Crumm Sara, Cofan Montserrat, Juskeviciute Egle, Hoek Jan B
Department of Pathology, Anatomy and Cell Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Hepatology. 2008 Sep;48(3):898-908. doi: 10.1002/hep.22421.
Liver regeneration after partial hepatectomy (PHx) is orchestrated by multiple signals from cytokines and growth factors. We investigated whether increased energy demand on the remnant liver after PHx contributes to regenerative signals. Changes in the tissue's energy state were determined from adenine nucleotide levels. Adenosine triphosphate (ATP) levels in remnant livers decreased markedly and rapidly (to 48% of control by 30 seconds post-PHx) and remained significantly lower than those in sham-operated controls for 24 to 48 hours. The ATP decrease was not reflected in corresponding increases in adenosine diphosphate (ADP) and adenosine monophosphate (AMP), resulting in a marked decline in total adenine nucleotides (TAN). We found no evidence of mitochondrial damage or uncoupling of oxidative phosphorylation. Multiple lines of evidence indicated that the decline in TAN was not caused by increased energy demand, but by ATP release from the liver. The extent of ATP loss was identical after 30% or 70% PHx, whereas fasting or hyperglycemia, conditions that greatly alter energy demand for gluconeogenesis, affected the ATP/ADP decline but not the loss of TAN. Presurgical treatment with the alpha-adrenergic antagonist phentolamine completely prevented loss of TAN, although changes in ATP/ADP were still apparent. Importantly, phentolamine treatment inhibited early signaling events associated with the priming stages of liver regeneration and suppressed the expression of c-fos. Pretreatment with the purinergic receptor antagonist suramin also partly suppressed early regenerative signals and c-fos expression, but without preventing TAN loss.
The rapid loss of adenine nucleotides after PHx generates early stress signals that contribute to the onset of liver regeneration.
部分肝切除术后（PHx）的肝脏再生由细胞因子和生长因子的多种信号协调。我们研究了PHx后残余肝脏能量需求增加是否有助于再生信号。根据腺嘌呤核苷酸水平确定组织能量状态的变化。残余肝脏中的三磷酸腺苷（ATP）水平显著且迅速下降（PHx后30秒降至对照的48%），并在24至48小时内显著低于假手术对照组。ATP的下降并未反映在二磷酸腺苷（ADP）和一磷酸腺苷（AMP）的相应增加上，导致总腺嘌呤核苷酸（TAN）显著下降。我们没有发现线粒体损伤或氧化磷酸化解偶联的证据。多条证据表明，TAN的下降不是由能量需求增加引起的，而是由肝脏释放ATP所致。30%或70%PHx后ATP损失的程度相同，而禁食或高血糖，这两种极大改变糖异生能量需求的情况，影响了ATP/ADP的下降，但不影响TAN的损失。术前用α-肾上腺素能拮抗剂酚妥拉明治疗完全防止了TAN的损失，尽管ATP/ADP的变化仍然明显。重要的是，酚妥拉明治疗抑制了与肝脏再生启动阶段相关的早期信号事件，并抑制了c-fos的表达。用嘌呤能受体拮抗剂苏拉明预处理也部分抑制了早期再生信号和c-fos表达，但没有防止TAN的损失。
PHx后腺嘌呤核苷酸的快速损失产生早期应激信号，有助于肝脏再生的开始。
