골수성 PAK4 결손에 의한 대사이상지방간염 완화 = Attenuation of metabolic dysfunction-associated steatohepatitis by myeloid PAK4 deficiency

다국어 초록 (Multilingual Abstract)

Metabolic dysfunction-associated steatohepatitis (MASH) is an advanced type of fatty liver disease characterized by hepatic lipid accumulation, inflammation, and fibrosis, with limited therapeutic options. The NLRP3 inflammasome, predominantly active in hepatic macrophages, is a key driver of MASH-associated inflammation. p21-activated kinase 4 (PAK4) is a serine/threonine kinase involved in metabolic regulation and inflammatory signaling, yet its role in hepatic macrophages in the context of MASH remains unclear. In this study, we discovered that PAK4 expression is elevated in liver macrophages from two diet-induced MASH mouse models. Myeloid-specific PAK4 deficient mice exhibited ameliorated hepatic steatosis, inflammation, and fibrosis, accompanied by suppressed NLRP3 inflammasome activation. In vitro, PAK4 deficiency in peritoneal macrophages attenuated M1 polarization, blockades NF-κB signaling and NLRP3 inflammasome activation. Pharmacological inhibition of PAK4 recapitulated these protective effects both in vitro and in vivo, reducing liver injury, lipid accumulation, fibrosis, and inflammasome activity. Our findings highlight macrophage PAK4 as a critical regulator of NLRP3-dependent inflammation in MASH pathogenesis and suggest that targeting PAK4 could be a promising therapeutic strategy for mitigating disease progression.

목차 (Table of Contents)

• Abstract ii
• Introduction 1
• Materials and methods 4
• Results 10
• Discussion 19
• References 24
• Table 28
• Figures 30
• Abstract (Korean) 43