Nucleoredoxin interaction with flightless‐I/actin complex is differentially altered in alcoholic liver disease

Abstract

Alcoholic liver disease (ALD) may be attributed to multiple hits driving several alterations. The aim of this work was to determine whether nucleoredoxin (NXN) interacts with flightless-I (FLII)/actin complex and how this ternary complex is altered during ALD progression induced by different ALD models. ALD was recapitulated in C57BL/6J female mice by the well-known ALD Lieber-DeCarli model, and by an in vitro human co-culture system overexpressing NXN. The effects of ethanol and low doses of lipopolysaccharides (LPS) and diethylnitrosamine (DEN) were also evaluated in vivo as a first approach of an ALD multi-hit protocol. We demonstrated that NXN interacts with FLII/actin complex. This complex was differentially altered in ALD in vivo and in vitro, and NXN overexpression partially reverted this alteration. We also showed that ethanol, LPS and DEN synergistically induced liver structural disarrangement, steatosis and inflammatory infiltration accompanied by increased levels of proliferation (Ki67), ethanol metabolism (CYP2E1), hepatocarcinogenesis (GSTP1) and LPS-inducible (MYD88 and TLR4) markers. In summary, we provide evidence showing that NXN/FLII/actin complex is involved in ALD progression and that NXN might be involved in the regulation of FLII/actin-dependent cellular functions. Moreover, we present a promising first approach of a multi-hit protocol to better recapitulate ALD pathogenesis.

Magnetic Fields Affect Alcoholic Liver Disease by Liver Cell Oxidative Stress and Proliferation Regulation

“…In mice experiments, it was also evident that the liver of the "heavy drinking" mice, but not the "light drinking" mice, underwent obvious cell proliferation. This is consistent with the previous finding that the expression of Ki67 in the liver was upregulated by alcohol [ 34 ]. This is likely due to liver regeneration after heavy alcohol consumption.…”

Multifunctional Roles of the Actin-Binding Protein Flightless I in Inflammation, Cancer and Wound Healing

“…NRX and its subfamily members (RdCVF and C9orf121, but not TRX) may have a common role through their interaction with Flii in TLR4/MyD88 signaling pathway (Hayashi et al, 2010). The ability of NRX and Flii to form a ternary complex with actin is disrupted by ethanol contributing to the progression of alcoholic liver disease in mice, which is also characterized by altered MyD88/TLR4 expression (Alarcon-Sanchez et al, 2020). Both RdCVF and NRX link Flii to MyD88, and synergistically prevent LPS-induced MyD88/TLR4 NFκB activation (Hayashi et al, 2010).…”

NXN suppresses metastasis of hepatocellular carcinoma by promoting degradation of Snail through binding to DUB3

“…Dysregulation of NXN has been indicated to increase the expression of fibrogenic genes [15,16]. Moreover, deficiency of NXN was observed to result in the progression of alcoholic liver disease (ALD) [26,27]. However, NXN overexpression partially reversed these alterations and reduced liver injury, indicating that NXN played an important role in maintaining tissue homeostasis.…”

“…As an enzyme, NXN might exhibit its functions by protein-protein interactions network. It was reported that NXN regulated ethanol-associated ALD progression by binding to FLII/actin or MYD88 [26,27]. By expelling KLHL12 from DVL protein, NXN resulted in the inhibition of Dvl ubiquitination to suppress the Wnt/β-catenin signaling [14].…”