Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis
Article first published online: 25 MAR 2013
© 2013 Journal of Gastroenterology and Hepatology Foundation and Wiley Publishing Asia Pty Ltd
Journal of Gastroenterology and Hepatology
Volume 28, Issue 4, pages 723–730, April 2013
How to Cite
Shirai, Y., Yoshiji, H., Noguchi, R., Kaji, K., Aihara, Y., Douhara, A., Moriya, K., Namisaki, T., Kawaratani, H. and Fukui, H. (2013), Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis. Journal of Gastroenterology and Hepatology, 28: 723–730. doi: 10.1111/jgh.12112
- Issue published online: 25 MAR 2013
- Article first published online: 25 MAR 2013
- Accepted manuscript online: 9 JAN 2013 11:50PM EST
- Manuscript Accepted: 14 DEC 2012
- liver fibrosis;
- non-alcoholic steatohepatitis;
- toll-like receptor-4
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.
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.
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.
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.