Hepatic Stellate Cells

Oxidative Medicine and Cellular Longevity

Cheng

et al. 2018

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Thymosin beta 4 (Tβ4), an actin-sequestering protein, is involved in tissue development and regeneration. It prevents inflammation and fibrosis in several tissues. We investigated the role of Tβ4 in chronic ethanol- and acute lipopolysaccharide- (LPS-) induced mouse liver injury. C57BL/6 mice were fed 5% ethanol in liquid diet for 4 weeks plus binge ethanol (5 g/kg, gavage) with or without LPS (2 mg/kg, intraperitoneal) for 6 hours. Tβ4 (1 mg/kg, intraperitoneal) was administered for 1 week. We demonstrated that Tβ4 prevented ethanol- and LPS-mediated increase in liver injury markers as well as changes in liver pathology. It also prevented ethanol- and LPS-mediated increase in oxidative stress by decreasing ROS and lipid peroxidation and increasing the antioxidants, reduced glutathione and manganese-dependent superoxide dismutase. It also prevented the activation of nuclear factor kappa B by blocking the phosphorylation of the inhibitory protein, IκB, thereby prevented proinflammatory cytokine production. Moreover, Tβ4 prevented fibrogenesis by suppressing the epigenetic repressor, methyl-CpG-binding protein 2, that coordinately reversed the expression of peroxisome proliferator-activated receptor-γ and downregulated fibrogenic genes, platelet-derived growth factor-β receptor, α-smooth muscle actin, collagen 1, and fibronectin, resulting in reduced fibrosis. Our data suggest that Tβ4 has antioxidant, anti-inflammatory, and antifibrotic potential during alcoholic liver injury.

Section: Resultsmentioning

confidence: 99%

Thymosin β4 Prevents Oxidative Stress, Inflammation, and Fibrosis in Ethanol- and LPS-Induced Liver Injury in Mice

Shah

Oxidative Medicine and Cellular Longevity

Cheng

et al. 2018

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“…VL17A cells express stable catalytically active CYP2E1 and ADH1, and thereby exhibit an enzymatic phenotype similar to hepatocytes in alcoholics [19]. Even though HSC express low levels of ADH, they do not express CYP2E1 [47]; thus, cocultures of VL17A cells and HSC represent a promising model to describe ALD-associated redox alterations since ethanol metabolism by VL17A cells leading to oxidative stress, which in turn activates HSC to boost the oxidative damage in the liver [48]. The usefulness of co-cultures is supported by the fact that the well-functioning of the liver is orchestrated by close interaction among different kinds of liver cells.…”

Section: Discussionmentioning

confidence: 99%

Ethanol targets nucleoredoxin/dishevelled interactions and stimulates phosphatidylinositol 4-phosphate production in vivo and in vitro

Arellanes‐Robledo

Biochemical Pharmacology

Ibrahim

et al. 2018

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Nucleoredoxin (NXN) is a redox-regulating protein potentially targeted by reactive oxygen species (ROS). It regulates molecular pathways that participate in several key cellular processes. However, the role of NXN in the alcohol liver disease (ALD) redox regulation has not been fully understood. Here, we investigated the effects of ethanol and ethanol plus lipopolysaccharide, a two-hit liver injury model (Ethanol/LPS), on NXN/dishevelled (DVL) interaction and on DVL-dependent phosphoinositides production both in mouse liver and in a co-culture system consisting of human hepatic stellate cells (HSC) and ethanol metabolizing-VL17A human hepatocyte cells. Ethanol and two-hit model increased Nxn protein and mRNA expression, and 4-hydroxynonenal adducts. Two-hit model promoted Nxn nuclear translocation and Dvl/Phosphatidylinositol 4-kinase type-IIα (Pi4k2a) interaction ratio but surprisingly decreased Dvl protein and mRNA levels and reverted ethanol-induced Nxn/Dvl and Dvl/frizzled (Fzd) interaction ratios. Ethanol resulted in a significant increase of Dvl protein and mRNA expression, and decreased Nxn/Dvl interaction ratio but promoted the interaction of Dvl with Fzd and Pi4k2a; formation of this complex induced phosphatidylinositol 4-phosphate [PI(4)P] production. Ethanol and LPS treatments provoked similar alterations on NXN/DVL interaction and its downstream effect in HSC/VL17A co-culture system. Interestingly, ROS and glutathione levels as well as most of ethanol-induced alterations were modified by NXN overexpression in the co-culture system. In conclusion, two-hit model of ethanol exposure disrupts NXN/DVL homeostatic status to allow DVL/FZD/PI4K2A complex formation and stimulates PI(4)P production. These results provide a new mechanism showing that NXN also participates in the regulation of phosphoinositides production that is altered by ethanol during alcoholic liver disease progression.

“…The activated hepatic stellate cells undergo continuous proliferation and express activation markers such as ␣-SMA and produce large amounts of extracellular matrix proteins, including type I collagen. 7,8 One of the key events in the activation of hepatic stellate cells is the expression of the PDGF-␤ receptor. 13 In our experimental system, increased expressions of ␣-SMA, PDGF-␤ receptor, and collagen type I expression are consistent with the conclusion that hepatic stellate cells are activated by CCl 4 -induced liver injury and that T␤4 treatment can suppress this activation.…”

Section: Discussionmentioning

confidence: 99%

“…During the initiation of CCl 4 -induced acute liver damage, hepatic stellate cells differentiate into myofibroblast-like cells. 7,8 Myofibroblast transdifferentiation is characterized by changes in the expression of the following genes that, together, generate the myofibroblast phenotype. 7 Specifically, MeCP2 operates as a powerful epigenetic repressor of gene transcription.…”

Section: -Induced Activation Of Hepatic Stellate Cellsmentioning

confidence: 99%

“…cent) stage they mainly produce an extracellular matrix present in basement membranes such as type IV collagen. 7,8 They store vitamin A and triglycerides and express regulators of the adipocyte phenotype such as peroxisome proliferator-activated receptor (PPAR␥ ), sterol regulatory element binding-protein1 (SREBP-1c), and methyl-CpG binding protein 2 (MeCP2) among others. [9][10][11][12] In the fibrotic liver, hepatic stellate cells undergo transdifferentiation from lipid-storing pericytes to myofibroblastic cells ( Fig.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Protective effects of thymosin β4 on carbon tetrachloride‐induced acute hepatotoxicity in rats

Annals of the New York Academy of Sciences

Shah

Arellanes‐Robledo

et al. 2012

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Thymosin β4 (Tβ4) plays a role in fibrosis, inflammation, and in the reparative process of injured cells and tissues. Here, we discuss our preliminary work on the protective effect of Tβ4 on carbon tetrachloride (CCl(4) )-induced acute hepatotoxicity. Our studies thus far indicate that Tβ4 can prevent necrosis, inflammatory infiltration, and upregulation of α1(and 2) collagen, α-SMA, PDGF-β receptor, and fibronectin mRNA expression; in addition, Tβ4 can prevent downregulation of PPARγ and upregulation of MECP2 mRNA levels in acute liver injury. Our initial work therefore indicates that Tβ4 can prevent the alteration of markers of hepatic stellate cell transdifferentiation, which suggests that Tβ4 could maintain the quiescent phenotypic state of hepatic stellate cells in the rat livers by restoring PPARγ and downregulating MeCP2 expression levels. More specifically, these preliminary studies suggest that Tβ4 might be an effective anti-inflammatory and antifibrotic drug for the treatment of liver fibrogenesis.