Hepatocyte Proliferation During Liver Regeneration Is Impaired in Mice with Methionine Diet-Induced Hyperhomocysteinemia

Abstract

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 p21 Cip1. 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. (Am J

Homocysteine Inhibits Hepatocyte Proliferation via Endoplasmic Reticulum Stress

“…A recent study has confirmed that TRB3 is a novel target gene of CHOP involved in the coordination of apoptosis during ER stress [28]. Our recent study indicates that expression of TRB3 is elevated in livers of mice with hyperhomocysteinemia [22]. In the current study, homocysteine induces TRB3 expression through the ER stress pathway in cultured hepatocytes.…”

“…Previous studies indicate that TRB3 inhibits the transmission of the Akt signal [22], [30]. Since phosphorylation of Akt at Ser473 was tightly correlated with its activation, we examined the effect of homocysteine on phosphorylation of Akt (Ser473).…”

“…48 h following transfection, the medium was replaced with fresh DMEM containing 10% FBS. Stable cell lines of HepG2 that express full-length CHOP or shRNA for TRB3 gene [22], were produced by transfection of pCMV3C-CHOP plasmid or pSilencer2.1-U6-shRNA followed by positive colony selection using G418 (Sigma) at a concentration of 500 µg/ml.…”

“…Moreover, our recent studies have shown that hyperhomocysteinemia disturbs hepatic glucose metabolism, resulting in insulin resistance [20], [21]. Recently, Liu et al [22] have reported that hyperhomocysteinemia induced by methionine diet impairs liver regeneration in mice.…”

Impaired liver regeneration is associated with reduced cyclin B1 in natural killer T cell-deficient mice

“…Wei-Hua et al showed that impaired liver regeneration in mice with hyperhomocysteinemia (HHcy) was also correlated with reduced cyclins and elevated expression of p53 and p21 Cip1 [16]. In contrast, p21 Cip1 knockout mice display accelerated hepatocyte proliferation after PH through G 1 phase.…”