Effect of combined farnesoid X receptor agonist and angiotensin II type 1 receptor blocker on ongoing hepatic fibrosis.

Autor: Namisaki, Tadashi, Kaji, Kosuke, Shimozato, Naotaka, Kaya, Daisuke, Ozutsumi, Takahiro, Tsuji, Yuki, Fujinaga, Yukihisa, Kitagawa, Koh, Furukawa, Masanori, Sato, Shinya, Sawada, Yasuhiko, Nishimura, Norihisa, Takaya, Hiroaki, Okura, Yasushi, Seki, Kenichiro, Kawaratani, Hideto, Moriya, Kei, Noguchi, Ryuichi, Asada, Kiyoshi, Akahane, Takemi
Zdroj: Indian Journal of Gastroenterology; Apr2022, Vol. 41 Issue 2, p169-180, 12p
Abstrakt: Objective: Nonalcoholic steatohepatitis (NASH) is difficult to diagnose in patients with no symptoms. We aimed to investigate the combined effect of farnesoid X receptor (FXR) agonist, obeticholic acid (OCA), and angiotensin II type 1 receptor blocker (ARB: losartan) on an ongoing hepatic fibrosis in a NASH rat model. Methods: Fischer 344 rats were fed with choline-deficient l-amino-acid-defined (CDAA) diet for 16 weeks. After 8-week administration of CDAA diet, OCA, losartan, or a combination of these drugs was administered at a dose of 30 mg/kg/day for 8 weeks by oral gavage. The in vivo and in vitro effects of OCA + losartan and liver fibrosis progression, lipopolysaccharide (LPS), Toll-like receptor 4 (TLR4) regulatory cascade, and gut barrier function were evaluated. Results: OCA + losartan alleviated hepatic fibrosis progression by suppressing α-SMA expression. It inhibited the proliferation of activated hepatic stellate cell (Ac-HSC) and mRNA expression of hepatic transforming growth factor-β1 (TGF-β1), TLR4, and tissue inhibitor of metalloproteinase-1 (TIMP-1) and decreased the hydroxyproline levels. OCA increased the hepatic matrix metalloproteinase-2 (MMP-2) mRNA expression. OCA decreased the mRNA expression of hepatic LPS-binding protein and intestinal permeability by ameliorating the disruption of CDAA diet–induced zonula occludens-1. Losartan directly inhibited the proliferation of Ac-HSC. The in vitro suppressive effects of OCA + losartan on the mRNA expressions of TGF-β1 and α1(I)-procollagen, TLR4, and TIMP-1 in Ac-HSCs were almost in parallel. Conclusions: OCA + losartan suppressed the ongoing hepatic fibrosis by attenuating gut barrier dysfunction and suppressing Ac-HSC proliferation. Combined therapy may be a promising novel approach for NASH with fibrosis. [ABSTRACT FROM AUTHOR]
Databáze: Complementary Index
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