Ibrahim, Sara and Dayoub, Rania and Saberi, Veronika and Buchner, Monika and Melter, Michael and Weiss, Thomas S. (2020) Augmenter of Liver Regeneration (ALR) regulates bile acid synthesis and attenuates bile acid-induced apoptosis via glycogen synthase kinase-3 beta (GSK-3 beta) inhibition. EXPERIMENTAL CELL RESEARCH, 397 (1): 112343. ISSN 0014-4827, 1090-2422
Full text not available from this repository. (Request a copy)Abstract
Bile acid synthesis is restricted to hepatocytes and is rate-limited by CYP7A1 (cholesterol 7 alpha hydroxylase). CYP7A1 expression undergoes tight regulation and is repressed after partial hepatectomy to prevent the accumulation of toxic bile acids. Augmenter of Liver Regeneration (ALR) is a hepatotrophic factor shown to support liver regeneration by augmenting cell proliferation and reducing apoptosis. Nevertheless, less is known about ALR's role in protecting hepatocytes from bile acid accumulation and bile acid-induced apoptosis. Therefore, HepG2 and Huh-7 cells were incubated with recombinant human ALR (rALR) and the expression of CYP7A1, bile acid-induced apoptosis as well as potential molecular mechanisms were analyzed. We found that rALR reduces CYP7A1 expression by increasing nuclear NF kappa B levels. Moreover, rALR reduced glycochenodeoxycholate (GCDC)-induced-apoptosis by decreased expression of pro-apoptotic Box and enhanced expression of antiapoptotic Mc1-1, which is regulated by phosphatidylinositol-3-kinase (PI3K)/Akt activation and glycogen synthase kinase-3 beta (GSK3 beta) phosphorylation. Inhibitors for PI3K/Akt (GSK690693) and GSK3 beta (SB415286) confirmed the specificity of rALR treatment for this pathway. In addition, rALR reduces pro-death signaling by decreasing GCDC-induced JNK phosphorylation. Taken all together, rALR might contribute to protecting hepatocytes from toxic concentrations of bile acids by down-regulating their de novo synthesis, attenuating apoptosis by activation of PI3K/Akt - GSK3 beta pathway and inhibition of JNK signaling. Thereby this suggests a new role of ALR in augmenting the process of liver regeneration.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | ; Augmenter of liver regeneration; Bile acids; Cholestasis; Glycogen synthase kinase-3 beta; Anti-apoptotic signaling; Myeloid cell leukemia 1 |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Kinder- und Jugendmedizin |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 08 Mar 2021 07:08 |
| Last Modified: | 08 Mar 2021 07:08 |
| URI: | https://pred.uni-regensburg.de/id/eprint/43284 |
Actions (login required)
 |
View Item |
