PGC-1α Promoter Histone Acetylation is Life Saving in Fibrotic Hepatectomy

Abstract

Background and Aim: A fibrotic liver may have impaired regenerative capacity. Liver transplantation is a donor-limited, expensive therapeutic option for the restoration of the structural and function integrity of the liver following regeneration failure. Thus, gaining the clinical ability to restore the regenerative capacity of the fibrotic liver is important. This study aimed to investigate the mechanisms involved in regenerative failure of the fibrotic liver after resection. Methods: A two-thirds partial hepatectomy (PH) was performed in C57Bl/6 mice with or without carbon tetrachloride (CCl4) treatment. Cell proliferation in the fibrotic liver post-PH was assessed by the intrahepatic expression of P53, PGC-1α, P21 and PCNA with RT-PCR, Western-blot and immunohistochemical staining. Histone epigenetic modification of the PGC-1α promoter was investigated by ChIP and RT-PCR assay. The impact of PGC-1α on liver regeneration after hepatectomy was further evaluated in PGC-1α gene knockout mice. Results: An association was detected between a decreased expression of PGC-1α and p53 in the fibrotic liver and liver injury and cell proliferation 24 hours after PH. Moreover, the oxidative stress observed following PH in the fibrotic liver inhibited the PGC-1α expression through histone deacetylation of the PGC-1α promoter. This PGC-1α mediated liver regeneration was further demonstrated in PGC-1αf/f alb cre /0 mice. Conclusion: Altered p53 expression, which was preceded by abnormal histone epigenetic modification of the promoter of PGC-1α, led to inefficient regeneration in the fibrotic liver after PH. Targeting the histone modification of PGC-1α may represent a strategy which may improve PH treatment in patients with liver fibrosis. Funding Statement: This work was supported by National Natural Science Foundation of China Award number 81470864. Declaration of Interests: All the authors declare no competing interests. Ethics Approval Statement: All experimental procedures were conducted in accordance with the guidelines of Laboratory Animal Welfare Assurance issued by the National Institute of Health (NIH) and were approved by the Animal Care and Use Committee of Capital Medical University.