Bile acid flux is necessary for normal liver regeneration.
Bile acid flux is necessary for normal liver regeneration.
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DOI：
10.1371/journal.pone.0097426
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发表时间：
2014
期刊：
影响因子：
3.7
通讯作者：
Naugler WE
中科院分区：
文献类型：
--
作者：
Naugler WE
许多控制2/3部分肝切除术（PH）后肝脏再生（LR）的信号已被识别，但主要信号仍未知。本研究的目的是证实PH后的残肝缺乏分泌通过肝肠循环（EHC）返回的BA池的能力，这反过来可能刺激LR。在标准PH后，记录BA通量，并通过qPCR测定BA信号传导（Fgf 15）和合成（Cyp 7a）。大鼠胆瘘（BF）和Asbt敲除小鼠模型在PH之前中断了EHC，LR的标准测定沿着完整的RNA测序。BF后CCl 4中毒在替代损伤模型中检验了该假设。PH后全身血液中BA立即升高，证实残余肝脏无法处理通过门静脉循环返回的BA。在大鼠BF模型中，当在PH之前排空BA池时，LR显著减弱，这一现象在十二指肠BA置换后逆转。Asbt敲除小鼠PH后以及BF大鼠CCl 44中毒后，肝细胞增殖同样减弱。大鼠PH模型中的完整RNA测序显示，在不存在BA的情况下，早期c-jun和AP-1基因表达途径下调，与减弱的LR一致。PH或CCl 4损伤后，BA返回肝脏的情况明显减弱LR，但肝细胞增殖仍然发生，推断BA流量和信号传导不是管理LR的唯一信号。涉及c-jun和AP-1的转录网络参与BA对肝细胞增殖的特异性作用。
Many signals governing liver regeneration (LR) following 2/3 partial hepatectomy (PH) are recognized, but the primary signal(s) remains unknown. The aim of the study was to confirm that the remnant liver after PH lacks capacity to secrete the BA pool returning via the enterohepatic ciruculation (EHC), which may in turn stimulate LR. After standard PH, BA flux was documented and BA signaling (Fgf15) and synthesis (Cyp7a) determined by qPCR. Rat biliary fistula (BF) and Asbt knockout mouse models interrupted the EHC prior to PH, and standard assays for LR employed along with complete RNA sequencing. CCl4 intoxication after BF tested the hypothesis in an alternate injury model. BA rise in systemic blood immediately following PH, confirming that the remnant liver cannot handle the BA returning via portal circulation. When the BA pool is drained prior to PH in the rat BF model, LR is markedly attenuated, a phenomenon reversed with duodenal BA replacement. Hepatocyte proliferation is similarly attenuated after PH in the Asbt knockout mouse as well as after CCl44 intoxication in rats with BF. Complete RNA sequencing in the rat PH model shows that early c-jun and AP-1 gene expression pathways are down regulated in the absence of BA, coincident with attenuated LR. Absent BA return to the liver after PH or CCl4 injury markedly attenuates LR, though hepatocyte proliferation still occurs, inferring that BA flux and signaling are not the sole signals governing LR. Transcriptional networks involving c-jun and AP-1 are involved in the BA-specific effects on hepatocyte proliferation.
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