The Role Of GOLPH2 In Liver Inflammation And Liver Damage

Golgi phosphoprotein 2 (GOLPH2, also GP73) is a typeⅡtransmembrane protein. It is located in the cis- and medial- membrane of Golgi apparatus and could be secreted from the cell through the intracellular trafficking system. Many reports indicated abnormal expression of GOLPH2 in liver diseases, and there are clinical evidences suggest that GOLPh2 might sever as a potential serum marker for hepatocellular carcinoma.The previous studies are mainly on the correlations between GOLPH2 expression levels and different disease; however, the potential pathological mechanisms remain unknown. The goal of this research is to understand the role and regulation of GOLPH2 expression during liver inflammation and damage.The expression level GOLPH2 is sensitive to liver inflammation and damage. Its up-regulated expression is observed 24h after LPS or CCl4 stimulation in the model, and reached to the maximal level at 48h post treatment. Such up-regulated expression of GOLPH2 is reversible.The regulation of GOLPH2 expression by cytokines was analyzed in cell culture. It shows that IL-1b and IL-6 could promote the expression of GOLPH2 in Hep3B and primary hepatocytes. However, TGF-βdown-regulates GOLPH2 in hepatocyte while TNF-αand IFN-γshowed no effect on GOLPH2 expression. These results suggest that GOLPH2 might be regulated by these cytokines secreted by immune cells in liver diseases.To determine the potential role of GOLPH2 during liver inflammation and damage, I analyzed a golph2 knockout mouse model generated using the Cre-Loxp recombinant system. A new splicing variant of GOLPH2 was identified in this mouse model. The results suggested two splicing sites in the 5'of exon 6, one of which is novel. Using this novel splicing site, GOLPH2 mRNA could be connected through exon 4 and exon 6 directly without damaging its ORF. With this alternative splicing mechanism, the"knockout"mouse could partially repaired its GOLPH2 mRNA and expresses a mutated GOLPH2 protein with the deletion of 20 amino acids coded by exon5. The mouse with this mutated form of GOLPH2 displayed uneven gender in its offspring and was observed more sensitive to liver infection and chemical damages. This study suggests that GOLPH2 is a stress response protein and might play important roles in the repairing of liver damages.