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

Namisaki, Tadashi; Moriya, Kyoji; Kitade, Mitsuteru; Takeda, Kosuke; Kaji, Kosuke; Okada, Yasushi; Shimozato, Naotaka; Sato, Shinya; Nishimura, Norihisa; Seki, Kazuhiko; Kawaratani, Hideto; Takaya, Hiroaki; Sawada, Yasuhiko; Akahane, Takemi; Saikawa, Soichiro; Nakanishi, Keisuke; Kubo, Takuya; Furukawa, Masanori; Noguchi, Ryuichi; Asada, Kiyoshi; Kitagawa, Koh; Ozutsumi, Takahiro; Tsuji, Yosuke; Kaya, Daisuke; Fujinaga, Yukihisa; Yoshiji, Hitoshi

doi:10.1002/hep4.1104

Cited by 13 publications

(16 citation statements)

References 40 publications

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“…The LPS–TLR4 signaling cascade in the liver is essential for CDAA‐induced hepatic fibrogenesis. However, consistent with our previous findings, intestinal TLR4‐mediated signaling was not involved in hepatic fibrogenesis . Translocated LPS derived from gut microflora mediates TLR4 activation in the liver; however, TLR4 in the intestine is required for this process .…”

Section: Discussionsupporting

confidence: 91%

“…Although ALT levels in the CDAA‐fed rats were significantly more elevated than those in the controls, the inflammation in the CDAA‐diet model was not as severe as that in the CCl4‐induced model of liver fibrosis, especially in the early stage . The CDAA‐diet model is widely used as a NASH model as it shows histological sequences similar to those shown in chronic liver diseases …”

Section: Discussionmentioning

confidence: 97%

“…Translocated LPS derived from gut microflora mediates TLR4 activation in the liver; however, TLR4 in the intestine is required for this process . We previously showed that TLR4‐mediated signaling in intestinal epithelial cells regulated hepatic fibrogenesis in porcine serum‐treated diabetic rats . Activation of TLR4 in the intestine induces intestinal mucosal inflammation by mediating ERK and c‐Jun NH2‐terminal kinase phosphorylations in high‐fat diet‐fed Sprague–Dawley rats .…”

Section: Discussionmentioning

confidence: 99%

“…However, consistent with our previous findings, intestinal TLR4-mediated signaling was not involved in hepatic fibrogenesis. 6,28,33 Translocated LPS derived from gut microflora mediates TLR4 activation in the liver; however, TLR4 in the intestine is required for this process. 34 We previously showed that TLR4-mediated signaling in intestinal epithelial cells regulated hepatic fibrogenesis in porcine serum-treated diabetic rats.…”

Section: Discussionmentioning

confidence: 99%

“…34 We previously showed that TLR4-mediated signaling in intestinal epithelial cells regulated hepatic fibrogenesis in porcine serum-treated diabetic rats. 33 Activation of TLR4 in the intestine induces intestinal mucosal inflammation by mediating ERK and c-Jun NH2-terminal kinase phosphorylations in high-fat diet-fed Sprague-Dawley rats. 35 Moreover, OCA reduces bacterial translocation along with intestinal mucosal TLR4 signaling and inhibits intestinal inflammation in a CCl4-induced hepatic cirrhosis rat model.…”

Section: Discussionmentioning

confidence: 99%

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Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Shimozato

