Hepatocyte proliferation during liver regeneration is impaired in mice with methionine diet-induced hyperhomocysteinemia.
Elevated homocysteine levels are defined as hyperhomocysteinemia (HHcy), a disorder that is associated with cardiovascular and neurodegenerative diseases as well as with hepatic fibrosis. Recent studies have shown that HHcy promotes hepatic injury by increasing oxidative stress. Although homocysteine induces cell cycle arrest in a variety of different cell types, it is not known whether HHcy has a definitive role in hepatocyte proliferation during liver regeneration. In this report, we investigated the effect of homocysteine on liver regeneration. Our results demonstrated that mice with HHcy exhibited an impairment in liver regeneration after partial hepatectomy, as measured by immunohistochemical staining of proliferation cell nuclear antigen and bromodeoxyuridine incorporation. Impaired proliferation was also correlated with reduced cyclin D1 induction and elevated expression levels of both p53 and p21Cip1. In addition, the phosphorylation of Akt, which plays an essential role in normal regeneration responses, was attenuated during the early phases of liver regeneration in HHcy mice. Our results also indicated that the cAMP/protein kinase A pathway mediated the inhibitory effect of homocysteine on liver regeneration. These findings provide evidence that impairment of liver regeneration by HHcy may result in delayed recovery from liver injury induced by homocysteine itself.
Liu
Wei-Hua
WH
Laboratory for Conservation and Utilization of Bio-Resources, Yunnan University, and the Department of General Surgery, The First People's Hospital of Kunming, Kunming, Yunnan 650091, China.
Zhao
Yue-Shui
YS
Gao
Shun-Yu
SY
Li
Shu-De
SD
Cao
Jun
J
Zhang
Ke-Qin
KQ
Zou
Cheng-Gang
CG
D000818:Animals; D049109:Cell Proliferation; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism; D017362:Cyclic AMP Response Element-Binding Protein / Q000378:metabolism; D019938:Cyclin D1 / Q000378:metabolism; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D004032:Diet; D006498:Hepatectomy; D022781:Hepatocytes / Q000166:cytology / Q000502:physiology*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000209:etiology / Q000503:physiopathology*; D008099:Liver / Q000473:pathology / Q000502:physiology; D008115:Liver Regeneration / Q000502:physiology*; D008715:Methionine / Q000008:administration & dosage* / Q000009:adverse effects; D051379:Mice; D008807:Mice, Inbred BALB C; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
C493957:Cdkn1a protein, mouse; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016159:Tumor Suppressor Protein p53; D019938:Cyclin D1; D008715:Methionine; D000242:Cyclic AMP; D051057:Proto-Oncogene Proteins c-akt