Hepatocyte-derived VEGFA accelerates the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via activating hepatic stellate cells
Hepatocyte-derived VEGFA accelerates the progression of non-alcoholic fatty liver disease to hepatocellular carcinoma via activating hepatic stellate cells
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DOI：
10.1038/s41401-022-00907-5
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发表时间：
2022-05
影响因子：
8.2
通讯作者：
Hao Shen;Hanyang Yu;Qian-yu Li;Yali Wei;J. Fu;H. Dong;D. Cao;Lin-na Guo;Lei Chen
中科院分区：
文献类型：
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作者：
Hao Shen;Hanyang Yu;Qian-yu Li;Yali Wei;J. Fu;H. Dong;D. Cao;Lin-na Guo;Lei Chen
非酒精性脂肪肝病 (NAFLD) 正在成为肝细胞癌 (HCC) 的流行危险因素。 NAFLD向HCC的进展与肝细胞间的旁分泌通讯密切相关。血管内皮生长因子 A (VEGFA) 在 NAFLD 和 HCC 中发挥关键作用；然而，VEGFA 在从 NAFLD 到 HCC 的病理转变中的细胞通讯仍不清楚。在这里，我们发现 VEGFA 升高在临床和小鼠 NAFLD-HCC 标本的肝细胞中分布相当广泛。值得注意的是，在肝细胞特异性缺失 Vegfa (VegfaΔhep) 小鼠中，从 NAFLD 到 HCC 的进展被减弱。从机制上讲，VEGFA 在脂肪酸培养基中通过 VEGF-VEGFR 信号传导将人肝星状细胞 (HSC) LX2 激活为纤维化表型，并且在 NAFLD-HCC 进展过程中，VegfaΔhepmice 中的 HSC 激活很大程度上减弱。此外，在 NAFLD-HCC 队列中观察到 VEGFA 与肝纤维化之间呈正相关，但在 HBV-HCC 队列中则不然。此外，LX2细胞可以被来自NAFLD衍生类器官的条件培养基激活，但不能被来自HBV肝脏的条件培养基激活，而这种激活被VEGFA抗体阻断。总之，我们的研究结果表明，肝细胞源性 VEGFA 通过激活 HSC 促进 NAFLD-HCC 的发展，并强调了精确靶向肝细胞 VEGFA 作为 NAFLD-HCC 有前景的治疗策略的潜力。
Non-alcoholic fatty liver disease (NAFLD) is emerging as an epidemic risk factor for hepatocellular carcinoma (HCC). The progression of NAFLD to HCC is closely associated with paracrine communication among hepatic cells. Vascular endothelial growth factor A (VEGFA) plays a key role in NAFLD and HCC; however, the cellular communication of VEGFA in the pathological transition from NAFLD to HCC remains unclear. Here, we found that VEGFA elevation was considerably distributed in hepatocytes of clinical and murine NAFLD-HCC specimens. Notably, progression from NAFLD to HCC was attenuated in hepatocyte-specific deletion ofVegfa(VegfaΔhep) mice. Mechanistically, VEGFA activated human hepatic stellate cell (HSC) LX2 into a fibrogenic phenotype via VEGF-VEGFR signaling in fatty acid medium, and HSC activation was largely attenuated inVegfaΔhepmice during NAFLD-HCC progression. Additionally, a positive correlation between VEGFA and hepatic fibrosis was observed in the NAFLD-HCC cohort, but not in the HBV-HCC cohort. Moreover, LX2 cells could be activated by conditioned medium from NAFLD-derived organoids, but not from HBV livers, whereas this activation was blocked by a VEGFA antibody. In summary, our findings reveal that hepatocyte-derived VEGFA contributes to NAFLD-HCC development by activating HSCs and highlight the potential of precisely targeting hepatocytic VEGFA as a promising therapeutic strategy for NAFLD-HCC.