Disfunction of endosome prevents developing alcoholic fatty liver disease via inhibition of TLR4, TLR7, and TLR9 signaling pathways

Abstract

The pathogenesis of alcoholic fatty liver disease has never been established. It has been that TLR‐signaling pathway plays an important role in the development. What primes TLR‐signaling pathway and any prevention remains unclear. Endosome includes TLR4, TLR7 and TLR9, which may contribute to innate immune response in macrophage. We hypothesized that disturbance of endosome reduces alcoholic fatty liver disease. To clarify the hypothesis, we evaluated fatty liver injury in alcohol‐fed rats after treatment with endosome inhibitors. Male Wistar rats were fed with Lieber‐DeCarli alcohol liquid diet for 4 weeks. Omeprazole or lansoprazole, endosome inhibitors, was treated to alcohol liquid diet‐fed rats. Immunohistochemical staining for TLR4, TLR7 and TLR9 was performed in formalin‐fixed, paraffin‐embedded liver sections. ER stress markers were analyzed by quantitative realtime PCR. Alcohol feeding caused expression of TLR4, TLR7 and TLR9 and accumulation of ER stress. Inhibition of endosome results in reduction of fatty liver change, especially lipid droplets inflammation in hepatocytes and no staining for TLR7 and TLR9. However, accumulation of ER stress was not changed by inhibition of proton pump. Therefore, chronic alcohol consumption causes developing fatty liver disease via TLR7 and TLR9, which expression can be reduced by inhibition of endosome.