Nataraj Kruti, Schonfeld Michael, Mah Samson, Li Zhuan, Weinman Steven, Tikhanovich Irina
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, Kansas, USA.
The Key Laboratory of Model Animals and Stem Cell Biology in Hunan Province, Changsha, Hunan, China.
Hepatol Commun. 2025 Aug 15;9(9). doi: 10.1097/HC9.0000000000000771. eCollection 2025 Sep 1.
Alcohol-associated liver disease (ALD) is a major cause of alcohol-associated mortality. Previously, we identified KDM5B as a sex-specific mediator of ALD development; however, the mechanism behind KDM5B-induced pathological changes is not established.
Kdm5b flox/flox female mice were fed a western diet and 20% alcohol in the drinking water for 8-16 weeks (WDA). To induce KO, mice received 2×1011 genome copies of AAV8-CMV-Cre, AAV8-TBG-Cre, or AAV8-control. To test the role of myeloid C/EBPβ, Cebpbfl/fl, or Cebpbfl/fl Lyz2-Cre mice were fed WDA for 16 weeks.
We found that Kdm5b KO prevented alcohol-induced liver fibrosis and liver inflammation in female mice. These changes were in part mediated by hepatocyte-to-non-parenchymal cell communication changes. KDM5B in hepatocytes promoted pro-inflammatory and pro-fibrotic changes in liver macrophages, endothelial cells, and stellate cells. Moreover, KDM5B promoted alcohol-induced early increase in EpCAM-positive liver progenitors and loss of liver function at later time points of alcohol feeding. We found that loss of liver function was dependent on a hepatocyte-to-macrophage communication feedback loop. KDM5B in hepatocytes inhibited macrophage C/EBPβ expression, which in turn resulted in loss of the mature KCs phenotype and prevented the ability of KCs to support hepatocyte differentiation, ultimately leading to loss of liver synthetic function.
KDM5B activation in hepatocytes drives pathogenic cell-cell communication, leading to alcohol-induced loss of liver function in ALD.
酒精性肝病（ALD）是酒精相关死亡的主要原因。此前，我们鉴定出KDM5B是ALD发展的性别特异性调节因子；然而，KDM5B诱导病理变化背后的机制尚未明确。
给Kdm5b flox/flox雌性小鼠喂食西方饮食，并在饮水中添加20%酒精，持续8 - 16周（WDA）。为诱导基因敲除，小鼠接受2×1011个基因组拷贝的AAV8 - CMV - Cre、AAV8 - TBG - Cre或AAV8 - 对照。为测试髓系C/EBPβ的作用，给Cebpbfl/fl或Cebpbfl/fl Lyz2 - Cre小鼠喂食WDA 16周。
我们发现Kdm5b基因敲除可预防雌性小鼠酒精诱导的肝纤维化和肝脏炎症。这些变化部分是由肝细胞与非实质细胞间通讯变化介导的。肝细胞中的KDM5B促进肝巨噬细胞、内皮细胞和星状细胞的促炎和促纤维化变化。此外，KDM5B促进酒精诱导的EpCAM阳性肝祖细胞早期增加以及在酒精喂养后期肝功能丧失。我们发现肝功能丧失依赖于肝细胞与巨噬细胞间的通讯反馈回路。肝细胞中的KDM5B抑制巨噬细胞C/EBPβ表达，进而导致成熟KCs表型丧失，并阻止KCs支持肝细胞分化的能力，最终导致肝脏合成功能丧失。
肝细胞中KDM5B的激活驱动致病性细胞间通讯，导致ALD中酒精诱导的肝功能丧失。