Namisaki

Kaji

et al. 2019

Hepatology Research

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Aim Non‐alcoholic steatohepatitis (NASH) has a broad clinicopathological spectrum (inflammation to severe fibrosis). The farnesoid X receptor agonist obeticholic acid (OCA) ameliorates the histological features of NASH; satisfactory antifibrotic effects have not yet been reported. Here, we investigated the combined effects of OCA + a dipeptidyl peptidase‐4 inhibitor (sitagliptin) on hepatic fibrogenesis in a rat model of NASH. Methods Fifty Fischer 344 rats were fed a choline‐deficient L‐amino‐acid‐defined (CDAA) diet for 12 weeks. The in vitro and in vivo effects of OCA + sitagliptin were assessed along with hepatic fibrogenesis, lipopolysaccharide–Toll‐like receptor 4 (TLR4) regulatory cascade and intestinal barrier function. Direct inhibitory effects of OCA + sitagliptin on activated hepatic stellate cells (Ac‐HSCs) were assessed in vitro. Results Treatment with OCA + sitagliptin potentially inhibited hepatic fibrogenesis along with Ac‐HSC proliferation and hepatic transforming growth factor (TGF)‐β1, α1(I)‐procollagen, and tissue inhibitor of metalloproteinase‐1 (TIMP‐1) mRNA expression and hydroxyproline levels. Obeticholic acid inhibited hepatic TLR4 expression and increased hepatic matrix metalloproteinase‐2 expression. Obeticholic acid decreased intestinal permeability by ameliorating CDAA diet‐induced zonula occludens‐1 disruption, whereas sitagliptin directly inhibited Ac‐HSC proliferation. The in vitro suppressive effects of OCA + sitagliptin on TGF‐β1 and α1(I)‐procollagen mRNA expression and p38 phosphorylation in Ac‐HSCs were almost consistent. Sitagliptin directly inhibited the regulation of Ac‐HSC. Conclusions Treatment with OCA + sitagliptin synergistically affected hepatic fibrogenesis by counteracting endotoxemia induced by intestinal barrier dysfunction and suppressing Ac‐HSC proliferation. Thus, OCA + sitagliptin could be a promising therapeutic strategy for NASH.

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Section: Discussionsupporting

confidence: 91%

Section: Discussionmentioning

confidence: 97%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 3 more Smart Citations

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Shimozato

Namisaki

Kaji

et al. 2019

Hepatology Research

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Role of Gut Microbiota in Dengue

Pedreañez,

Carrero,

Vargas

et al. 2024

Reviews in Medical Virology

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Dengue is a disease caused by a flavivirus (DENV) and transmitted by the bite of a mosquito, primarily the Aedes aegypti and Aedes albopictus species. Previous studies have demonstrated a relationship between the host gut microbiota and the evolution of dengue. It seems to be a bidirectional relationship, in which the DENV can affect the microbiota by inducing alterations related to intestinal permeability, leading to the release of molecules from microbiota dysbiosis that can influence the evolution of dengue. The role of angiotensin II (Ang II) in the microbiota/dengue relationship is not well understood, but it is known that the renin‐angiotensin system (RAS) is present in the intestinal tract and interacts with the gut microbiota. The possible effect of Ang II on the microbiota/Ang II/dengue relationship can be summarised as follows: the presence of Ang II induced hypertension, the increase in angiotensinogen, chymase, and microRNAs during the disease, the induction of vascular dysfunction, the production of trimethylamine N‐oxide and the brain/microbiota relationship, all of which are elements present in dengue that could be part of the microbiota/Ang II/dengue interactions. These findings suggest the potential use of Ang II synthesis blockers and the use of AT1 receptor antagonists as therapeutic drugs in dengue.

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Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

Tølbøl¹,

Stierstorfer²,

Rippmann³

et al. 2018

Dig Dis Sci

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Background There is a marked need for improved animal models of nonalcoholic steatohepatitis (NASH) to facilitate the development of more efficacious drug therapies for the disease. Methods Here, we investigated the development of fibrotic NASH in male Wistar rats fed a choline-deficient l -amino acid-defined (CDAA) diet with or without cholesterol supplementation for subsequent assessment of drug treatment efficacy in NASH biopsy-confirmed rats. The metabolic profile and liver histopathology were evaluated after 4, 8, and 12 weeks of dieting. Subsequently, rats with biopsy-confirmed NASH were selected for pharmacological intervention with vehicle, elafibranor (30 mg/kg/day) or obeticholic acid (OCA, 30 mg/kg/day) for 5 weeks. Results The CDAA diet led to marked hepatomegaly and fibrosis already after 4 weeks of feeding, with further progression of collagen deposition and fibrogenesis-associated gene expression during the 12-week feeding period. Cholesterol supplementation enhanced the stimulatory effect of CDAA on gene transcripts associated with fibrogenesis without significantly increasing collagen deposition. Pharmacological intervention with elafibranor, but not OCA, significantly reduced steatohepatitis scores, and fibrosis-associated gene expression, however, was unable to prevent progression in fibrosis scores. Conclusion CDAA-fed rats develop early-onset progressive NASH, which offers the opportunity to probe anti-NASH compounds with potential disease-modifying properties.

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

Cited by 13 publications

References 40 publications

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Combined effect of a farnesoid X receptor agonist and dipeptidyl peptidase‐4 inhibitor on hepatic fibrosis

Role of Gut Microbiota in Dengue

Disease Progression and Pharmacological Intervention in a Nutrient-Deficient Rat Model of Nonalcoholic Steatohepatitis

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