title: Cross talk between toll-like receptor-4 signaling and angiotensin-II in liver fibrosis development in the rat model of non-alcoholic steatohepatitis.
abstract: OBJECTIVE
  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.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Kashihara, Nara, Japan.
authors.forename: Yusaku
authors.initials: Y
authors.lastname: Shirai
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.forename: Kosuke
authors.initials: K
authors.lastname: Kaji
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Fukui
mesh_terms: D000804:Angiotensin II / Q000378:metabolism*; D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology; D000818:Animals; D002450:Cell Communication / Q000187:drug effects*; D017931:DNA Primers / Q000737:chemistry; D004195:Disease Models, Animal; D018450:Disease Progression; D004305:Dose-Response Relationship, Drug; D005234:Fatty Liver / Q000378:metabolism / Q000517:prevention & control*; D015870:Gene Expression / Q000187:drug effects; D055166:Hepatic Stellate Cells / Q000187:drug effects / Q000378:metabolism; D008103:Liver Cirrhosis / Q000378:metabolism / Q000517:prevention & control*; D019808:Losartan / Q000494:pharmacology; D008297:Male; D016328:NF-kappa B / Q000378:metabolism; D065626:Non-alcoholic Fatty Liver Disease; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D013997:Time Factors; D051197:Toll-Like Receptor 4 / Q000378:metabolism*; D016212:Transforming Growth Factor beta / Q000378:metabolism
chemical_list: D047228:Angiotensin II Type 1 Receptor Blockers; D017931:DNA Primers; D016328:NF-kappa B; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D016212:Transforming Growth Factor beta; D000804:Angiotensin II; D019808:Losartan