All‐<i>trans</i>‐retinoic acid ameliorates carbon tetrachloride‐induced liver fibrosis in mice through modulating cytokine production

Hisamori, Shigeo; Tabata, Chiharu; Kadokawa, Yoshio; Okoshi, Kae; Tabata, Rie; Mori, Akira; Nagayama, Satoshi; Watanabe, Go; Kubo, Hajime; Sakai, Yoshiharu

doi:10.1111/j.1478-3231.2008.01745.x

Cited by 57 publications

(42 citation statements)

References 25 publications

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“…Retinoid receptor signaling in hepatocytes is implicated in liver carcinogenesis, and a synthetic acyclic retinoid, peretinoin, has been assessed as a potential cancer chemoprevention measure [227, 228]. In HSCs, all-trans retinoic acid (ATRA) (an RAR ligand) moderately inhibits expression of procollagen I, III, IV, fibronectin, laminin, αSMA, TGFβ, and IL-6, but with no effect on cell proliferation, whereas 9-cis (RXR ligand) moderately inhibits proliferation without affecting the fibrogenic gene expression in rodents [229, 230]. These receptors, also together with PPARγ signaling, have additive inhibitory effects on HSC activation [231, 232].…”

Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,036

894

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Progressive liver fibrosis, induced by chronic viral and metabolic disorders, leads to more than one million deaths annually via development of cirrhosis, although no antifibrotic therapy has been approved to date. Transdifferentiation (or “activation”) of hepatic stellate cells is the major cellular source of matrix protein-secreting myofibroblasts, the major driver of liver fibrogenesis. Paracrine signals from injured epithelial cells, fibrotic tissue microenvironment, immune and systemic metabolic dysregulation, enteric dysbiosis, and hepatitis viral products can directly or indirectly induce stellate cell activation. Dysregulated intracellular signaling, epigenetic changes, and cellular stress response represent candidate targets to deactivate stellate cells by inducing reversion to inactivated state, cellular senescence, apoptosis, and/or clearance by immune cells. Cell type- and target-specific pharmacological intervention to therapeutically induce the deactivation will enable more effective and less toxic precision antifibrotic therapies.

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Section: Mechanisms Of Hsc Activationmentioning

confidence: 99%

Hepatic stellate cells as key target in liver fibrosis

Higashi

Friedman

Hoshida

2017

Advanced Drug Delivery Reviews

1,036

894

View full text Add to dashboard Cite

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“…Several studies have shown that exposure of activated HSCs to retinol [11] , retinyl palmitate [12] , and RA [13,14] inhibited their proliferation, as well as the synthesis of collagen and TGF-β. However, some findings suggested that during the development of liver fibrosis, endogenous RA stimulates the synthesis of plasminogen activator (PA) and induces PA/plasmin-dependent latent TGF-β activation in HSC cultures, culminating in the augmented collagen synthesis, thus promoting fibrogenesis [15][16][17] .…”

Section: Disscussionmentioning

confidence: 99%

Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats

Wang

Dan

Jiang

2008

J. Huazhong Univ. Sci. Technol. [Med. Sci.]

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The aim of this study was to investigate the effect and possible mechanism of all-trans retinoic acid (ATRA) on liver fibrosis induced by common bile duct ligation (CBDL) in rats. Fifty-three female Wistar rats were randomly divided into 5 groups: sham operation group (group J, 5 animals) and groups A, B, C and D (12 animals in each group). The rats in groups A, B, C and D were subjected to CBDL to induce liver fibrosis, while those in group J to sham operation. From the 3rd week the rats in groups B, C and D respectively received daily administration of ATRA via gastric tube at three different doses [0.1, 1.5 and 7.5 mg/kg body weight (BW)]. Animals were sacrificed at 6th week. Rats' liver tissues were observed for pathologic changes under a light microscope. The protein levels of type I collagen (COL I), matrix metalloproteinase-2 (MMP2), MMP13 and tissue inhibitors of metalloproteinase-1 (TIMP-1) in liver tissues were determined by immunohistochemical techniques. The expression levels of TGF-beta1 and CTGF mRNA in liver tissues were detected by semi-quantitative reverse transcription-polymerase chain reaction (RT-PCR). The results showed that loss of normal hepatic architecture and formation of obvious fibrosis were observed in group A, while ATRA treatment for 4 weeks notably alleviated the pathological changes of hepatocytes. The expression of COL I and TIMP-1 proteins in group A was increased, while decreased in ATRA-treated CBDL groups (P<0.05). ATRA (1.5 and 7.5 mg/kg BW) reduced the expression levels of COL I protein more greatly than that of 0.1 mg/kg BW (P<0.05). ATRA treatment increased the protein levels of MMP2 and MMP13. The expression levels of TGF-beta1 and CTGF mRNA in group A were increased. In comparison with group A, the mRNA levels of TGF-beta1 and CTGF in ATRA-treated CBDL groups were significantly decreased (P<0.05). It was concluded that ATRA could inhibit CBDL-induced liver fibrosis in rats by suppressing the expression of TGF-beta1 and CTGF so as to diminish the inhibition of TIMP-1 on MMP2 and MMP13 and increase the activity of MMP2 and MMP13.

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“…As for liver function, ATRA has become one of the potential candidates for treatment of liver cirrhosis because it suppresses liver fibrosis through reduction of production of transforming growth factor β 1 (TGF β-1), interleukin 6, and type I collagen (11,12 (15). One of the limitations of bisphosphonate is that this may be influenced by renal dysfunction (15,16).…”

Section: One Of the Most Characteristic Features In The Present Case mentioning

confidence: 99%

Successful Treatment by All-Trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia Complicated by Liver Cirrhosis and Polycystic Kidney

et al. 2009

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All‐trans‐retinoic acid ameliorates carbon tetrachloride‐induced liver fibrosis in mice through modulating cytokine production

Abstract: Our findings indicate that ATRA ameliorates liver fibrosis. As the oral administration of the drug results in good compliance, ATRA could be a novel approach in the treatment of liver fibrosis.

Cited by 57 publications

References 25 publications

Hepatic stellate cells as key target in liver fibrosis

Hepatic stellate cells as key target in liver fibrosis

Effect of all-trans retinoic acid on liver fibrosis induced by common bile duct ligation in rats

Successful Treatment by All-Trans Retinoic Acid in a Patient with Acute Promyelocytic Leukemia Complicated by Liver Cirrhosis and Polycystic Kidney

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