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.

• Authors: Brisa Rodope Alarcón-Sánchez, Dafne Guerrero-Escalera, Sandra Rosas-Madrigal, Diana Ivette Aparicio-Bautista, Karina Reyes-Gordillo, M Raj Lakshman, Arturo Ortiz-Fernández, Héctor Quezada, Óscar Medina-Contreras, Saúl Villa-Treviño, Julio Isael Pérez-Carreón, Jaime Arellanes-Robledo
• Journal: Basic & clinical pharmacology & toxicology (Basic Clin Pharmacol Toxicol) Vol. 127 Issue 5 Pg. 389-404 (Nov 2020) ISSN: 1742-7843 [Electronic] England
• PMID: 32524749 (Publication Type: Journal Article)
• Copyright: © 2020 Nordic Association for the Publication of BCPT (former Nordic Pharmacological Society). Published by John Wiley & Sons Ltd.

Chemical References

• Lipopolysaccharides
• Microfilament Proteins
• Diethylnitrosamine
• Ethanol
• Oxidoreductases
• nucleoredoxin
• Cytochrome P-450 CYP2E1

Topics

• Animals
• Body Weight (drug effects)
• Cell Proliferation (drug effects)
• Cytochrome P-450 CYP2E1 (metabolism)
• Diethylnitrosamine (pharmacology)
• Ethanol
• Fatty Liver (metabolism, pathology)
• Female
• Lipopolysaccharides (pharmacology)
• Liver (metabolism, pathology)
• Liver Diseases, Alcoholic (metabolism, pathology)
• Mice
• Mice, Inbred C57BL
• Microfilament Proteins (metabolism)
• Oxidoreductases (metabolism)