Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis

• Published in: Journal of gastroenterology and hepatology Vol. 28; no. 4; pp. 723 - 730
• Main Authors: Shirai, Yusaku, Yoshiji, Hitoshi, Noguchi, Ryuichi, Kaji, Kosuke, Aihara, Yosuke, Douhara, Akitoshi, Moriya, Kei, Namisaki, Tadashi, Kawaratani, Hideto, Fukui, Hiroshi
• Format: Journal Article
• Language: English
• Published: Australia Blackwell Publishing Ltd 01.04.2013
• Subjects: Angiotensin II - metabolism; Angiotensin II Type 1 Receptor Blockers - pharmacology; angiotensin-II; Animals; Cell Communication - drug effects; Disease Models, Animal; Disease Progression; DNA Primers - chemistry; Dose-Response Relationship, Drug; Fatty Liver - metabolism; Fatty Liver - prevention & control; Gene Expression - drug effects; Hepatic Stellate Cells - drug effects; Hepatic Stellate Cells - metabolism; lipopolysaccharide; Liver Cirrhosis - metabolism; Liver Cirrhosis - prevention & control; liver fibrosis; Losartan - pharmacology; Male; NF-kappa B - metabolism; Non-alcoholic Fatty Liver Disease; non-alcoholic steatohepatitis; Rats; Rats, Inbred F344; Real-Time Polymerase Chain Reaction; RNA, Messenger - metabolism; Signal Transduction - physiology; Time Factors; Toll-Like Receptor 4 - metabolism; toll-like receptor-4; Transforming Growth Factor beta - metabolism
• ISSN: 0815-9319; 1440-1746
• DOI: 10.1111/jgh.12112

Background and Aim The innate immune system, including toll‐like receptor‐4 (TLR4) signaling cascade and angiotensin‐II (AT‐II) play important roles in the progression of liver fibrosis development; the cross talk between TLR4 and AT‐II has not been elucidated yet. The aim of the current study was to elucidate the effect of AT‐II type 1 receptor blocker (ARB), on the liver fibrosis development, especially in conjunction with the interaction of TLR4 and AT‐II in the rat model of non‐alcoholic steatohepatitis. Methods Fischer 344 rats were fed a choline‐deficient, l‐amino‐acid‐defined diet for 8 weeks and the effects of losartan were elucidated in conjunction with activated hepatic stellate cells (Ac‐HSC) activation, TLR4, nuclear factor‐κB (NF‐κB), and transforming growth factor‐β (TGF‐β) expressions. In vitro study was carried out to elucidate the effect of AT‐II on several indices including TLR4, myeloid differentiation factor 88, NF‐κB, and TGF‐β expressions in the rat HSC. Results ARB markedly inhibited liver fibrosis development along with suppression of the number of Ac‐HSC and TGF‐β. These inhibitory effects of ARB were almost in parallel with suppression of the hepatic TLR4 and NF‐κB expressions. This in vitro study showed that AT‐II significantly augmented the TLR4 expression in a dose‐ and time‐dependent manner via AT‐II type 1 receptor in the Ac‐HSC. AT‐II also augmented the lipopolysaccharide‐induced myeloid differentiation factor 88 (MyD88), NF‐κB, and TGF‐β and these increments were attenuated by treatment with ARB. Conclusions These studies indicated that the cross talk between TLR4 signaling cascade and AT‐II plays a pivotal role in liver fibrosis development in non‐alcoholic steatohepatitis.