Background: HCC incidence is increasing worldwide due to the obesity epidemic, which drives metabolic dysfunction-associated steatohepatitis (MASH) that can lead to HCC. However, the molecular pathways driving MASH-HCC are poorly understood. We have previously reported that male mice with haploinsufficiency of hypoxia-associated factor, HAF (SART1 +/-) spontaneously develop MASH-HCC. However, the cell type(s) responsible for HCC associated with HAF loss are unclear. Results: We generated SART1-floxed mice, which were crossed with mice expressing Cre-recombinase within hepatocytes (Alb-Cre; hepS-/-) or myeloid cells (LysM-Cre, macS-/-). HepS -/- mice (both male and female) developed HCC associated with profound inflammatory and lipid dysregulation suggesting that HAF protects against HCC primarily within hepatocytes. HAF-deficient hepatocytes showed decreased P-p65 and P-p50 and in many components of the NF-κB pathway, which was recapitulated using HAF siRNA in vitro. HAF depletion also triggered apoptosis, suggesting that HAF protects against HCC by suppressing hepatocyte apoptosis. We show that HAF regulates NF-κB activity by regulating transcription of TRADD and RIPK1. Mice fed a high-fat diet (HFD) showed marked suppression of HAF, P-p65 and TRADD within their livers after 26 weeks, but showed profound upregulation of these proteins after 40 weeks, implicating deregulation of the HAF-NF-κB axis in the progression to MASH. In humans, HAF was significantly decreased in livers with simple steatosis but significantly increased in HCC compared with normal liver. Conclusions: HAF is novel transcriptional regulator of the NF-κB pathway and is a key determinant of cell fate during progression to MASH and MASH-HCC.

中文翻译：

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HAF 通过 NF-κB 通路的转录调控防止肝细胞凋亡和进展为 MASH 和肝细胞癌


背景： 由于肥胖流行，全球 HCC 发病率不断增加，这导致代谢功能障碍相关脂肪性肝炎 （MASH） 可导致 HCC。然而，驱动 MASH-HCC 的分子途径知之甚少。我们之前已经报道过，缺氧相关因子 HAF （SART1 +/-） 单倍体不足的雄性小鼠自发发生 MASH-HCC。然而，导致与 HAF 丢失相关的 HCC 的细胞类型尚不清楚。结果： 我们生成了 SART1 絮凝小鼠，将其与肝细胞 （Alb-Cre;hepS-/-） 或骨髓细胞 （LysM-Cre， macS-/-） 内表达 Cre 重组酶的小鼠杂交。HepS -/- 小鼠（雄性和雌性）发展为与严重炎症和脂质失调相关的 HCC，表明 HAF 主要在肝细胞内预防 HCC。HAF 缺陷型肝细胞显示 P-p65 和 P-p50 以及 NF-κB 通路的许多组分减少，这在体外使用 HAF siRNA 进行了概括。HAF 耗竭还触发了细胞凋亡，表明 HAF 通过抑制肝细胞凋亡来预防 HCC。我们表明 HAF 通过调节 TRADD 和 RIPK1 的转录来调节 NF-κB 活性。喂食高脂饮食 （HFD） 的小鼠在 26 周后肝脏内显示 HAF 、 P-p65 和 TRADD 的显著抑制，但在 40 周后显示这些蛋白质的严重上调，表明 HAF-NF-κB 轴在进展为 MASH 中失调。在人类中，与正常肝脏相比，单纯性脂肪变性肝脏的 HAF 显著降低，但 HCC 的 HAF 显著增加。结论： HAF 是 NF-κB 通路的新型转录调节因子，是 MASH 和 MASH-HCC 进展过程中细胞命运的关键决定因素。