title: Beneficial effects of combined ursodeoxycholic acid and angiotensin-II type 1 receptor blocker on hepatic fibrogenesis in a rat model of nonalcoholic steatohepatitis.
abstract: OBJECTIVE
  Ursodeoxycholic acid (UDCA) is considered to be effective in the treatment of nonalcoholic steatohepatitis (NASH), particularly in combination with other pharmacological agents. UDCA reportedly counteracts the effects of endotoxemia. Previously, we demonstrated attenuated hepatic fibrogenesis and suppression of activated hepatic stellate cells (Ac-HSC) with an angiotensin-II (AT-II) type 1 receptor blocker (ARB). Here we evaluated the simultaneous effect of both agents on hepatic fibrogenesis in a rat model of NASH.
  
  
  METHODS
  Fischer 344 rats were fed a choline-deficient L-amino-acid-defined (CDAA) diet for 8 weeks. The therapeutic effect of UDCA and ARB was evaluated along with hepatic fibrogenesis, lipopolysaccharide (LPS)-Toll-like receptor 4 (TLR4) regulatory cascade, and intestinal barrier function. The direct inhibitory effect of both UDCA and ARB on Ac-HSC was assessed in vitro.
  
  
  RESULTS
  Both UDCA and ARB had a potent inhibitory effect on hepatic fibrogenesis with suppression of the HSC activation and hepatic expression of transforming growth factor (TGF)-β1 and TLR4. UDCA decreased intestinal permeability by ameliorating zonula occuludens-1 (ZO-1) disruption induced by the CDAA diet. ARB was found to directly suppress regulation of Ac-HSC.
  
  
  CONCLUSIONS
  UDCA and ARB have a synergistic repressive effect on hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing the activation of Ac-HSC. Because both agents are currently used in clinical practice, combined UDCA and ARB may represent a promising novel therapeutic approach for NASH.
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan. tadashin@naramed-u.ac.jp.
authors.forename: Tadashi
authors.initials: T
authors.lastname: Namisaki
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Ryuichi
authors.initials: R
authors.lastname: Noguchi
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Kei
authors.initials: K
authors.lastname: Moriya
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Mitsuteru
authors.initials: M
authors.lastname: Kitade
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Aihara
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Akitoshi
authors.initials: A
authors.lastname: Douhara
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Norihisa
authors.initials: N
authors.lastname: Nishimura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Kosuke
authors.initials: K
authors.lastname: Takeda
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Okura
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Hideto
authors.initials: H
authors.lastname: Kawaratani
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Takaya
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Seki
authors.affiliation: Third Department of Internal Medicine, Nara Medical University, Shijo-cho 840, Kashihara, Nara, 634-8522, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Yoshiji
mesh_terms: D000199:Actins / Q000378:metabolism; D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D002478:Cells, Cultured; D016207:Cytokines / Q000378:metabolism; D004353:Drug Evaluation, Preclinical / Q000379:methods; D004359:Drug Therapy, Combination; D004731:Endotoxins / Q000378:metabolism; D018836:Inflammation Mediators / Q000378:metabolism; D008103:Liver Cirrhosis / Q000188:drug therapy* / Q000209:etiology / Q000378:metabolism / Q000473:pathology; D008297:Male; D065626:Non-alcoholic Fatty Liver Disease / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D012333:RNA, Messenger / Q000235:genetics; D011916:Rats, Inbred F344; D060888:Real-Time Polymerase Chain Reaction / Q000379:methods; D015398:Signal Transduction / Q000187:drug effects; D051197:Toll-Like Receptor 4 / Q000096:biosynthesis / Q000235:genetics; D014580:Ursodeoxycholic Acid / Q000627:therapeutic use*
chemical_list: D000199:Actins; D047228:Angiotensin II Type 1 Receptor Blockers; D016207:Cytokines; D004731:Endotoxins; D018836:Inflammation Mediators; D012333:RNA, Messenger; D051197:Toll-Like Receptor 4; D014580:Ursodeoxycholic Acid; C495347:Tlr4 protein, rat; C498862:Acta2 protein, rat
keywords: ARB; Hepatic fibrogenesis; Nonalcoholic steatohepatitis; UDCA