Department of Nanomedice and Drug Targeting, Groningen Research Institute of Pharmacy (GRIP), University of Groningen, Antonius Deusinglaan 1, 9713 AV Groningen, The Netherlands.
Department of Surgery, Massachusetts General Hospital, Harvard Medical School, Boston, MA 02114, USA.
Cells. 2020 Dec 17;9(12):2708. doi: 10.3390/cells9122708.
Alkaline phosphatase (AP) activity is highly upregulated in plasma during liver diseases. Previously, we demonstrated that AP is able to detoxify lipopolysaccharide (LPS) by dephosphorylating its lipid A moiety. Because a role of gut-derived LPS in liver fibrogenesis has become evident, we now examined the relevance of phosphate groups in the lipid A moiety in this process. The effects of mono-phosphoryl and di-phosphoryl lipid A (MPLA and DPLA, respectively) were studied in vitro and LPS-dephosphorylating activity was studied in normal and fibrotic mouse and human livers. The effects of intestinal AP were studied in mice with CCL4-induced liver fibrosis. DPLA strongly stimulated fibrogenic and inflammatory activities in primary rat hepatic stellate cells (rHSCs) and RAW264.7 macrophages with similar potency as full length LPS. However, MPLA did not affect any of the parameters. LPS-dephosphorylating activity was found in mouse and human livers and was strongly increased during fibrogenesis. Treatment of fibrotic mice with intravenous intestinal-AP significantly attenuated intrahepatic desmin- and αSMA -HSC and CD68- macrophage accumulation. In conclusion, the lack of biological activity of MPLA, contrasting with the profound activities of DPLA, shows the relevance of LPS-dephosphorylating activity. The upregulation of LPS-dephosphorylating activity in fibrotic livers and the protective effects of exogenous AP during fibrogenesis indicate an important physiological role of intestinal-derived AP during liver fibrosis.
碱性磷酸酶（AP）在肝脏疾病期间在血浆中高度上调。以前，我们证明 AP 能够通过去磷酸化其脂质 A 部分来解毒脂多糖（LPS）。由于肠道来源的 LPS 在肝纤维化中的作用已经很明显，我们现在研究了脂质 A 部分中的磷酸基团在此过程中的相关性。在体外研究了单磷酸化和二磷酸化脂质 A（MPLA 和 DPLA，分别）的作用，并在正常和纤维化的小鼠和人肝脏中研究了 LPS 去磷酸化活性。在 CCL4 诱导的肝纤维化小鼠中研究了肠道 AP 的作用。DPLA 强烈刺激原代大鼠肝星状细胞（rHSCs）和 RAW264.7 巨噬细胞的纤维化和炎症活性，其效力与全长 LPS 相似。然而，MPLA 没有影响任何参数。在小鼠和人肝脏中发现了 LPS 去磷酸化活性，并且在纤维化过程中强烈增加。用静脉内肠 AP 治疗纤维化小鼠可显著减轻肝内结蛋白和αSMA-HSC 和 CD68-巨噬细胞的积累。总之，MPLA 的缺乏生物学活性，与 DPLA 的深刻活性形成对比，表明 LPS 去磷酸化活性的相关性。在纤维化肝脏中 LPS 去磷酸化活性的上调以及外源性 AP 在纤维化过程中的保护作用表明，肠道来源的 AP 在肝纤维化期间具有重要的生理作用。
