Lack of Cyclin E1 aggravates ethanol-induced liver injury and hepatic steatosis in the murine model of acute ALD

Background:

Cyclin E1 is a central player involved in the G1/S cell cycle transition and cell cycle progression. Our group has recently shown the crucial role of Cyclin E1 for initiation of liver fibrosis and hepatocarcinogenesis. In the present study, we focus on the participation of Cyclin E1 in the development of alcoholic liver disease (ALD). ALD is characterized by hepatic steatosis, persistent cell death of hepatocytes and inflammation, and is one of the major causes of liver diseases in western countries. The alteration in hepatic proliferation could be one of the factors that may exacerbate alcohol-induced liver damage.

Aim:

In the present study, we evaluated the consequences of the constitutive Cyclin E1 ablation in acute ethanol-induced liver injury.

Methods:

Total Cyclin E1 knockout mice (CcnE1-/-) and wild type littermate controls (WT) were administered either a single (6 g/kg bw) or multiple (3 consecutive days) ethanol binges through oral gavage. Serum parameters of liver functionality were measured and hepatic tissues were collected for biochemical and histological analyses.

Results:

Acute alcohol binge drinking induced up to 4-fold increase of Cyclin E1 gene expression in the liver of WT mice. Application of EtOH to Cyclin E1 knockout mice displayed aggravated liver injury – as indicated by significant upregulation of serum transaminases levels and elevated cell death. Liver injury was accompanied by moderate inflammatory infiltration as indicated by clusters of CD11b+ and F4/80+ cells as well as increased gene expression of pro-inflammatory markers such as MCP-1 and TLR4. Remarkably, EtOH-fed Cyclin E1-/- mice displayed significantly extended steatosis and increased hepatic triglyceride content, that was associated with overexpression of the fatty acid transporter gene, CD36. Importantly, the analysis of hepatic proliferation revealed that alcohol feeding triggered mild and similar cell cycle activation in both experimental groups.

Conclusion:

The pronounced susceptibility to ethanol-derived liver injury observed in Cyclin E1-/- mice suggests an unexpected new role of Cyclin E1 in the development of ALD, that seems to be independent of its canonical function as a cell cycle regulator.