The liver regeneration-associated protein ALR (Augmenter of Liver Regeneration) was
shown to exhibit anti-apoptotic, anti-oxidative and autophagic properties. Increased
ALR levels have a beneficial impact on liver regeneration, but in chronic liver injury
such as cholestasis and NAFLD (non-alcoholic fatty liver disease) expression of ALR
is diminished. While several factors are known to induce ALR expression, little is
known about its negative regulation. Preliminary results demonstrated that interleukin-1β
(IL-1β), e. g. secreted by Kupffer cells in cholestasis, can induce ALR promoter activity.
Therefore, we aimed to investigate the regulation of ALR expression by IL-1β. HepG2
and Huh-7 cells were treated with different concentrations of IL-1β and qRT-PCR as
well as western-blots were performed. IL-1β treatment reduced ALR mRNA and protein
expression in a time- and dose-dependent manner in both cell lines. Expression of
hepcidin served as a positive control. Furthermore we analyzed potential transcription
factors (TFs) mediating the effect of IL-1β on ALR expression. We found reduced mRNA
expression of SP1, a known inducer of ALR, upon IL-1β treatment. In addition Egr-1,
another ALR-inducing TF, was hampered to activate ALR expression after IL-1β treatment.
Ongoing work elucidates a potential impact of AP1, a TF previously shown to bind onto
the ALR promotor repressing its activity. Additionally, expression of HNF4α, a TF
known to induce ALR expression, may be reduced by IL-1β and will therefore be analyzed.
In conclusion, insights into the regulation of ALR might result in therapeutic strategies
to boost its expression and increase its hepatoprotective properties.
