Modulating hepatocarcinogenesis by porto-systemic vein shunting in a high-fat diet mouse model

Abstract

Abstract Objective Non-alcoholic fatty liver disease (NAFLD) is an increasingly common disease, which can lead to hepatocellular carcinoma (HCC). It is associated with an increased portal pressure, which can alter the intestinal barrier, increase the translocation of bacterial products, and further worsen NAFLD. We hypothesized that this vicious circle can be broken by surgical porto-systemic vein shunting (PSVS), and previously demonstrated that PSVS can decrease the histological features of NAFLD in a high-fat diet (HFD) mouse model. We now test whether PSVS can also impact de-novo hepatocarcinogenesis. Methods C57BL/6 mice received HFD starting from 4 weeks of age. HCC was induced by intraperitoneal injection of DEN at 25mg/kg on week 2 and PSVS (n = 18) (or sham surgery (n = 18)) are created at 8 weeks. HCC burden was assessed by MRI and, finally, by macroscopic and histomorphology assessments. HCC features of aggressiveness, including solid growth pattern and fat component have been also evaluated. Results At 40 weeks of HFD feeding, tumors were identified in all the animals. Shunted HFD mice showed a reduced number of tumor nodules compared to sham (median nodules 8 vs 14, -42.9%; p = 0.0471) while associated to a greater average total tumor volume (709.3 vs 197 mm3, +258,6%; p = 0.0245). This correlated with an increased median tumor volume in shunted mice (16.30 vs 72.45 mm3, +344,5%; p = 0.0011). Notably, HCC histology of shunted mice was hallmarked by accentuated trend concerning HCC fatty change combined to a less pronounced solid growth pattern (p = 0.193). Conclusion PSVS leads to the presence of larger HCCs, potentially linked to the proportionally increased arterial supply of the liver. However, it demonstrates a protective effect on HCC carcinogenesis (< number of tumors). Collectively, this data suggests that portal pressure could represent a potential therapeutic target to attenuate liver steatosis and NAFLD-related HCC carcinogenesis.