Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.
Homocysteine inhibits hepatocyte proliferation via endoplasmic reticulum stress.
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同型半胱氨酸通过内质网应激抑制肝细胞增殖。
DOI：
10.1371/journal.pone.0054265
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发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Ma L
中科院分区：
文献类型：
--
作者：
Yu X;Lv J;Zhu Y;Duan L;Ma L
同型半胱氨酸是冠状动脉、脑血管和外周血管疾病的独立危险因素。最近的研究表明，同型半胱氨酸水平在肝功能受损的患者中升高，但同型半胱氨酸在肝功能障碍发生发展中的确切作用尚不清楚。在本研究中，我们检测了同型半胱氨酸对体外培养的肝细胞增殖的影响。我们的结果表明，同型半胱氨酸通过上调原代培养肝细胞中P53和p21Cip1的mRNA和蛋白水平来抑制肝细胞的增殖。同型半胱氨酸诱导P53阳性肝癌细胞株HepG2细胞生长停滞，而对P53阴性肝癌细胞株Hep3B无生长抑制作用。P53抑制剂Pificerin-α可抑制p21Cip1的表达，并减轻同型半胱氨酸诱导的细胞生长停滞。同型半胱氨酸通过内质网应激途径诱导TRB3表达，导致Akt去磷酸化。下调内源性TRB3可显著抑制同型半胱氨酸对细胞增殖和Akt磷酸化的抑制作用。LiCl通过抑制TRB3介导的Akt去磷酸化逆转同型半胱氨酸介导的细胞生长停滞。这些结果表明，TRB3和p21Cip1都是同型半胱氨酸信号通路中的关键分子，并为高同型半胱氨酸血症时肝再生障碍提供了机制解释。
Homocysteine is an independent risk factor for coronary, cerebral, and peripheral vascular diseases. Recent studies have shown that levels of homocysteine are elevated in patients with impaired hepatic function, but the precise role of homocysteine in the development of hepatic dysfunction is unclear. In this study, we examined the effect of homocysteine on hepatocyte proliferation in vitro. Our results demonstrated that homocysteine inhibited hepatocyte proliferation by up-regulating protein levels of p53 as well as mRNA and protein levels of p21Cip1 in primary cultured hepatocytes. Homocysteine induced cell growth arrest in p53-positive hepatocarcinoma cell line HepG2, but not in p53-null hepatocarcinoma cell line Hep3B. A p53 inhibitor pifithrin-α inhibited the expression of p21Cip1 and attenuated homocysteine-induced cell growth arrest. Homocysteine induced TRB3 expression via endoplasmic reticulum stress pathway, resulting in Akt dephosphorylation. Knock-down of endogenous TRB3 significantly suppressed the inhibitory effect of homocysteine on cell proliferation and the phosphorylation of Akt. LiCl reversed homocysteine-mediated cell growth arrest by inhibiting TRB3-mediated Akt dephosphorylation. These results demonstrate that both TRB3 and p21Cip1 are critical molecules in the homocysteine signaling cascade and provide a mechanistic explanation for impairment of liver regeneration in hyperhomocysteinemia.
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影响因子：
4
作者：
Kim, AJ;Shi, YY;Werstuck, GH
通讯作者：
Werstuck, GH
DOI：
10.1073/pnas.96.15.8745
发表时间：
1999-07-20
影响因子：
11.1
作者：
Chalecka-Franaszek, E;Chuang, DM
通讯作者：
Chuang, DM
影响因子：
4.8
作者：
Namekata, K;Enokido, Y;Kimura, H
通讯作者：
Kimura, H
影响因子：
4.8
作者：
Jousse, Celine;Deval, Christiane;Fafournoux, Pierre
通讯作者：
Fafournoux, Pierre
DOI：
10.1073/pnas.112336399
发表时间：
2002-07-23
影响因子：
11.1
作者：
Halsted, CH;Villanueva, JA;James, SJ
通讯作者：
James, SJ