Peroxisome proliferator-activated receptor gamma coactivator 1-alpha protects a fibrotic liver from partial hepatectomy-induced advanced liver injury through regulating cell cycle arrest.

BACKGROUND: A fibrotic liver may have an impaired regenerative capacity. Because liver transplantation is donor limited, understanding the regenerative ability of a fibrotic liver is important.

METHODS: A two-thirds partial hepatectomy (PH) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4 ) treatment. Liver regeneration in the fibrotic liver after PH was assessed by the intrahepatic expression of the cell cycle regulators p53, p21, cyclin D1, c-Fos and CDK2 using Western blot analysis. In addition, the expression of PGC-1α and the cell proliferation-related proteins PCNA and phosphate histone H3 was determined by Western blot and immunohistochemical staining analyses. Histone epigenetic modification of the PGC-1α promoter was investigated through chromatin immunoprecipitation (ChIP) and reverse transcription-quantitative polymerase chain reaction (RT-qPCR) assays. The impact of PGC-1α on liver regeneration after PH was further evaluated in PGC-1α-knockout mice.

RESULTS: A decreased expression of PGC-1α and liver regeneration-related genes in the fibrotic liver was detected after a PH. Histone acetylation at the PGC-1α promoter led to increases in PGC-1α expression and the survival rate in the fibrotic group after a PH. PGC-1α-mediated liver regeneration was further demonstrated in PGC-1αf/f albcre+/0 mice.

CONCLUSION: Targeting PGC-1α may represent a strategy to improve the treatment of PH in patients with liver fibrosis.