The role of hepatic cell senescence in human non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH) is not well understood. To examine this, we performed liver biopsies and extensive characterization of 58 individuals with or without NAFLD/NASH. Here, we show that hepatic cell senescence is strongly related to NAFLD/NASH severity, and machine learning analysis identified senescence markers, the BMP4 inhibitor Gremlin 1 in liver and visceral fat, and the amount of visceral adipose tissue as strong predictors. Studies in liver cell spheroids made from human stellate and hepatocyte cells show BMP4 to be anti-senescent, anti-steatotic, anti-inflammatory and anti-fibrotic, whereas Gremlin 1, which is particularly highly expressed in visceral fat in humans, is pro-senescent and antagonistic to BMP4. Both senescence and anti-senescence factors target the YAP/TAZ pathway, making this a likely regulator of senescence and its effects. We conclude that senescence is an important driver of human NAFLD/NASH and that BMP4 and Gremlin 1 are novel therapeutic targets.

肝细胞衰老在人类非酒精性脂肪肝（NAFLD）和非酒精性脂肪性肝炎（NASH）中的作用尚不清楚。为了检验这一点，我们对 58 名患有或不患有 NAFLD/NASH 的个体进行了肝脏活检和广泛的特征分析。在这里，我们表明肝细胞衰老与 NAFLD/NASH 严重程度密切相关，并且机器学习分析确定了衰老标记物、肝脏和内脏脂肪中的 BMP4 抑制剂 Gremlin 1 以及内脏脂肪组织的量作为强预测因子。对由人星状细胞和肝细胞制成的肝细胞球体的研究表明，BMP4 具有抗衰老、抗脂肪变性、抗炎和抗纤维化作用，而 Gremlin 1 在人类内脏脂肪中表达特别高，具有促衰老且对抗 BMP4。衰老和抗衰老因子都以 YAP/TAZ 通路为目标，使其成为衰老及其影响的可能调节因子。我们得出结论，衰老是人类 NAFLD/NASH 的重要驱动因素，BMP4 和 Gremlin 1 是新的治疗靶点。