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Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress

Xue Yu1, Jiajun Lv, Yunzhen Zhu

  • 1Department of Cardiology, Beijing Hospital, Ministry of Health, Beijing, China.

Plos One
|January 26, 2013
PubMed

Insights

High homocysteine levels impair liver regeneration by inhibiting hepatocyte proliferation. This occurs through p53, p21(Cip1), and TRB3 signaling, impacting Akt phosphorylation and cell growth arrest.

Area of Science:

  • Hepatology
  • Molecular Biology
  • Biochemistry

Background:

  • Homocysteine is a risk factor for vascular diseases.
  • Elevated homocysteine is linked to impaired liver function, but its role is unclear.
  • Understanding homocysteine's effect on hepatocytes is crucial for liver health.

Purpose of the Study:

  • To investigate the impact of homocysteine on hepatocyte proliferation in vitro.
  • To elucidate the molecular mechanisms underlying homocysteine-induced hepatic dysfunction.

Main Methods:

  • Primary hepatocyte culture and hepatocarcinoma cell lines (HepG2, Hep3B).
  • Analysis of p53, p21(Cip1), TRB3, and Akt phosphorylation.
  • Use of p53 inhibitor (pifithrin-α) and TRB3 knockdown.
  • Intervention with LiCl to reverse homocysteine effects.

Main Results:

  • Homocysteine inhibited hepatocyte proliferation by up-regulating p53 and p21(Cip1).
  • Cell growth arrest was p53-dependent.
  • Homocysteine induced TRB3 expression via endoplasmic reticulum stress, leading to Akt dephosphorylation.
  • TRB3 knockdown and LiCl treatment reversed homocysteine's inhibitory effects.

Conclusions:

  • p53, p21(Cip1), and TRB3 are key mediators in homocysteine's effect on liver cells.
  • Homocysteine impairs liver regeneration through a signaling cascade involving TRB3 and Akt.
  • This study provides mechanistic insights into hyperhomocysteinemia-related liver dysfunction.

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