Perturbation of Specific Signaling Pathways Is Involved in Initiation of Mouse Liver Fibrosis

Background and Aims To identify the regulatory role of protein phosphatase 2A (PP2A) in the development of liver disease, we generated a mouse model with hepatocyte-specific deletion of Ppp2r1a gene (encoding PP2A A alpha subunit). Approach and Results Homozygote (HO) mice and matched wild-type littermates were investigated at 3, 6, 9, 12, 15, and 18 months of age. Pathological examination showed that PP2A A alpha deficiency in hepatocytes resulted in progressive liver fibrosis phenotype from 9 months of age. No hepatocyte death was observed in HO mice. However, perturbation of pathways including epidermal growth factor receptor 1 (EGFR1), amino acid metabolism, and translation factors as well as leptin and adiponectin led to pronounced hepatic fibrosis. In vitro studies demonstrated the involvement of specific B subunit complexes in the regulation of EGFR1 signaling pathway and cross talk between defected hepatocytes and stimulation of interstitial hyperplasia. It is noteworthy that HO mice failed to develop hepatocellular carcinoma for as long as 22 months of age. We further demonstrate that PP2A A beta-containing holoenzymes played a critical role in preventing hepatocyte apoptosis and antagonizing tumorigenesis through specific pathways on A alpha loss. Furthermore, PP2A A alpha and A beta were functionally distinct, and the A beta isoform failed to substitute for A alpha in the development of inflammation and liver fibrosis. Conclusions These observations identify pathways that contribute to the pathogenesis of liver fibrosis and provide putative therapeutic targets for its treatment.

Automated summary

This study found that deficiency of PP2A Aα subunit in hepatocytes resulted in progressive liver fibrosis, but did not lead to hepatocellular carcinoma in HO mice. PP2A Aβ-containing holoenzymes played a critical role in preventing hepatocyte apoptosis and antagonizing tumorigenesis. PP2A Aα and Aβ isoforms were functionally distinct, with Aβ unable to substitute for Aα in inflammation and liver fibrosis development.