Division of Abdominal Surgery, Department of Surgery, Geneva University Hospitals and Faculty of Medicine, Geneva, Switzerland.
Transplantation and Hepatology Laboratory, University of Geneva, Geneva, Switzerland.
PLoS One. 2023 Dec 29;18(12):e0296265. doi: 10.1371/journal.pone.0296265. eCollection 2023.
Non-alcoholic fatty liver disease (NAFLD) is one of the leading cause of hepatocellular carcinoma (HCC). This association is supported by the translocation of bacteria products into the portal system, which acts on the liver through the gut-liver axis. We hypothesize that portosystemic shunting can disrupt this relationship, and prevent NAFLD-associated HCC.
HCC carcinogenesis was tested in C57BL/6 mice fed a high-fat high-sucrose diet (HFD) and injected with diethylnitrosamine (DEN) at two weeks of age, and in double transgenic LAP-tTA and TRE-MYC (LAP-Myc) mice fed a methionine-choline-deficient diet. Portosystemic shunts were established by transposing the spleen to the sub-cutaneous tissue at eight weeks of age.
Spleen transposition led to a consistent deviation of part of the portal flow and a significant decrease in portal pressure. It was associated with a decrease in the number of HCC in both models. This effect was supported by the presence of less severe liver steatosis after 40 weeks, and lower expression levels of liver fatty acid synthase. Also, shunted mice exhibited lower liver oxygen levels, a key factor in preventing HCC as confirmed by the development of less HCCs in mice with hepatic artery ligation.
The present data show that portosystemic shunting prevents NAFLD-associated HCC, utilizing two independent mouse models. This effect is supported by the development of less steatosis, and a restored liver oxygen level. Portal pressure modulation and shunting deserve further exploration as potential prevention/treatment options for NAFLD and HCC.
非酒精性脂肪性肝病（NAFLD）是肝细胞癌（HCC）的主要病因之一。这种关联得到了细菌产物易位进入门脉系统的支持，这些产物通过肠-肝轴作用于肝脏。我们假设门体分流可以破坏这种关系，并预防非酒精性脂肪性肝病相关的 HCC。
在 2 周龄时用高脂肪高蔗糖饮食（HFD）喂养 C57BL/6 小鼠并注射二乙基亚硝胺（DEN），以及在给予蛋氨酸-胆碱缺乏饮食的双转基因 LAP-tTA 和 TRE-MYC（LAP-Myc）小鼠中测试 HCC 发生。通过将脾脏转移到 8 周龄时的皮下组织来建立门体分流。
脾脏转移导致部分门静脉血流的持续偏离和门静脉压力的显著下降。它与两种模型中 HCC 数量的减少有关。这一效应得到了 40 周后肝脏脂肪变性程度较轻和肝脏脂肪酸合酶表达水平较低的支持。此外，分流小鼠的肝脏氧水平较低，这是预防 HCC 的一个关键因素，这一点得到了肝动脉结扎小鼠 HCC 较少的发展的证实。
本研究数据表明，门体分流利用两种独立的小鼠模型预防非酒精性脂肪性肝病相关的 HCC。这种效应得到了较少脂肪变性和恢复的肝脏氧水平的支持。门静脉压力调节和分流值得进一步探索，作为非酒精性脂肪性肝病和 HCC 的潜在预防/治疗选择。
