RT Journal Article
T1 Lack of Cyclin E1 in hepatocytes aggravates ethanol-induced liver injury and hepatic steatosis in experimental murine model of acute and chronic alcohol-associated liver disease
A1 Ramadori, Pierluigi
A1 Woitok, Marius Maximilian
A1 Estévez Vázquez, Olga
A1 Benede Ubieto, Raquel
A1 Leal Lassalle, Héctor
A1 Lamas Paz, Arantza
A1 Guo, Feifei
A1 Fabre, Jeanne
A1 Otto, Julia
A1 Verwaayen, Anna
A1 Reissing, Johanna
A1 Bruns, Tony
A1 Erschfeld, Stephanie
A1 Haas, Ute
A1 Paffen, Daniela
A1 Nelson, Leonard J.
A1 Vaquero Martín, Francisco Javier
A1 Bañares Cañizares, Rafael
A1 Trautwein, Christian
A1 Cubero Palero, Francisco Javier
A1 Liedtke, Christian
A1 Nevzorova, Yulia
AB Background: Cyclin E1 is the regulatory subunit of cyclin-dependent kinase 2 (Cdk2) and one of the central players in cell cycle progression. We recently showed its crucial role for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we investigated the role of Cyclin E1 in the development of alcohol-associated liver disease (ALD).Methods: Mice with constitutive (E1-/-), hepatocyte-specific (Cyclin E1Δhepa), or intestinal-epithelial-cell-specific (Cyclin E1ΔIEC) inactivation of Cyclin E1 and corresponding wild type littermate controls (WT) were administered either a Lieber-DeCarli ethanol diet (LDE) for 3 weeks or acute ethanol binges (6 g/kg) through oral gavage. Serum parameters of liver functionality were measured; hepatic tissues were collected for biochemical and histological analyses.Results: The administration of acute EtOH binge and chronic LDE diet to E1-/- mice enhanced hepatic steatosis, worsened liver damage and triggered body weight loss. Similarly, in the acute EtOH binge model, Cyclin E1Δhepa mice revealed a significantly worsened liver phenotype. In contrast, inactivation of Cyclin E1 only in intestinal epithelial cell (IECs)did not lead to any significant changes in comparison to WT mice after acute EtOH challenge. Remarkably, both acute and chronic EtOH administration in E1-/- animals resulted in increased levels of ADH and decreased expression of ALDH1/2. The additional application of a pan-Cdk inhibitor (S-CR8) further promoted liver damage in EtOH-treated WT mice.Conclusion: Our data point to a novel unexpected role of Cyclin E1 in hepatocytes for alcohol metabolism, which seems to be independent of the canonical Cyclin E1/Cdk2 function as a cell cycle regulator.
PB Elsevier
SN 0925-4439
YR 2023
FD 2023-02-01
LK https://hdl.handle.net/20.500.14352/88036
UL https://hdl.handle.net/20.500.14352/88036
LA eng
NO Fundación Alemana de Investigación (DFG)
NO Ministerio de Asuntos Económicos y Transformación Digital (MINECO)
NO Ministerio de Ciencia e Innovación (MICIN)
NO Unión Europea
NO Comunidad de Madrid. Fundación para la Investigación Biomédica del Hospital Universitario de Getafe (FIBHGM)
NO European Cooperation in Science & Technology (COST)
NO Universidad Complutense de Madrid /Banco Santander
DS Docta Complutense
RD 21 ago 2024