Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial–mesenchymal transition in mouse hepatocytes

Shrestha, Nirajan; Chand, Lokendra; Han, Myung‐Kwan; Lee, Seung Ok; Kim, Chan Young; Jeong, Young Beom

doi:10.1016/j.fct.2016.04.024

Cited by 82 publications

(56 citation statements)

References 47 publications

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“…Next, we conducted Masson Trichrome stain since CCl 4 is well known to induce liver fibrosis [27, 28]. However, hepatic fibrosis was not observed in all groups (Fig 6), suggests generation of hepatic fibrosis need to inject multiple times.…”

Section: Resultsmentioning

confidence: 99%

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice

et al. 2017

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The aim of this study was to determine whether calcium potentiates acute carbon tetrachloride (CCl4) -induced toxicity. Elevated calcium levels were induced in mice by pre-treatment with cholecalciferol (vitamin D3; V.D3), a compound that has previously been shown to induce hypercalcemia in human and animal models. As seen previously, mice injected with CCl4 exhibited increased plasma levels of alanine aminotransferase, aspartate aminotransferase, and creatinine; transient body weight loss; and increased lipid peroxidation along with decreased total antioxidant power, glutathione, ATP, and NADPH. Pre-treatment of these animals with V.D3 caused further elevation of the values of these liver functional markers without altering kidney functional markers; continued weight loss; a lower lethal threshold dose of CCl4; and enhanced effects on lipid peroxidation and total antioxidant power. In contrast, exposure to V.D3 alone had no effect on plasma markers of liver or kidney damage or on total antioxidant power or lipid peroxidation. The potentiating effect of V.D3 was positively correlated with elevation of hepatic calcium levels. Furthermore, direct injection of CaCl2 also enhanced CCl4-induced hepatic injury. Since CaCl2 induced hypercalcemia transiently (within 3 h of injection), our results suggest that calcium enhances the CCl4-induced hepatotoxicity at an early stage via potentiation of oxidative stress.

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Section: Resultsmentioning

confidence: 99%

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice

et al. 2017

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“…E‐cadherin is a cell–cell junction protein that has many signaling partners in common with the integrin–focal adhesion kinase signaling pathway; it is involved in mechanical transduction and is greatly affected by fibrosis. Molecules involved in the genesis of liver fibrosis, such as transforming growth factor beta, are also implicated in the loss of E‐cadherin, and knockout of CDH1 , the gene encoding E‐cadherin, has been shown to induce an inflammatory response and periductal fibrosis . Furthermore, fibrocystin‐deficiency diseases, such as congenital hepatic fibrosis, down‐regulate E‐cadherin expression .…”

Section: Discussionmentioning

confidence: 99%

Liver‐enriched transcription factor expression relates to chronic hepatic failure in humans

Guzman‐Lepe

Cervantes-Álvarez

l’Hortet

et al. 2018

Hepatology Communications

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The mechanisms by which the liver fails in end‐stage liver disease remain elusive. Disruption of the transcription factor network in hepatocytes has been suggested to mediate terminal liver failure in animals. However, this hypothesis remains unexplored in human subjects. To study the relevance of transcription factor expression in terminal stages of chronic liver failure in humans, we analyzed the expression of liver‐enriched transcription factors (LETFs) hepatocyte nuclear factor (HNF)4α, HNF1α, forkhead box protein A2 (FOXA2), CCAAT/enhancer‐binding protein (CEBP)α, and CEBPβ. We then selected downstream genes responsible for some hepatic functions (ornithine transcarbamylase [OTC], cytochrome P450 3A4 [CYP3A4], coagulation factor VII [F7], cadherin 1 [CDH1], phospho‐ezrin (Thr567)/radixin (Thr564)/moesin (Thr558) [p‐ERM], phospho‐myosin light chain [p‐MLC], low‐density lipoprotein receptor‐related protein 1 [LRP1]) in liver tissue from patients at different stages of decompensated liver function based upon Child‐Pugh classification, Model for End‐Stage Liver Disease score, and degree of inflammatory activity/fibrosis. We first examined differential expression of LETF and determined whether a relationship exists between transcript and protein expression, and liver function. We found HNF4α expression was down‐regulated and correlated well with the extent of liver dysfunction (P = 0.001), stage of fibrosis (P = 0.0005), and serum levels of total bilirubin (P = 0.009; r = 0.35), albumin (P < 0.001; r = 0.52), and prothrombin time activity (P = 0.002; r = 0.41). HNF4α expression also correlated with CYP3A4, OTC, and F7 as well as CDH1 RNA levels. The Rho/Rho‐associated protein kinase pathways, which have been implicated in the regulation of HNF4α, were also differentially expressed, in concert with LRP1, a reported upstream regulator of RhoA function. Conclusion: HNF4α and other members of the LETFs appear to be important regulators of hepatocyte function in patients with chronic hepatic failure. (Hepatology Communications 2018;2:582‐594)

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“…EMT, a dynamic process, is found in liver, lung, and kidney fibrosis. During EMT process, epithelial cells lose phenotypic properties (E‐cadherin and zonula occludens) and acquire mesenchymal cells characteristics (alpha‐smooth muscle actin, N‐cadherin, fibronectin, and vimentin) . Liver fibrosis is associated with the accumulation of activated fibroblasts and EMT occurrence .…”

Section: Introductionmentioning

confidence: 99%

TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

Zhang

Chang

Wang

et al. 2019

Environmental Toxicology

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Nickel oxide nanoparticles (Nano NiO) bears hepatotoxicity, while whether it leads to liver fibrosis remains unclear. The aim of this study was to establish the Nano NiO‐induced hepatic fibrosis model in vivo and investigate the roles of transforming growth factor β1 (TGF‐β1) in Smad pathway activation, epithelial‐mesenchymal transition (EMT) occurrence, and extracellular matrix (ECM) deposition in vitro. Male Wistar rats were exposed to 0.015, 0.06, and 0.24 mg/kg Nano NiO by intratracheal instilling twice a week for 9 weeks. HepG2 cells were treated with 100 μg/mL Nano NiO and TGF‐β1 inhibitor (SB431542) to explore the mechanism of collagen formation. Results of Masson staining as well as the elevated levels of type I collagen (Col‐I) and Col‐III suggested that Nano NiO resulted in hepatic fibrosis in rats. Furthermore, Nano NiO increased the protein expression of TGF‐β1, p‐Smad2, p‐Smad3, alpha‐smooth muscle actin (α‐SMA), matrix metalloproteinase9 (MMP9), and tissue inhibitors of metalloproteinase1 (TIMP1), while decreased the protein content of E‐cadherin and Smad7 in rat liver and HepG2 cells. Most importantly, Nano NiO‐triggered the abnormal expression of the abovementioned proteins were all alleviated by co‐treatment with SB431542, implying that TGF‐β1‐mediated Smad pathway, EMT and MMP9/TIMP1 imbalance were involved in overproduction of collagen in HepG2 cells. In conclusion, these findings indicated that Nano NiO induced hepatic fibrosis via TGF‐β1‐mediated Smad pathway activation, EMT occurrence, and ECM deposition.

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Glutamine inhibits CCl4 induced liver fibrosis in mice and TGF-β1 mediated epithelial–mesenchymal transition in mouse hepatocytes

Cited by 82 publications

References 47 publications

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice

Vitamin D3-induced hypercalcemia increases carbon tetrachloride-induced hepatotoxicity through elevated oxidative stress in mice

Liver‐enriched transcription factor expression relates to chronic hepatic failure in humans

TGF‐β1 mediated Smad signaling pathway and EMT in hepatic fibrosis induced by Nano NiO in vivo and in vitro

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