mouse model of nutritional fibrotic steatohepatitis. Male C57BL/6J mice were fed a methionine‑choline deficient (MCD) diet for 8 weeks to induce nonalcoholic fibrotic steatohepatitis. The PPARγ agonist, pioglitazone, and PPARγ inhibitor, GW9662, were administered to the mice, respectively. The effects of the induction of PPARγ on liver biochemistry and histology, the modulation of TLR4 and its downstream pathway, and the expression levels of inflammatory and fibrogenic genes were assessed using reverse transcription‑quantitative polymerase chain reaction and Western blot analyses. The MCD‑fed mice exhibited progressive hepatic steatosis, necrotic inflammation and fibrosis, along with increase levels of serum alanine aminotransferase and aspartate aminotransferase, accompanied by the upregulation of TLR4, the TLR4‑myeloid differentiation primary response gene 88‑dependent pathway and downstream genes, and proinflammatory and profibrotic genes; and downregulation of basic membrane protein and activin membrane‑bound inhibitor. The administration of pioglitazone was found to reverse hepatic nutritional fibrosis via restoration of the expression levels of proinflammatory and profibrotic genes in the MCD‑fed mice. The results of the present study provide novel evidence supporting the protective role of pioglitazone in ameliorating nutritional fibrotic steatohepatitis, through modulation of the TLR4‑mediated signaling pathway.