Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis
Yusaku Shirai
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorCorresponding Author
Hitoshi Yoshiji
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Correspondence
Dr Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. Email: [email protected]
Search for more papers by this authorRyuichi Noguchi
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorKosuke Kaji
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorYosuke Aihara
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorAkitoshi Douhara
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorKei Moriya
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorTadashi Namisaki
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorHideto Kawaratani
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorHiroshi Fukui
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorYusaku Shirai
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorCorresponding Author
Hitoshi Yoshiji
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Correspondence
Dr Hitoshi Yoshiji, Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara 634-8522, Japan. Email: [email protected]
Search for more papers by this authorRyuichi Noguchi
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorKosuke Kaji
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorYosuke Aihara
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorAkitoshi Douhara
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorKei Moriya
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorTadashi Namisaki
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorHideto Kawaratani
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorHiroshi Fukui
Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan
Search for more papers by this authorAbstract
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.
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