Augmenter of liver regeneration enhances cell proliferation through the microRNA‐26a/Akt/cyclin D1 pathway in hepatic cells

Abstract

Aim Hepatocytes can proliferate and regenerate when injured by toxins, viral infections, and so on. Augmenter of liver regeneration (ALR) is a key regulator of liver regeneration, but the mechanism is unknown. The role of ALR in other cell types is not known. In the present study, we investigated the relationship between microRNA (miRNA)‐26a and ALR in the Huh7 cell line and adipose tissue‐derived mesenchymal cells from chronic liver disease patients and healthy individuals. Methods Huh7 cells were transfected independently with ALR and miRNA‐26a expression vectors, and their effects on cell proliferation, the expression of miRNA‐26a, and activation of the phosphatase and tensin homolog and Akt signaling pathways were determined. The experiments were repeated on mesenchymal stem cells derived from healthy individuals and chronic liver disease patients to see whether the observations can be replicated in primary cells. Results Overexpression of ALR or miRNA‐26a resulted in an increase of the phosphorylation of Akt and cyclin D1 expression, whereas it resulted in decreased levels of p‐GSK‐3β and phosphatase and tensin homolog in Huh7 cells. The inhibition of ALR expression by ALR siRNA or anti‐miR‐26a decreased the Akt/cyclin D1 signaling pathway, leading to decreased proliferation. Mesenchymal stem cells isolated from the chronic liver disease patients had a higher ALR expression, while the mesenchymal stem cells isolated from healthy volunteers responded to the growth factor treatments for increased ALR expression. It was found that there was a significant increase in miRNA‐26a expression and proliferation. Conclusions These data clearly showed that ALR induced the expression of miRNA‐26a, which downregulated phosphatase and tensin homolog, resulting in an increased p‐Akt/cyclin D1 pathway and enhanced proliferation in hepatic cells.

Augmenter of Liver Regeneration (ALR) Protects Kidney from Ischemia/Reperfusion (I/R) Injury via Regulation of TLR4/MAPK Signaling Pathway

“…Recent studies have highlighted that immune regulation is another unique biological role of ALR. Gupta et al assumed that a possible mechanism for ALR in liver regeneration is to inhibit certain activities of the organ's inherent natural killer cells [ 30 , 31 ]. We found that exogenous ALR inhibits the activation of NF- κ B by downregulating the expression of TLR4 protein and mRNA, thereby inhibiting the inflammatory response of NRK-52E cells induced through hypoxia and reoxygenation [ 21 ].…”

Periplaneta americana Extracts Accelerate Liver Regeneration via a Complex Network of Pathways

“…However, more recent reports demonstrated that numerous signaling pathways are involved in this process and their interactions are complex. Gupta et al (2019) found that ALR (augmenter of liver regeneration, a protein that was identified to specifically support liver regeneration) induced miRNA-26a expression, upregulated the p-Akt/cyclin D1 pathway, and promoted hepatic cell proliferation. Lai et al (2015) found that EGR-1 (early growth response 1 gene)-induced GGPPS plays an important role in post-PH liver regeneration via RAS/MAPK signaling.…”

The protective roles of augmenter of liver regeneration in hepatocytes in the non-alcoholic fatty liver disease

“…Silencing of ALR inhibited the proliferation and triggered the apoptosis of U266 human multiple myeloma cells ( Zeng et al, 2017 ). Conversely, ALR overexpression in hepatic cells enhanced cell proliferation via the microRNA-26a/p-Akt/cyclin D1 pathway ( Gupta et al, 2019a ).…”