Department of Medicine, Aab Cardiovascular Research Institute, University of Rochester School of Medicine and Dentistry, Rochester, NY.
Key Laboratory of Fertility Preservation and Maintenance of Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Ningxia Medical University, Yinchuan, China.
Hepatology. 2020 Nov;72(5):1717-1734. doi: 10.1002/hep.31176. Epub 2020 Sep 28.
Liver fibrosis (LF) is a central pathological process that occurs in most types of chronic liver diseases. Advanced LF causes cirrhosis, hepatocellular carcinoma, and liver failure. However, the exact molecular mechanisms underlying the initiation and progression of LF remain largely unknown.
This study was designed to investigate the role of protein kinase D3 (PKD3; gene name Prkd3) in the regulation of liver homeostasis. We generated global Prkd3 knockout (Prkd3 ) mice and myeloid-cell-specific Prkd3 knockout (Prkd3 ) mice, and we found that both Prkd3 mice and Prkd3 mice displayed spontaneous LF. PKD3 deficiency also aggravated CCl -induced LF. PKD3 is highly expressed in hepatic macrophages (HMs), and PKD3 deficiency skewed macrophage polarization toward a profibrotic phenotype. Activated profibrotic macrophages produced transforming growth factor beta that, in turn, activates hepatic stellate cells to become matrix-producing myofibroblasts. Moreover, PKD3 deficiency decreased the phosphatase activity of SH2-containing protein tyrosine phosphatase-1 (a bona-fide PKD3 substrate), resulting in sustained signal transducer and activator of transcription 6 activation in macrophages. In addition, we observed that PKD3 expression in HMs was down-regulated in cirrhotic human liver tissues.
PKD3 deletion in mice drives LF through the profibrotic macrophage activation.
肝纤维化（LF）是大多数慢性肝病中发生的核心病理过程。晚期 LF 会导致肝硬化、肝细胞癌和肝衰竭。然而，LF 起始和进展的确切分子机制在很大程度上仍然未知。
本研究旨在研究蛋白激酶 D3（PKD3；基因名称 Prkd3）在调节肝脏稳态中的作用。我们生成了全局 Prkd3 敲除（Prkd3 ）小鼠和髓系细胞特异性 Prkd3 敲除（Prkd3 ）小鼠，发现两种 Prkd3 小鼠均自发出现 LF。PKD3 缺失也加重了 CCl 诱导的 LF。PKD3 在肝巨噬细胞（HMs）中高度表达，PKD3 缺失使巨噬细胞极化向促纤维化表型倾斜。活化的促纤维化巨噬细胞产生转化生长因子-β，进而激活肝星状细胞成为产生细胞外基质的肌成纤维细胞。此外，PKD3 缺失降低了含 SH2 结构域的蛋白酪氨酸磷酸酶-1 的磷酸酶活性（PKD3 的一个真正底物），导致巨噬细胞中转录激活因子 6 的持续激活。此外，我们观察到 HM 中的 PKD3 表达在肝硬化人类肝组织中下调。
PKD3 在小鼠中的缺失通过促纤维化巨噬细胞的激活驱动 LF。
