February 12, 2020

Joint research paper on PKD3 function in liver homeostasis published in Hepatology.

Deletion of Protein Kinase D3 Promotes Liver Fibrosis in Mice

Shuya Zhang, Huan Liu, Meimei Yin, Xiuying Pei, Angelika Hausser, Eri Ishikawa, Sho Yamasaki, Zheng Gen Jin

Abstract

Liver fibrosis is a central pathological process that occurs in most types of chronic liver diseases. Advanced liver fibrosis causes cirrhosis, hepatocellular carcinoma, and liver failure. However, the exact molecular mechanisms underlying the initiation and progression of liver fibrosis 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∆LysM) mice, and we found that both Prkd3‐/‐ mice and Prkd3∆LysM mice displayed spontaneous liver fibrosis. PKD3 deficiency also aggravated carbon tetrachloride (CCL4)‐induced liver fibrosis. PKD3 is highly expressed in hepatic macrophages, and PKD3 deficiency skewed macrophage polarization toward a profibrotic phenotype. The activated profibrotic macrophages produced TGF‐β that in turn activates hepatic stellate cells (HSCs) to become matrix‐producing myofibroblasts. Moreover, PKD3 deficiency decreased the phosphatase activity of SHP1 (a bona fide PKD3 substrate) resulting in sustained STAT6 activation in macrophages. In addition, we observed that PKD3 expression in hepatic macrophages was downregulated in cirrhotic human liver tissues. Conclusion: PKD3 deletion in mice drives liver fibrosis through the profibrotic macrophage activation.

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